315 results on '"Dranoff G"'
Search Results
52. Gene therapy of metastatic cancer by in vivo retroviral gene targeting
- Author
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Hurford, R.K., Dranoff, G., Mulligan, R.C., and Tepper, R.I.
- Subjects
Gene therapy -- Methods ,Metastasis -- Care and treatment ,Business ,Health care industry - Abstract
According to the authors' abstract of an article published in Nature Genetics, 'We have achieved efficient transduction of tumour metastases in vivo by the vascular delivery of retroviral producer cells. [...]
- Published
- 1995
53. Development of cell-based vaccines for AIDS
- Author
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Gee, C.E., Dranoff, G., and Mulligan, R.C.
- Subjects
AIDS vaccines -- Research - Abstract
"Development of Cell-Based Vaccines for AIDS." C.E. Gee, G. Dranoff and R.C. Mulligan. The Whitehead Institute for Biomedical Research, Cambridge, Massachusetts. According to an abstract submitted by the authors to [...]
- Published
- 1994
54. Defining the critical hurdles in cancer immunotherapy
- Author
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Fox Bernard A, Schendel Dolores J, Butterfield Lisa H, Aamdal Steinar, Allison James P, Ascierto Paolo, Atkins Michael B, Bartunkova Jirina, Bergmann Lothar, Berinstein Neil, Bonorino Cristina C, Borden Ernest, Bramson Jonathan L, Britten Cedrik M, Cao Xuetao, Carson William E, Chang Alfred E, Characiejus Dainius, Choudhury A Raja, Coukos George, de Gruijl Tanja, Dillman Robert O, Dolstra Harry, Dranoff Glenn, Durrant Lindy G, Finke James H, Galon Jerome, Gollob Jared A, Gouttefangeas Cécile, Grizzi Fabio, Guida Michele, Håkansson Leif, Hege Kristen, Herberman Ronald B, Hodi F Stephen, Hoos Axel, Huber Christoph, Hwu Patrick, Imai Kohzoh, Jaffee Elizabeth M, Janetzki Sylvia, June Carl H, Kalinski Pawel, Kaufman Howard L, Kawakami Koji, Kawakami Yutaka, Keilholtz Ulrich, Khleif Samir N, Kiessling Rolf, Kotlan Beatrix, Kroemer Guido, Lapointe Rejean, Levitsky Hyam I, Lotze Michael T, Maccalli Cristina, Maio Michele, Marschner Jens-Peter, Mastrangelo Michael J, Masucci Giuseppe, Melero Ignacio, Melief Cornelius, Murphy William J, Nelson Brad, Nicolini Andrea, Nishimura Michael I, Odunsi Kunle, Ohashi Pamela S, O'Donnell-Tormey Jill, Old Lloyd J, Ottensmeier Christian, Papamichail Michael, Parmiani Giorgio, Pawelec Graham, Proietti Enrico, Qin Shukui, Rees Robert, Ribas Antoni, Ridolfi Ruggero, Ritter Gerd, Rivoltini Licia, Romero Pedro J, Salem Mohamed L, Scheper Rik J, Seliger Barbara, Sharma Padmanee, Shiku Hiroshi, Singh-Jasuja Harpreet, Song Wenru, Straten Per, Tahara Hideaki, Tian Zhigang, van Der Burg Sjoerd H, von Hoegen Paul, Wang Ena, Welters Marij JP, Winter Hauke, Withington Tara, Wolchok Jedd D, Xiao Weihua, Zitvogel Laurence, Zwierzina Heinz, Marincola Francesco M, Gajewski Thomas F, Wigginton Jon M, and Disis Mary L
- Subjects
Medicine - Abstract
Abstract Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer.
- Published
- 2011
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55. A phase I trial of vaccination with lethally irradiated lymphoma cells admixed with granulocyte-macrophage colony-stimulating factor secreting K562 cells for the treatment of follicular lymphoma.
- Author
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Jacobsen E, Plant A, Redd R, Armand P, McDonough M, Ihuoma U, Fisher DC, LaCasce A, Ritz J, Dranoff G, and Freedman A
- Abstract
Several vaccine strategies have been tested for the treatment of follicular lymphoma; however, none have proven successful. In a phase I dose-escalation protocol, we developed a vaccine consisting of lethally irradiated whole lymphoma cells admixed with K562 cells that constitutively secreted granulocyte-macrophage colony-stimulating factor (GM-K562)(ClinicalTrials.gov identifier: NCT00487305). Patients with grade 1, 2, or 3 A follicular lymphoma were divided into 2 study tiers based on prior treatment and received a maximum of 6 vaccines. Vaccines contained dose levels of 5 × 10
6 or 1 × 107 GM-K562 cells admixed with autologous tumor cells at doses ranging from 1 × 105 to 5 × 107 .Correlative studies did not demonstrate a significant immune response as assessed by delayed-type hypersensitivity reactions, B and T cell subsets, and natural killer cell subsets. Future vaccine studies should focus on identifying lymphoma-specific immunogenic proteins and modifying the vaccine immune adjuvant.- Published
- 2024
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56. A molecular glue degrader of the WIZ transcription factor for fetal hemoglobin induction.
- Author
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Ting PY, Borikar S, Kerrigan JR, Thomsen NM, Aghania E, Hinman AE, Reyes A, Pizzato N, Fodor BD, Wu F, Belew MS, Mao X, Wang J, Chitnis S, Niu W, Hachey A, Cobb JS, Savage NA, Burke A, Paulk J, Dovala D, Lin J, Clifton MC, Ornelas E, Ma X, Ware NF, Sanchez CC, Taraszka J, Terranova R, Knehr J, Altorfer M, Barnes SW, Beckwith REJ, Solomon JM, Dales NA, Patterson AW, Wagner J, Bouwmeester T, Dranoff G, Stevenson SC, and Bradner JE
- Subjects
- Animals, Humans, Mice, Adaptor Proteins, Signal Transducing metabolism, Adaptor Proteins, Signal Transducing genetics, Crystallography, X-Ray, Drug Discovery, Macaca fascicularis, Proteolysis drug effects, Small Molecule Libraries chemistry, Small Molecule Libraries pharmacology, Small Molecule Libraries therapeutic use, Ubiquitin-Protein Ligases metabolism, Ubiquitin-Protein Ligases genetics, Anemia, Sickle Cell drug therapy, Anemia, Sickle Cell metabolism, Antisickling Agents chemistry, Antisickling Agents pharmacology, Antisickling Agents therapeutic use, Fetal Hemoglobin genetics, Fetal Hemoglobin metabolism, Kruppel-Like Transcription Factors metabolism, Nerve Tissue Proteins metabolism
- Abstract
Sickle cell disease (SCD) is a prevalent, life-threatening condition attributable to a heritable mutation in β-hemoglobin. Therapeutic induction of fetal hemoglobin (HbF) can ameliorate disease complications and has been intently pursued. However, safe and effective small-molecule inducers of HbF remain elusive. We report the discovery of dWIZ-1 and dWIZ-2, molecular glue degraders of the WIZ transcription factor that robustly induce HbF in erythroblasts. Phenotypic screening of a cereblon (CRBN)-biased chemical library revealed WIZ as a previously unknown repressor of HbF. WIZ degradation is mediated by recruitment of WIZ(ZF7) to CRBN by dWIZ-1, as resolved by crystallography of the ternary complex. Pharmacological degradation of WIZ was well tolerated and induced HbF in humanized mice and cynomolgus monkeys. These findings establish WIZ degradation as a globally accessible therapeutic strategy for SCD.
- Published
- 2024
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57. Phase II trial of vaccination with autologous, irradiated melanoma cells engineered by adenoviral mediated gene transfer to secrete granulocyte-macrophage colony stimulating factor in patients with stage III and IV melanoma.
- Author
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Sussman TA, Severgnini M, Giobbie-Hurder A, Friedlander P, Swanson SJ, Jaklitsch M, Clancy T, Goguen LA, Lautz D, Swanson R, Daley H, Ritz J, Dranoff G, and Hodi FS
- Abstract
Background: In the era of immune checkpoint blockade, the role of cancer vaccines in immune priming has provided additional potential for therapeutic improvements. Prior studies have demonstrated delayed type hypersensitivity and anti-tumor immunity with vaccines engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF). The safety, efficacy and anti-tumor immunity of GM-CSF secreting vaccine in patients with previously treated stage III or IV melanoma needs further investigation., Methods: In this phase II trial, excised lymph node metastases were processed to single cells, transduced with an adenoviral vector encoding GM-CSF, irradiated, and cryopreserved. Individual vaccines were composed of 1x10
6 , 4x106 , or 1x107 tumor cells, and were injected intradermally and subcutaneously at weekly and biweekly intervals. The primary endpoints were feasibility of producing vaccine in stage III patients and determining the proportion of patients alive at two years in stage IV patients., Results: GM-CSF vaccine was successfully developed and administered in all 61 patients. Toxicities were restricted to grade 1-2 local skin reactions. The median OS for stage III patients (n = 20) was 71.1 (95% CI, 43.7 to NR) months and 14.9 (95%CI, 12.1 to 39.7) months for stage IV patients. The median PFS in stage III patients was 50.7 (95%CI, 36.3 to NR) months and 4.1 (95% CI, 3.0-6.3) months in stage IV patients. In the overall population, the disease control rate was 39.3% (95%CI, 27.1 to 52.7%). In stage III patients, higher pre-treatment plasma cytokine levels of MMP-1, TRAIL, CXCL-11, CXCL-13 were associated with improved PFS (p<0.05 for all). An increase in post-vaccination levels of IL-15 and TRAIL for stage III patients was associated with improved PFS (p=0.03 for both). Similarly, an increase in post-vaccination IL-16 level for stage IV patients was associated with improved PFS (p=0.02) and clinical benefit., Conclusions: Vaccination with autologous melanoma cells secreting GM-CSF augments antitumor immunity in stage III and IV patients with melanoma, is safe, and demonstrates disease control. Luminex data suggests that changes in inflammatory cytokines and immune cell infiltration promote tumor antigen presentation and subsequent tumor cell destruction. Additional investigation to administer this vaccine in combination with immune checkpoint inhibitors is needed., Competing Interests: Author MS was employed by Curis, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Sussman, Severgnini, Giobbie-Hurder, Friedlander, Swanson, Jaklitsch, Clancy, Goguen, Lautz, Swanson, Daley, Ritz, Dranoff and Hodi.)- Published
- 2024
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58. Granulocyte-Macrophage Colony-Stimulating Factor Influence on Soluble and Membrane-Bound ICOS in Combination with Immune Checkpoint Blockade.
- Author
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Li X, Li J, Zheng Y, Lee SJ, Zhou J, Giobbie-Hurder A, Butterfield LH, Dranoff G, and Hodi FS
- Subjects
- Humans, Ipilimumab pharmacology, Ipilimumab therapeutic use, Inducible T-Cell Co-Stimulator Protein, Granulocyte-Macrophage Colony-Stimulating Factor pharmacology, Immune Checkpoint Inhibitors
- Abstract
With the successful development of immune checkpoint blockade, there remains the continued need to improve efficacy and decrease toxicities. The addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) to ipilimumab has previously demonstrated both an improvement in efficacy and decrease in the incidence of high-grade adverse events. ICOS+CD4+ or ICOS+CD8+ peripheral blood T cells are significantly greater in the patients treated with ipilimumab plus GM-CSF than in the patients treated with ipilimumab alone. To better understand the effects of GM-CSF on inducible T-cell costimulator (ICOS) and clinical outcomes, the relative roles of identified soluble ICOS and membrane-bound ICOS were evaluated. The ICOS splice variant was secreted and found to have immunologic suppressive effects. Changes in soluble ICOS splice variant levels in treated patients correlated with clinical outcomes. GM-CSF enhanced membrane-bound ICOS in an IL12-dependent manner but did not increase soluble ICOS levels. Whereas soluble ICOS plays a role in immune suppression, GM-CSF efficacy involves increasing membrane-bound ICOS and induction of dendritic cell development. Thus, soluble ICOS splice variants may be used as a biomarker for GM-CSF and immune checkpoint blockade-based therapies., (©2023 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2023
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59. Targeting the IL1β Pathway for Cancer Immunotherapy Remodels the Tumor Microenvironment and Enhances Antitumor Immune Responses.
- Author
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Diwanji R, O'Brien NA, Choi JE, Nguyen B, Laszewski T, Grauel AL, Yan Z, Xu X, Wu J, Ruddy DA, Piquet M, Pelletier MR, Savchenko A, Charette L, Rodrik-Outmezguine V, Baum J, Millholland JM, Wong CC, Martin AM, Dranoff G, Pruteanu-Malinici I, Cremasco V, Sabatos-Peyton C, and Jayaraman P
- Subjects
- Animals, Mice, Cell Line, Tumor, Docetaxel pharmacology, Immunity, Immunotherapy, Neoplasms drug therapy, Tumor Microenvironment, Interleukin-1beta antagonists & inhibitors
- Abstract
High levels of IL1β can result in chronic inflammation, which in turn can promote tumor growth and metastasis. Inhibition of IL1β could therefore be a promising therapeutic option in the treatment of cancer. Here, the effects of IL1β blockade induced by the mAbs canakinumab and gevokizumab were evaluated alone or in combination with docetaxel, anti-programmed cell death protein 1 (anti-PD-1), anti-VEGFα, and anti-TGFβ treatment in syngeneic and humanized mouse models of cancers of different origin. Canakinumab and gevokizumab did not show notable efficacy as single-agent therapies; however, IL1β blockade enhanced the effectiveness of docetaxel and anti-PD-1. Accompanying these effects, blockade of IL1β alone or in combination induced significant remodeling of the tumor microenvironment (TME), with decreased numbers of immune suppressive cells and increased tumor infiltration by dendritic cells (DC) and effector T cells. Further investigation revealed that cancer-associated fibroblasts (CAF) were the cell type most affected by treatment with canakinumab or gevokizumab in terms of change in gene expression. IL1β inhibition drove phenotypic changes in CAF populations, particularly those with the ability to influence immune cell recruitment. These results suggest that the observed remodeling of the TME following IL1β blockade may stem from changes in CAF populations. Overall, the results presented here support the potential use of IL1β inhibition in cancer treatment. Further exploration in ongoing clinical studies will help identify the best combination partners for different cancer types, cancer stages, and lines of treatment., (©2023 American Association for Cancer Research.)
- Published
- 2023
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60. Discovery and characterization of a selective IKZF2 glue degrader for cancer immunotherapy.
- Author
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Bonazzi S, d'Hennezel E, Beckwith REJ, Xu L, Fazal A, Magracheva A, Ramesh R, Cernijenko A, Antonakos B, Bhang HC, Caro RG, Cobb JS, Ornelas E, Ma X, Wartchow CA, Clifton MC, Forseth RR, Fortnam BH, Lu H, Csibi A, Tullai J, Carbonneau S, Thomsen NM, Larrow J, Chie-Leon B, Hainzl D, Gu Y, Lu D, Meyer MJ, Alexander D, Kinyamu-Akunda J, Sabatos-Peyton CA, Dales NA, Zécri FJ, Jain RK, Shulok J, Wang YK, Briner K, Porter JA, Tallarico JA, Engelman JA, Dranoff G, Bradner JE, Visser M, and Solomon JM
- Subjects
- Animals, Humans, Mice, Ikaros Transcription Factor, Immunotherapy, T-Lymphocytes, Regulatory metabolism, Neoplasms therapy, Neoplasms metabolism, Transcription Factors metabolism
- Abstract
Malignant tumors can evade destruction by the immune system by attracting immune-suppressive regulatory T cells (Treg) cells. The IKZF2 (Helios) transcription factor plays a crucial role in maintaining function and stability of Treg cells, and IKZF2 deficiency reduces tumor growth in mice. Here we report the discovery of NVP-DKY709, a selective molecular glue degrader of IKZF2 that spares IKZF1/3. We describe the recruitment-guided medicinal chemistry campaign leading to NVP-DKY709 that redirected the degradation selectivity of cereblon (CRBN) binders from IKZF1 toward IKZF2. Selectivity of NVP-DKY709 for IKZF2 was rationalized by analyzing the DDB1:CRBN:NVP-DKY709:IKZF2(ZF2 or ZF2-3) ternary complex X-ray structures. Exposure to NVP-DKY709 reduced the suppressive activity of human Treg cells and rescued cytokine production in exhausted T-effector cells. In vivo, treatment with NVP-DKY709 delayed tumor growth in mice with a humanized immune system and enhanced immunization responses in cynomolgus monkeys. NVP-DKY709 is being investigated in the clinic as an immune-enhancing agent for cancer immunotherapy., Competing Interests: Declaration of interests All authors are past or current employees of Novartis Institutes for Biomedical Research. Some of the authors have patents related to this work: WO2019038717, 3-(1-oxoisoindolin-2-YL)Piperidine-2-6-Dione derivatives and uses thereof (R.E.J.B., S.B., A.C., A.F., and M.V.); and WO2020128972, Dosing regimen and pharmaceutical combinations comprising 3-(1-oxoisoindolin-2-YL)Piperidine-2-6-Dione derivatives (S.B., E.d’H., G.D., R.R.F., D.H., and J.K.-A.)., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2023
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61. Preclinical Characterization and Phase I Study of an Anti-HER2-TLR7 Immune-Stimulator Antibody Conjugate in Patients with HER2+ Malignancies.
- Author
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Janku F, Han SW, Doi T, Amatu A, Ajani JA, Kuboki Y, Cortez A, Cellitti SE, Mahling PC, Subramanian K, Schoenfeld HA, Choi SM, Iaconis LA, Lee LH, Pelletier MR, Dranoff G, Askoxylakis V, and Siena S
- Subjects
- Humans, Toll-Like Receptor 7 agonists, Receptor, ErbB-2, Tumor Microenvironment, Immunoconjugates adverse effects, Neoplasms drug therapy, Antineoplastic Agents, Antineoplastic Agents, Immunological therapeutic use
- Abstract
Immune-stimulator antibody conjugates (ISAC) combining tumor-targeting monoclonal antibodies with immunostimulatory agents allow targeted delivery of immune activators into tumors. NJH395 is a novel, first-in-class ISAC comprising a Toll-like receptor 7 (TLR7) agonist conjugated to an anti-HER2 antibody via a noncleavable linker payload. Preclinical characterization showed ISAC-mediated activation of myeloid cells in the presence of antigen-expressing cancer cells, with antigen targeting and TLR7 agonism contributing to antitumor activity. Safety, efficacy, immunogenicity, pharmacokinetics, and pharmacodynamics were investigated in a phase I, multicenter, open-label study in patients with HER2+ non-breast advanced malignancies (NCT03696771). Data from 18 patients enrolled in single ascending dose escalation demonstrated delivery of the TLR7-agonist payload in HER2+ tumor cells and induction of type I IFN responses, which correlated with immune modulation in the tumor microenvironment. Cytokine release syndrome was a common, but manageable, drug-related adverse event. Antidrug antibodies and neuroinflammation at high doses represented significant clinical challenges. Data provide proof-of-mechanism and critical insights for novel immunotherapies., (©2022 American Association for Cancer Research.)
- Published
- 2022
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62. Invariant NKT cell-augmented GM-CSF-secreting tumor vaccine is effective in advanced prostate cancer model.
- Author
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Varghese B, Lynch L, Vriend LE, Draganov D, Clark JM, Kissick HT, Varghese S, Sanda MG, Dranoff G, Arredouani MS, Balk SP, and Exley MA
- Subjects
- Male, Mice, Animals, Humans, Granulocyte-Macrophage Colony-Stimulating Factor metabolism, Lymphocyte Activation, Galactosylceramides, Interleukin-12 pharmacology, Vaccines, Combined pharmacology, Antigens, Viral, Tumor, EGF Family of Proteins metabolism, EGF Family of Proteins pharmacology, Oligopeptides pharmacology, Mice, Inbred C57BL, Natural Killer T-Cells, Cancer Vaccines, Prostatic Neoplasms therapy, Prostatic Neoplasms metabolism
- Abstract
Invariant natural killer T cells (iNKT cells) express a semi-invariant T cell receptor that recognizes certain glycolipids (including α-galactosylceramide, αGC) bound to CD1d, and can induce potent antitumor responses. Here, we assessed whether αGC could enhance the efficacy of a GM-CSF-producing tumor cell vaccine in the transgenic SV40 T antigen-driven TRAMP prostate cancer model. In healthy mice, we initially found that optimal T cell responses were obtained with αGC-pulsed TRAMP-C2 cells secreting GM-CSF and milk fat globule epidermal growth factor protein-8 (MFG-E8) with an RGD to RGE mutation (GM-CSF/RGE TRAMP-C2), combined with systemic low dose IL-12. In a therapeutic model, transgenic TRAMP mice were then castrated at ~ 20 weeks, followed by treatment with the combination vaccine. Untreated mice succumbed to tumor by ~ 40 weeks, but survival was markedly prolonged by vaccine treatment, with most mice surviving past 80 weeks. Prostates in the treated mice were heavily infiltrated with T cells and iNKT cells, which both secreted IFNγ in response to tumor cells. The vaccine was not effective if the αGC, IL-12, or GM-CSF secretion was eliminated. Finally, immunized mice were fully resistant to challenge with TRAMP-C2 cells. Together these findings support further development of therapeutic vaccines that exploit iNKT cell activation., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2022
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63. Characterization of sabatolimab, a novel immunotherapy with immuno-myeloid activity directed against TIM-3 receptor.
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Schwartz S, Patel N, Longmire T, Jayaraman P, Jiang X, Lu H, Baker L, Velez J, Ramesh R, Wavreille AS, Verneret M, Fan H, Hu T, Xu F, Taraszka J, Pelletier M, Miyashiro J, Rinne M, Dranoff G, Sabatos-Peyton C, and Cremasco V
- Abstract
Objectives: Sabatolimab is a humanized monoclonal antibody (hIgG4, S228P) directed against human T-cell immunoglobulin domain and mucin domain-3 (TIM-3). Herein, we describe the development and characterization of sabatolimab., Methods: Sabatolimab was tested for binding to its target TIM-3 and blocking properties. The functional effects of sabatolimab were tested in T-cell killing and myeloid cell cytokine assays. Antibody-mediated cell phagocytosis (ADCP) by sabatolimab was also assessed., Results: Sabatolimab was shown to (i) enhance T-cell killing and inflammatory cytokine production by dendritic cells (DCs); (ii) facilitate the phagocytic uptake of TIM-3-expressing target cells; and (iii) block the interaction between TIM-3 and its ligands PtdSer/galectin-9., Conclusion: Taken together, our results support both direct anti-leukemic effects and immune-mediated modulation by sabatolimab, reinforcing the notion that sabatolimab represents a novel immunotherapy with immuno-myeloid activity, holding promise for the treatment of myeloid cell neoplasms., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Immunology.)
- Published
- 2022
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64. The feasibility of using an autologous GM-CSF-secreting breast cancer vaccine to induce immunity in patients with stage II-III and metastatic breast cancers.
- Author
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Anderson KS, Erick TK, Chen M, Daley H, Campbell M, Colson Y, Mihm M, Zakka LR, Hopper M, Barry W, Winer EP, Dranoff G, and Overmoyer B
- Subjects
- Feasibility Studies, Female, Genetic Vectors, Granulocyte-Macrophage Colony-Stimulating Factor genetics, Humans, Breast Neoplasms immunology, Breast Neoplasms pathology, Breast Neoplasms therapy, Cancer Vaccines toxicity
- Abstract
Purpose: The antigenic targets of immunity and the role of vaccination in breast cancer are unknown. We performed a phase I study of an autologous GM-CSF-secreting breast cancer vaccine in patients with metastatic and stage II-III breast cancer., Methods: Tumor cells from patients with metastatic (n = 15) and stage II-III (n = 7) disease were transduced with a replication-defective adenoviral vector encoding GM-CSF, and then irradiated. Twelve and seven patients with metastatic and stage II-III disease, respectively, received weekly vaccination for three weeks, followed by every other week until disease progression or vaccine supply was exhausted (metastatic) or until six total vaccine doses were administered (stage II-III)., Results: Among those patients with metastatic disease who received vaccinations, eight had progressive disease at two months, three had stable disease for 4-13 months, and one has had no evidence of disease for 13 years. Of the patients with stage II-III disease, five died of metastatic disease between 1.16 and 8.49 years after the start of vaccinations (median 6.24 years) and two are alive as of September 2021. Toxicities included injection site reactions, fatigue, fever, upper respiratory symptoms, joint pain, nausea, and edema. Four of five evaluable patients with metastatic disease developed a skin reaction with immune cell infiltration after the fifth injection of unmodified, irradiated tumor cells., Conclusion: We conclude that tumor cells can be harvested from patients with metastatic or stage II-III breast cancer to prepare autologous GM-CSF-secreting vaccines that induce coordinated immune responses with limited toxicity. TRIAL REGISTRATION AND DATE OF REGISTRATION: clinicaltrials.gov, NCT00317603 (April 25, 2006) and NCT00880464 (April 13, 2009)., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2022
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65. A vaccine targeting resistant tumours by dual T cell plus NK cell attack.
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Badrinath S, Dellacherie MO, Li A, Zheng S, Zhang X, Sobral M, Pyrdol JW, Smith KL, Lu Y, Haag S, Ijaz H, Connor-Stroud F, Kaisho T, Dranoff G, Yuan GC, Mooney DJ, and Wucherpfennig KW
- Subjects
- Histocompatibility Antigens Class I, Humans, Killer Cells, Natural, NK Cell Lectin-Like Receptor Subfamily K metabolism, Myelodysplastic Syndromes, Neoplasms prevention & control, Skin Diseases, Genetic, Vaccines
- Abstract
Most cancer vaccines target peptide antigens, necessitating personalization owing to the vast inter-individual diversity in major histocompatibility complex (MHC) molecules that present peptides to T cells. Furthermore, tumours frequently escape T cell-mediated immunity through mechanisms that interfere with peptide presentation
1 . Here we report a cancer vaccine that induces a coordinated attack by diverse T cell and natural killer (NK) cell populations. The vaccine targets the MICA and MICB (MICA/B) stress proteins expressed by many human cancers as a result of DNA damage2 . MICA/B serve as ligands for the activating NKG2D receptor on T cells and NK cells, but tumours evade immune recognition by proteolytic MICA/B cleavage3,4 . Vaccine-induced antibodies increase the density of MICA/B proteins on the surface of tumour cells by inhibiting proteolytic shedding, enhance presentation of tumour antigens by dendritic cells to T cells and augment the cytotoxic function of NK cells. Notably, this vaccine maintains efficacy against MHC class I-deficient tumours resistant to cytotoxic T cells through the coordinated action of NK cells and CD4+ T cells. The vaccine is also efficacious in a clinically important setting: immunization following surgical removal of primary, highly metastatic tumours inhibits the later outgrowth of metastases. This vaccine design enables protective immunity even against tumours with common escape mutations., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2022
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66. GM-CSF secreting leukemia cell vaccination for MDS/AML after allogeneic HSCT: a randomized, double-blinded, phase 2 trial.
- Author
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Ho VT, Kim HT, Brock J, Galinsky I, Daley H, Reynolds C, Weber A, Pozdnyakova O, Severgnini M, Nikiforow S, Cutler C, Koreth J, Alyea EP, Antin JH, Gooptu M, Romee R, Shapiro R, Chen YB, Rosenblatt J, Avigan D, Hodi FS, Dranoff G, Wu CJ, Ritz J, and Soiffer RJ
- Subjects
- Granulocyte-Macrophage Colony-Stimulating Factor therapeutic use, Humans, Vaccination, Graft vs Host Disease etiology, Graft vs Host Disease prevention & control, Hematopoietic Stem Cell Transplantation adverse effects, Leukemia, Myeloid, Acute drug therapy
- Abstract
Vaccination using irradiated, adenovirus transduced autologous myeloblasts to secrete granulocyte-macrophage colony-stimulating factor (GVAX) early after allogeneic hematopoietic stem cell transplantation (HSCT) can induce potent immune responses. We conducted a randomized phase 2 trial of GVAX after HSCT for myelodysplastic syndrome with excess blasts or relapsed/refractory acute myeloid leukemia. Myeloblasts were harvested before HSCT to generate the vaccine. Randomization to GVAX vs placebo (1:1) was stratified according to disease, transplant center, and conditioning. Graft-versus-host disease (GVHD) prophylaxis included tacrolimus and methotrexate. GVAX or placebo vaccination was started between day 30 and 45 if there was engraftment and no GVHD. Vaccines were administered subcutaneously/intradermally weekly × 3, then every 2 weeks × 3. Tacrolimus taper began after vaccine completion. A total of 123 patients were enrolled, 92 proceeded to HSCT, and 57 (GVAX, n = 30; placebo, n = 27) received at least 1 vaccination. No Common Toxicity Criteria grade 3 or worse vaccine-related adverse events were reported, but injection site reactions were more common after GVAX (10 vs 1; P = .006). With a median follow-up of 39 months (range, 9-89 months), 18-month progression-free survival, overall survival, and relapse incidence were 53% vs 55% (P = .79), 63% vs 59% (P = .86), and 30% vs 37% (P = .51) for GVAX and placebo, respectively. Nonrelapse mortality at 18 months was 17% vs 7.7% (P = .18), grade II to IV acute GVHD at 12 months was 34% vs 12% (P = .13), and chronic GVHD at 3 years was 49% vs 57% for GVAX and placebo (P = .26). Reconstitution of T, B, and natural killer cells was not decreased or enhanced by GVAX. There were no differences in serum major histocompatibility chain-related protein A/B or other immune biomarkers between GVAX and placebo. GVAX does not improve survival after HSCT for myelodysplastic syndrome/acute myeloid leukemia. This trial was registered at www.clinicaltrials.gov as #NCT01773395., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2022
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67. Colon stroma mediates an inflammation-driven fibroblastic response controlling matrix remodeling and healing.
- Author
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Jasso GJ, Jaiswal A, Varma M, Laszewski T, Grauel A, Omar A, Silva N, Dranoff G, Porter JA, Mansfield K, Cremasco V, Regev A, Xavier RJ, and Graham DB
- Subjects
- ADAM Proteins deficiency, ADAM Proteins genetics, Animals, Cell Differentiation, Colitis chemically induced, Colitis genetics, Colitis pathology, Colon immunology, Colon pathology, Extracellular Matrix immunology, Fibroblasts pathology, Fibrosis, Gene Expression Regulation, Humans, Inflammation, Interleukin-11 genetics, Interleukin-11 immunology, Intestinal Mucosa pathology, Male, Mesenchymal Stem Cells pathology, Mice, Mice, Inbred C57BL, Sequence Analysis, RNA, Single-Cell Analysis, Sodium Dodecyl Sulfate administration & dosage, Transcription, Genetic, Transcriptome, Wound Healing genetics, Wound Healing immunology, ADAM Proteins immunology, Colitis immunology, Extracellular Matrix metabolism, Fibroblasts immunology, Intestinal Mucosa immunology, Mesenchymal Stem Cells immunology
- Abstract
Chronic inflammation is often associated with the development of tissue fibrosis, but how mesenchymal cell responses dictate pathological fibrosis versus resolution and healing remains unclear. Defining stromal heterogeneity and identifying molecular circuits driving extracellular matrix deposition and remodeling stands to illuminate the relationship between inflammation, fibrosis, and healing. We performed single-cell RNA-sequencing of colon-derived stromal cells and identified distinct classes of fibroblasts with gene signatures that are differentially regulated by chronic inflammation, including IL-11-producing inflammatory fibroblasts. We further identify a transcriptional program associated with trans-differentiation of mucosa-associated fibroblasts and define a functional gene signature associated with matrix deposition and remodeling in the inflamed colon. Our analysis supports a critical role for the metalloprotease Adamdec1 at the interface between tissue remodeling and healing during colitis, demonstrating its requirement for colon epithelial integrity. These findings provide mechanistic insight into how inflammation perturbs stromal cell behaviors to drive fibroblastic responses controlling mucosal matrix remodeling and healing., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: R.J.X. is a cofounder of Celsius Therapeutics and Jnana Therapeutics.
- Published
- 2022
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68. An IMiD-inducible degron provides reversible regulation for chimeric antigen receptor expression and activity.
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Carbonneau S, Sharma S, Peng L, Rajan V, Hainzl D, Henault M, Yang C, Hale J, Shulok J, Tallarico J, Porter J, Brogdon JL, Dranoff G, Bradner JE, Hild M, and Guimaraes CP
- Subjects
- Adolescent, Animals, Cell Line, Cell Proliferation drug effects, Female, Humans, Ikaros Transcription Factor chemistry, Immunologic Factors chemistry, Male, Mice, Mice, Congenic, Mice, Inbred NOD, Mice, SCID, Middle Aged, Molecular Structure, Neoplasms, Experimental drug therapy, Neoplasms, Experimental immunology, Neoplasms, Experimental pathology, Receptors, Chimeric Antigen genetics, Young Adult, Ikaros Transcription Factor immunology, Immunologic Factors pharmacology, Receptors, Chimeric Antigen immunology, T-Lymphocytes immunology
- Abstract
The recent development of successful CAR (chimeric antigen receptor) T cell therapies has been accompanied by a need to better control potentially fatal toxicities that can arise from adverse immune reactions. Here we present a ligand-controlled CAR system, based on the IKZF3 ZF2 β-hairpin IMiD-inducible degron, which allows for the reversible control of expression levels of type I membrane proteins, including CARs. Testing this system in an established mouse xenotransplantation model for acute lymphoblastic leukemia, we validate the ability of the CAR19-degron to target and kill CD19-positive cells displaying complete control/clearance of the tumor. We also demonstrate that the activity of CAR19-degron can be regulated in vivo when dosing a US Food and Drug Administration-approved drug, lenalidomide., Competing Interests: Declaration of interests Seth Carbonneau, James E. Bradner, Marc Hild, and Carla P. Guimaraes are co-inventors on a patent application (PCT/US2018/056472) submitted by Novartis AG., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2021
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69. SHP2 blockade enhances anti-tumor immunity via tumor cell intrinsic and extrinsic mechanisms.
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Wang Y, Mohseni M, Grauel A, Diez JE, Guan W, Liang S, Choi JE, Pu M, Chen D, Laszewski T, Schwartz S, Gu J, Mansur L, Burks T, Brodeur L, Velazquez R, Kovats S, Pant B, Buruzula G, Deng E, Chen JT, Sari-Sarraf F, Dornelas C, Varadarajan M, Yu H, Liu C, Lim J, Hao HX, Jiang X, Malamas A, LaMarche MJ, Geyer FC, McLaughlin M, Costa C, Wagner J, Ruddy D, Jayaraman P, Kirkpatrick ND, Zhang P, Iartchouk O, Aardalen K, Cremasco V, Dranoff G, Engelman JA, Silver S, Wang H, Hastings WD, and Goldoni S
- Subjects
- Animals, Cell Line, Tumor, Gene Knockout Techniques, HEK293 Cells, Humans, Mice, Mice, Inbred BALB C, Neoplasm Proteins genetics, Neoplasms, Experimental genetics, Protein Tyrosine Phosphatase, Non-Receptor Type 11 genetics, Signal Transduction genetics, Immunity, Cellular, Neoplasm Proteins immunology, Neoplasms, Experimental immunology, Protein Tyrosine Phosphatase, Non-Receptor Type 11 immunology, Signal Transduction immunology, T-Lymphocytes immunology
- Abstract
SHP2 is a ubiquitous tyrosine phosphatase involved in regulating both tumor and immune cell signaling. In this study, we discovered a novel immune modulatory function of SHP2. Targeting this protein with allosteric SHP2 inhibitors promoted anti-tumor immunity, including enhancing T cell cytotoxic function and immune-mediated tumor regression. Knockout of SHP2 using CRISPR/Cas9 gene editing showed that targeting SHP2 in cancer cells contributes to this immune response. Inhibition of SHP2 activity augmented tumor intrinsic IFNγ signaling resulting in enhanced chemoattractant cytokine release and cytotoxic T cell recruitment, as well as increased expression of MHC Class I and PD-L1 on the cancer cell surface. Furthermore, SHP2 inhibition diminished the differentiation and inhibitory function of immune suppressive myeloid cells in the tumor microenvironment. SHP2 inhibition enhanced responses to anti-PD-1 blockade in syngeneic mouse models. Overall, our study reveals novel functions of SHP2 in tumor immunity and proposes that targeting SHP2 is a promising strategy for cancer immunotherapy.
- Published
- 2021
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70. A CRISPR Screen Reveals Resistance Mechanisms to CD3-Bispecific Antibody Therapy.
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Liu SQ, Grantham A, Landry C, Granda B, Chopra R, Chakravarthy S, Deutsch S, Vogel M, Russo K, Seiss K, Tschantz WR, Rejtar T, Ruddy DA, Hu T, Aardalen K, Wagner JP, Dranoff G, and D'Alessio JA
- Subjects
- Animals, Cell Line, Tumor, Clustered Regularly Interspaced Short Palindromic Repeats, Humans, Immunotherapy, Interferon-gamma pharmacology, Interleukin-3 Receptor alpha Subunit immunology, Lymphocyte Activation, Mice, Mice, Inbred NOD, T-Lymphocytes, Cytotoxic immunology, Antibodies, Bispecific pharmacology, Antineoplastic Agents pharmacology, CD3 Complex immunology, T-Lymphocytes, Cytotoxic drug effects
- Abstract
CD3-bispecific antibodies represent an important therapeutic strategy in oncology. These molecules work by redirecting cytotoxic T cells to antigen-bearing tumor cells. Although CD3-bispecific antibodies have been developed for several clinical indications, cases of cancer-derived resistance are an emerging limitation to the more generalized application of these molecules. Here, we devised whole-genome CRISPR screens to identify cancer resistance mechanisms to CD3-bispecific antibodies across multiple targets and cancer types. By validating the screen hits, we found that deficiency in IFNγ signaling has a prominent role in cancer resistance. IFNγ functioned by stimulating the expression of T-cell killing-related molecules in a cell type-specific manner. By assessing resistance to the clinical CD3-bispecific antibody flotetuzumab, we identified core fucosylation as a critical pathway to regulate flotetuzumab binding to the CD123 antigen. Disruption of this pathway resulted in significant resistance to flotetuzumab treatment. Proper fucosylation of CD123 was required for its normal biological functions. In order to treat the resistance associated with fucosylation loss, flotetuzumab in combination with an alternative targeting CD3-bispecific antibody demonstrated superior efficacy. Together, our study reveals multiple mechanisms that can be targeted to enhance the clinical potential of current and future T-cell-engaging CD3-bispecific antibody therapies., (©2020 American Association for Cancer Research.)
- Published
- 2021
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71. Chimeric Antigen Receptor T Cells Targeting NKG2D-Ligands Show Robust Efficacy Against Acute Myeloid Leukemia and T-Cell Acute Lymphoblastic Leukemia.
- Author
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Driouk L, Gicobi JK, Kamihara Y, Rutherford K, Dranoff G, Ritz J, and Baumeister SHC
- Subjects
- Cell Line, Tumor, Humans, Leukemia, Myeloid, Acute immunology, Ligands, NK Cell Lectin-Like Receptor Subfamily K metabolism, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma immunology, T-Lymphocytes transplantation, Treatment Outcome, Immunotherapy, Adoptive methods, Leukemia, Myeloid, Acute therapy, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma therapy, Receptors, Chimeric Antigen metabolism, T-Lymphocytes physiology
- Abstract
CAR T cell approaches to effectively target AML and T-ALL without off-tumor effects on healthy myeloid or T cell compartments respectively are an unmet medical need. NKG2D-ligands are a promising target given their absence on healthy cells and surface expression in a wide range of malignancies. NKG2D-ligand expression has been reported in a substantial group of patients with AML along with evidence for prognostic significance. However, reports regarding the prevalence and density of NKG2D-ligand expression in AML vary and detailed studies to define whether low level expression is sufficient to trigger NKG2D-ligand directed CART cell responses are lacking. NKG2D ligand expression in T-ALL has not previously been interrogated. Here we report that NKG2D-ligands are expressed in T-ALL cell lines and primary T-ALL. We confirm that NKG2D-ligands are frequently surface expressed in primary AML, albeit at relatively low levels. Utilizing CAR T cells incorporating the natural immune receptor NKG2D as the antigen binding domain, we demonstrate striking in vitro activity of CAR T cells targeting NKG2D-ligands against AML and T-ALL cell lines and show that even low-level ligand expression in primary AML targets results in robust NKG2D-CAR activity. We found that NKG2D-ligand expression can be selectively enhanced in low-expressing AML cell lines and primary AML blasts via pharmacologic HDAC inhibition. Such pharmacologic NKG2D-ligand induction results in enhanced NKG2D-CAR anti-leukemic activity without affecting healthy PBMC, thereby providing rationale for the combination of HDAC-inhibitors with NKG2D-CAR T cell therapy as a potential strategy to achieve clinical NKG2D-CAR T cell efficacy in AML., Competing Interests: GD is currently an employee of Novartis and owns Novartis stock. JR reports research funding from Amgen, Equillium, and Kite Pharma, and consulting income from Avrobio, Falcon Therapeutics, Infinity Pharmaceuticals, LifeVault Bio, Rheos Medicines, Talaris Therapeutics and TScan Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Driouk, Gicobi, Kamihara, Rutherford, Dranoff, Ritz and Baumeister.)
- Published
- 2020
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72. TGFβ-blockade uncovers stromal plasticity in tumors by revealing the existence of a subset of interferon-licensed fibroblasts.
- Author
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Grauel AL, Nguyen B, Ruddy D, Laszewski T, Schwartz S, Chang J, Chen J, Piquet M, Pelletier M, Yan Z, Kirkpatrick ND, Wu J, deWeck A, Riester M, Hims M, Geyer FC, Wagner J, MacIsaac K, Deeds J, Diwanji R, Jayaraman P, Yu Y, Simmons Q, Weng S, Raza A, Minie B, Dostalek M, Chikkegowda P, Ruda V, Iartchouk O, Chen N, Thierry R, Zhou J, Pruteanu-Malinici I, Fabre C, Engelman JA, Dranoff G, and Cremasco V
- Subjects
- Animals, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cancer-Associated Fibroblasts drug effects, Carcinoma immunology, Carcinoma pathology, Cell Line, Tumor transplantation, Cell Plasticity drug effects, Cell Plasticity immunology, Disease Models, Animal, Drug Synergism, Female, Humans, Immune Checkpoint Inhibitors pharmacology, Immune Checkpoint Inhibitors therapeutic use, Mice, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor immunology, Stromal Cells drug effects, Stromal Cells immunology, Transforming Growth Factor beta metabolism, Tumor Microenvironment drug effects, Tumor Microenvironment immunology, Antineoplastic Combined Chemotherapy Protocols pharmacology, Cancer-Associated Fibroblasts immunology, Carcinoma drug therapy, Interferon-beta immunology, Transforming Growth Factor beta antagonists & inhibitors
- Abstract
Despite the increasing interest in targeting stromal elements of the tumor microenvironment, we still face tremendous challenges in developing adequate therapeutics to modify the tumor stromal landscape. A major obstacle to this is our poor understanding of the phenotypic and functional heterogeneity of stromal cells in tumors. Herein, we perform an unbiased interrogation of tumor mesenchymal cells, delineating the co-existence of distinct subsets of cancer-associated fibroblasts (CAFs) in the microenvironment of murine carcinomas, each endowed with unique phenotypic features and functions. Furthermore, our study shows that neutralization of TGFβ in vivo leads to remodeling of CAF dynamics, greatly reducing the frequency and activity of the myofibroblast subset, while promoting the formation of a fibroblast population characterized by strong response to interferon and heightened immunomodulatory properties. These changes correlate with the development of productive anti-tumor immunity and greater efficacy of PD1 immunotherapy. Along with providing the scientific rationale for the evaluation of TGFβ and PD1 co-blockade in the clinical setting, this study also supports the concept of plasticity of the stromal cell landscape in tumors, laying the foundation for future investigations aimed at defining pathways and molecules to program CAF composition for cancer therapy.
- Published
- 2020
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73. GM-CSF, IL-3, and IL-5 Family of Cytokines: Regulators of Inflammation.
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Dougan M, Dranoff G, and Dougan SK
- Subjects
- Animals, Autoimmune Diseases immunology, Granulocyte-Macrophage Colony-Stimulating Factor deficiency, Granulocyte-Macrophage Colony-Stimulating Factor genetics, Granulocyte-Macrophage Colony-Stimulating Factor therapeutic use, Hematopoiesis immunology, Humans, Inflammation therapy, Interleukin-3 antagonists & inhibitors, Interleukin-3 deficiency, Interleukin-3 genetics, Interleukin-5 antagonists & inhibitors, Interleukin-5 deficiency, Interleukin-5 genetics, Mice, Mice, Knockout, Multigene Family, Neoplasms immunology, Neoplasms therapy, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor genetics, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor immunology, Receptors, Interleukin-3 genetics, Receptors, Interleukin-3 immunology, Receptors, Interleukin-5 genetics, Receptors, Interleukin-5 immunology, Recombinant Proteins immunology, Recombinant Proteins therapeutic use, Signal Transduction, Structure-Activity Relationship, Vaccination, Wound Healing immunology, Granulocyte-Macrophage Colony-Stimulating Factor immunology, Inflammation immunology, Interleukin-3 immunology, Interleukin-5 immunology
- Abstract
The β common chain cytokines GM-CSF, IL-3, and IL-5 regulate varied inflammatory responses that promote the rapid clearance of pathogens but also contribute to pathology in chronic inflammation. Therapeutic interventions manipulating these cytokines are approved for use in some cancers as well as allergic and autoimmune disease, and others show promising early clinical activity. These approaches are based on our understanding of the inflammatory roles of these cytokines; however, GM-CSF also participates in the resolution of inflammation, and IL-3 and IL-5 may also have such properties. Here, we review the functions of the β common cytokines in health and disease. We discuss preclinical and clinical data, highlighting the potential inherent in targeting these cytokine pathways, the limitations, and the important gaps in understanding of the basic biology of this cytokine family., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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74. Author Correction: Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors.
- Author
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Chongsathidkiet P, Jackson C, Koyama S, Loebel F, Cui X, Farber SH, Woroniecka K, Elsamadicy AA, Dechant CA, Kemeny HR, Sanchez-Perez L, Cheema TA, Souders NC, Herndon JE, Coumans JV, Everitt JI, Nahed BV, Sampson JH, Gunn MD, Martuza RL, Dranoff G, Curry WT, and Fecci PE
- Abstract
In the version of this article originally published, the figure callout in this sentence was incorrect: "Furthermore, in S1P1-KI mice themselves, whereas PD-1 blockade was ineffectual as monotherapy, the effects of 4-1BB agonism and checkpoint blockade proved additive, with the combination prolonging median survival and producing a 50% long-term survival rate (Fig. 6f)." The callout should have been to Supplementary Fig. 6b. The error has been corrected in the PDF and HTML versions of the article.
- Published
- 2019
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75. Cancer Immunotherapy: Beyond Checkpoint Blockade.
- Author
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Dougan M, Dranoff G, and Dougan SK
- Abstract
Blocking antibodies to the immune checkpoint receptors or their ligands have revolutionized the treatment of diverse malignancies. Many tumors are recognized by adaptive immunity, but these adaptive responses can be inhibited by immunosuppressive mechanisms within the tumor, often through pathways outside of the currently targeted checkpoints. For this reason, only a minority of cancer patients achieve durable responses to current immunotherapies. Multiple novel approaches strive to expand immunotherapy's reach. These may include targeting alternative immune checkpoints. However, many investigational strategies look beyond checkpoint blockade. These include cellular therapies to bypass endogenous immunity and efforts to stimulate new adaptive antitumor responses using vaccines, adjuvants, and combinations with cytotoxic therapy, as well as strategies to inhibit innate immune suppression and modulate metabolism within the tumor microenvironment. The challenge for immunotherapy going forward will be to select rational strategies for overcoming barriers to effective antitumor responses from the myriad possible targets.
- Published
- 2019
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76. Identification and characterization of an alternative cancer-derived PD-L1 splice variant.
- Author
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Hassounah NB, Malladi VS, Huang Y, Freeman SS, Beauchamp EM, Koyama S, Souders N, Martin S, Dranoff G, Wong KK, Pedamallu CS, Hammerman PS, and Akbay EA
- Subjects
- Cell Line, Tumor, Exons, Humans, Interferon-gamma antagonists & inhibitors, Lymphokines pharmacology, Protein Isoforms blood, Protein Isoforms isolation & purification, Alternative Splicing, B7-H1 Antigen genetics
- Abstract
Therapeutic blockade of the PD-1/PD-L1 axis is recognized as an effective treatment for numerous cancer types. However, only a subset of patients respond to this treatment, warranting a greater understanding of the biological mechanisms driving immune evasion via PD-1/PD-L1 signaling and other T-cell suppressive pathways. We previously identified a head and neck squamous cell carcinoma with human papillomavirus integration in the PD-L1 locus upstream of the transmembrane domain-encoding region, suggesting expression of a truncated form of PD-L1 (Parfenov et al., Proc Natl Acad Sci USA 111(43):15544-15549, 2014). In this study, we extended this observation by performing a computational analysis of 33 other cancer types as well as human cancer cell lines, and identified additional PD-L1 isoforms with an exon 4 enrichment expressed in 20 cancers and human cancer cell lines. We demonstrate that cancer cell lines with high expression levels of exon 4-enriched PD-L1 generate a secreted form of PD-L1. Further biochemical studies of exon 4-enriched PD-L1 demonstrated that this form is secreted and maintains the capacity to bind PD-1 as well as to serve as a negative regulator on T cell function, as measured by inhibition of IL-2 and IFNg secretion. Overall, we have demonstrated that truncated forms of PD-L1 exist in numerous cancer types, and have validated that truncated PD-L1 can be secreted and negatively regulate T cell function.
- Published
- 2019
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77. Drug Discovery for Kinetoplastid Diseases: Future Directions.
- Author
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Rao SPS, Barrett MP, Dranoff G, Faraday CJ, Gimpelewicz CR, Hailu A, Jones CL, Kelly JM, Lazdins-Helds JK, Mäser P, Mengel J, Mottram JC, Mowbray CE, Sacks DL, Scott P, Späth GF, Tarleton RL, Spector JM, and Diagana TT
- Subjects
- Animals, Chagas Disease drug therapy, Host-Parasite Interactions, Humans, Immunomodulation, Leishmaniasis drug therapy, Mice, Models, Animal, Antiprotozoal Agents pharmacology, Drug Discovery trends, Euglenozoa Infections drug therapy, Kinetoplastida drug effects
- Abstract
Kinetoplastid parasites have caused human disease for millennia. Significant achievements have been made toward developing new treatments for leishmaniasis (particularly on the Indian subcontinent) and for human African trypanosomiasis (HAT). Moreover, the sustained decrease in the incidence of HAT has made the prospect of elimination a tantalizing reality. Despite the gains, no new chemical or biological entities to treat kinetoplastid diseases have been registered in more than three decades, and more work is needed to discover safe and effective therapies for patients with Chagas disease and leishmaniasis. Advances in tools for drug discovery and novel insights into the biology of the host-parasite interaction may provide opportunities for accelerated progress. Here, we summarize the output from a gathering of scientists and physicians who met to discuss the current status and future directions in drug discovery for kinetoplastid diseases.
- Published
- 2019
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78. Suppression of Myeloid Cell Arginase Activity leads to Therapeutic Response in a NSCLC Mouse Model by Activating Anti-Tumor Immunity.
- Author
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Miret JJ, Kirschmeier P, Koyama S, Zhu M, Li YY, Naito Y, Wu M, Malladi VS, Huang W, Walker W, Palakurthi S, Dranoff G, Hammerman PS, Pecot CV, Wong KK, and Akbay EA
- Subjects
- Adult, Aged, Aged, 80 and over, Animals, Arginase genetics, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung immunology, Cell Line, Tumor, Disease Models, Animal, Humans, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms immunology, Mice, Middle Aged, RNA-Seq, Arginase antagonists & inhibitors, Carcinoma, Non-Small-Cell Lung enzymology, Lung Neoplasms enzymology, Myeloid Cells enzymology
- Abstract
Background: Tumor orchestrated metabolic changes in the microenvironment limit generation of anti-tumor immune responses. Availability of arginine, a semi-essential amino acid, is critical for lymphocyte proliferation and function. Levels of arginine are regulated by the enzymes arginase 1,2 and nitric oxide synthase (NOS). However, the role of arginase activity in lung tumor maintenance has not been investigated in clinically relevant orthotopic tumor models., Methods: RNA sequencing (RNA-seq) of sorted cell populations from mouse lung adenocarcinomas derived from immunocompetent genetically engineered mouse models (GEMM)s was performed. To complement mouse studies, a patient tissue microarray consisting of 150 lung adenocarcinomas, 103 squamous tumors, and 54 matched normal tissue were stained for arginase, CD3, and CD66b by multiplex immunohistochemistry. Efficacy of a novel arginase inhibitor compound 9 in reversing arginase mediated T cell suppression was determined in splenocyte ex vivo assays. Additionally, the anti-tumor activity of this compound was determined in vitro and in an autochthonous immunocompetent Kras
G12D GEMM of lung adenocarcinoma model., Results: Analysis of RNA-seq of sorted myeloid cells suggested that arginase expression is elevated in myeloid cells in the tumor as compared to the normal lung tissue. Accordingly, in the patient samples arginase 1 expression was mainly localized in the granulocytic myeloid cells and significantly elevated in both lung adenocarcinoma and squamous tumors as compared to the controls. Our ex vivo analysis demonstrated that myeloid derived suppressor cell (MDSC)s cause T cell suppression by arginine depletion, and suppression of arginase activity by a novel ARG1/2 inhibitor, compound 9, led to restoration of T cell function by increasing arginine. Treatment of KrasG12D GEMM of lung cancer model with compound 9 led to a significant tumor regression associated with increased T cell numbers and function, while it had no activity across several murine and human non-small cell (NSCLC) lung cancer lines in vitro., Conclusions: We show that arginase expression is elevated in mouse and patient lung tumors. In a KRASG12D GEMM arginase inhibition diminished growth of established tumors. Our data suggest arginase as an immunomodulatory target that should further be investigated in lung tumors with high arginase activity.- Published
- 2019
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79. Phase I Trial of Autologous CAR T Cells Targeting NKG2D Ligands in Patients with AML/MDS and Multiple Myeloma.
- Author
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Baumeister SH, Murad J, Werner L, Daley H, Trebeden-Negre H, Gicobi JK, Schmucker A, Reder J, Sentman CL, Gilham DE, Lehmann FF, Galinsky I, DiPietro H, Cummings K, Munshi NC, Stone RM, Neuberg DS, Soiffer R, Dranoff G, Ritz J, and Nikiforow S
- Subjects
- Adult, Aged, Cytokines immunology, Female, Humans, Ligands, Male, Middle Aged, NK Cell Lectin-Like Receptor Subfamily K genetics, NK Cell Lectin-Like Receptor Subfamily K immunology, Receptors, Chimeric Antigen immunology, T-Lymphocytes immunology, Immunotherapy, Adoptive, Leukemia, Myeloid, Acute therapy, Multiple Myeloma therapy, Myelodysplastic Syndromes therapy
- Abstract
NKG2D ligands are widely expressed in solid and hematologic malignancies but absent or poorly expressed on healthy tissues. We conducted a phase I dose-escalation study to evaluate the safety and feasibility of a single infusion of NKG2D-chimeric antigen receptor (CAR) T cells, without lymphodepleting conditioning in subjects with acute myeloid leukemia/myelodysplastic syndrome or relapsed/refractory multiple myeloma. Autologous T cells were transfected with a γ-retroviral vector encoding a CAR fusing human NKG2D with the CD3ζ signaling domain. Four dose levels (1 × 10
6 -3 × 107 total viable T cells) were evaluated. Twelve subjects were infused [7 acute myeloid leukemia (AML) and 5 multiple myeloma]. NKG2D-CAR products demonstrated a median 75% vector-driven NKG2D expression on CD3+ T cells. No dose-limiting toxicities, cytokine release syndrome, or CAR T cell-related neurotoxicity was observed. No significant autoimmune reactions were noted, and none of the ≥ grade 3 adverse events were attributable to NKG2D-CAR T cells. At the single injection of low cell doses used in this trial, no objective tumor responses were observed. However, hematologic parameters transiently improved in one subject with AML at the highest dose, and cases of disease stability without further therapy or on subsequent treatments were noted. At 24 hours, the cytokine RANTES increased a median of 1.9-fold among all subjects and 5.8-fold among six AML patients. Consistent with preclinical studies, NKG2D-CAR T cell-expansion and persistence were limited. Manufactured NKG2D-CAR T cells exhibited functional activity against autologous tumor cells in vitro , but modifications to enhance CAR T-cell expansion and target density may be needed to boost clinical activity., (©2018 American Association for Cancer Research.)- Published
- 2019
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80. FAP Delineates Heterogeneous and Functionally Divergent Stromal Cells in Immune-Excluded Breast Tumors.
- Author
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Cremasco V, Astarita JL, Grauel AL, Keerthivasan S, MacIsaac K, Woodruff MC, Wu M, Spel L, Santoro S, Amoozgar Z, Laszewski T, Migoni SC, Knoblich K, Fletcher AL, LaFleur M, Wucherpfennig KW, Pure E, Dranoff G, Carroll MC, and Turley SJ
- Subjects
- Animals, Breast Neoplasms immunology, Cancer-Associated Fibroblasts metabolism, Cancer-Associated Fibroblasts pathology, Cell Proliferation, Endopeptidases, Female, Gene Expression Regulation, Humans, Membrane Glycoproteins metabolism, Mice, Inbred BALB C, Mice, Inbred C57BL, Nitric Oxide metabolism, Pericytes metabolism, Pericytes pathology, Stromal Cells pathology, T-Lymphocytes pathology, Breast Neoplasms pathology, Gelatinases metabolism, Membrane Proteins metabolism, Serine Endopeptidases metabolism, Stromal Cells metabolism, Tumor Microenvironment immunology
- Abstract
Cancer-associated fibroblasts (CAFs) are generally associated with poor clinical outcome. CAFs support tumor growth in a variety of ways and can suppress antitumor immunity and response to immunotherapy. However, a precise understanding of CAF contributions to tumor growth and therapeutic response is lacking. Discrepancies in this field of study may stem from heterogeneity in the composition and function of fibroblasts in the tumor microenvironment. Furthermore, it remains unclear whether CAFs directly interact with and suppress T cells. Here, mouse and human breast tumors were used to examine stromal cells expressing fibroblast activation protein (FAP), a surface marker for CAFs. Two discrete populations of FAP
+ mesenchymal cells were identified on the basis of podoplanin (PDPN) expression: a FAP+ PDPN+ population of CAFs and a FAP+ PDPN- population of cancer-associated pericytes (CAPs). Although both subsets expressed extracellular matrix molecules, the CAF transcriptome was enriched in genes associated with TGFβ signaling and fibrosis compared with CAPs. In addition, CAFs were enriched at the outer edge of the tumor, in close contact with T cells, whereas CAPs were localized around vessels. Finally, FAP+ PDPN+ CAFs suppressed the proliferation of T cells in a nitric oxide-dependent manner, whereas FAP+ PDPN- pericytes were not immunosuppressive. Collectively, these findings demonstrate that breast tumors contain multiple populations of FAP-expressing stromal cells of dichotomous function, phenotype, and location., (©2018 American Association for Cancer Research.)- Published
- 2018
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81. Clinical implications of monitoring nivolumab immunokinetics in non-small cell lung cancer patients.
- Author
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Osa A, Uenami T, Koyama S, Fujimoto K, Okuzaki D, Takimoto T, Hirata H, Yano Y, Yokota S, Kinehara Y, Naito Y, Otsuka T, Kanazu M, Kuroyama M, Hamaguchi M, Koba T, Futami Y, Ishijima M, Suga Y, Akazawa Y, Machiyama H, Iwahori K, Takamatsu H, Nagatomo I, Takeda Y, Kida H, Akbay EA, Hammerman PS, Wong KK, Dranoff G, Mori M, Kijima T, and Kumanogoh A
- Subjects
- Aged, Aged, 80 and over, Antineoplastic Agents, Immunological pharmacology, Carcinoma, Non-Small-Cell Lung blood, Carcinoma, Non-Small-Cell Lung immunology, Cell Proliferation, Female, Flow Cytometry, Follow-Up Studies, Humans, Ki-67 Antigen analysis, Ki-67 Antigen metabolism, Lung, Lung Neoplasms blood, Lung Neoplasms immunology, Male, Middle Aged, Nivolumab pharmacology, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor immunology, Prospective Studies, T-Lymphocytes metabolism, Time Factors, Treatment Outcome, Antineoplastic Agents, Immunological therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Drug Monitoring methods, Lung Neoplasms drug therapy, Nivolumab therapeutic use, T-Lymphocytes immunology
- Abstract
Background: The PD-1-blocking antibody nivolumab persists in patients several weeks after the last infusion. However, no study has systematically evaluated the maximum duration that the antibody persists on T cells or the association between this duration and residual therapeutic efficacy or potential adverse events., Methods: To define the duration of binding and residual efficacy of nivolumab after discontinuation, we developed a simplified strategy for T cell monitoring and used it to analyze T cells from peripheral blood from 11 non-small cell lung cancer patients previously treated with nivolumab. To determine the suitability of our method for other applications, we compared transcriptome profiles between nivolumab-bound and nivolumab-unbound CD8 T cells. We also applied T cell monitoring in 2 nivolumab-treated patients who developed progressive lung tumors during long-term follow-up., Results: Prolonged nivolumab binding was detected more than 20 weeks after the last infusion, regardless of the total number of nivolumab infusions (2-15 doses) or type of subsequent treatment, in 9 of the 11 cases in which long-term monitoring was possible. Ki-67 positivity, a proliferation marker, in T cells decreased in patients with progressive disease. Transcriptome profiling identified the signals regulating activation of nivolumab-bound T cells, which may contribute to nivolumab resistance. In 2 patients who restarted nivolumab, T cell proliferation markers exhibited the opposite trend and correlated with clinical response., Conclusions: Although only a few samples were analyzed, our strategy of monitoring both nivolumab binding and Ki-67 in T cells might help determine residual efficacy under various types of concurrent or subsequent treatment., Trial Registration: University Hospital Medical Information Network Clinical Trials Registry, UMIN000024623., Funding: This work was supported by Japan Society for the Promotion of Science KAKENHI (JP17K16045, JP18H05282, and JP15K09220), Japan Agency for Medical Research and Development (JP17cm0106310, JP18cm0106335 and JP18cm059042), and Core Research for Evolutional Science and Technology (JPMJCR16G2).
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- 2018
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82. T-Cell Exhaustion Signatures Vary with Tumor Type and Are Severe in Glioblastoma.
- Author
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Woroniecka K, Chongsathidkiet P, Rhodin K, Kemeny H, Dechant C, Farber SH, Elsamadicy AA, Cui X, Koyama S, Jackson C, Hansen LJ, Johanns TM, Sanchez-Perez L, Chandramohan V, Yu YA, Bigner DD, Giles A, Healy P, Dranoff G, Weinhold KJ, Dunn GP, and Fecci PE
- Subjects
- Adult, Aged, Aged, 80 and over, Animals, CD8-Positive T-Lymphocytes immunology, Female, Flow Cytometry, Gene Expression Regulation, Neoplastic immunology, Glioblastoma genetics, Glioblastoma pathology, Humans, Interferon-gamma genetics, Interleukin-2 genetics, Lymphocytes, Tumor-Infiltrating pathology, Male, Mice, Middle Aged, Receptors, Antigen, T-Cell, alpha-beta genetics, T-Lymphocytes pathology, Tumor Microenvironment immunology, Tumor Necrosis Factor-alpha genetics, Glioblastoma immunology, Lymphocytes, Tumor-Infiltrating immunology, Receptors, Antigen, T-Cell, alpha-beta immunology, T-Lymphocytes immunology
- Abstract
Purpose: T-cell dysfunction is a hallmark of glioblastoma (GBM). Although anergy and tolerance have been well characterized, T-cell exhaustion remains relatively unexplored. Exhaustion, characterized in part by the upregulation of multiple immune checkpoints, is a known contributor to failures amid immune checkpoint blockade, a strategy that has lacked success thus far in GBM. This study is among the first to examine, and credential as bona fide , exhaustion among T cells infiltrating human and murine GBM. Experimental Design: Tumor-infiltrating and peripheral blood lymphocytes (TILs and PBLs) were isolated from patients with GBM. Levels of exhaustion-associated inhibitory receptors and poststimulation levels of the cytokines IFNγ, TNFα, and IL2 were assessed by flow cytometry. T-cell receptor Vβ chain expansion was also assessed in TILs and PBLs. Similar analysis was extended to TILs isolated from intracranial and subcutaneous immunocompetent murine models of glioma, breast, lung, and melanoma cancers. Results: Our data reveal that GBM elicits a particularly severe T-cell exhaustion signature among infiltrating T cells characterized by: (1) prominent upregulation of multiple immune checkpoints; (2) stereotyped T-cell transcriptional programs matching classical virus-induced exhaustion; and (3) notable T-cell hyporesponsiveness in tumor-specific T cells. Exhaustion signatures differ predictably with tumor identity, but remain stable across manipulated tumor locations. Conclusions: Distinct cancers possess similarly distinct mechanisms for exhausting T cells. The poor TIL function and severe exhaustion observed in GBM highlight the need to better understand this tumor-imposed mode of T-cell dysfunction in order to formulate effective immunotherapeutic strategies targeting GBM. Clin Cancer Res; 24(17); 4175-86. ©2018 AACR See related commentary by Jackson and Lim, p. 4059 ., (©2018 American Association for Cancer Research.)
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- 2018
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83. Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors.
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Chongsathidkiet P, Jackson C, Koyama S, Loebel F, Cui X, Farber SH, Woroniecka K, Elsamadicy AA, Dechant CA, Kemeny HR, Sanchez-Perez L, Cheema TA, Souders NC, Herndon JE, Coumans JV, Everitt JI, Nahed BV, Sampson JH, Gunn MD, Martuza RL, Dranoff G, Curry WT, and Fecci PE
- Subjects
- Animals, Brain Neoplasms pathology, Endocytosis, Glioblastoma pathology, Humans, Lymphoid Tissue pathology, Lymphopenia immunology, Lysophospholipids metabolism, Mice, Inbred C57BL, Sphingosine analogs & derivatives, Sphingosine metabolism, Spleen pathology, Bone Marrow immunology, Brain Neoplasms immunology, Glioblastoma immunology, T-Lymphocytes immunology
- Abstract
T cell dysfunction contributes to tumor immune escape in patients with cancer and is particularly severe amidst glioblastoma (GBM). Among other defects, T cell lymphopenia is characteristic, yet often attributed to treatment. We reveal that even treatment-naïve subjects and mice with GBM can harbor AIDS-level CD4 counts, as well as contracted, T cell-deficient lymphoid organs. Missing naïve T cells are instead found sequestered in large numbers in the bone marrow. This phenomenon characterizes not only GBM but a variety of other cancers, although only when tumors are introduced into the intracranial compartment. T cell sequestration is accompanied by tumor-imposed loss of S1P1 from the T cell surface and is reversible upon precluding S1P1 internalization. In murine models of GBM, hindering S1P1 internalization and reversing sequestration licenses T cell-activating therapies that were previously ineffective. Sequestration of T cells in bone marrow is therefore a tumor-adaptive mode of T cell dysfunction, whose reversal may constitute a promising immunotherapeutic adjunct.
- Published
- 2018
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84. Manufacturing development and clinical production of NKG2D chimeric antigen receptor-expressing T cells for autologous adoptive cell therapy.
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Murad JM, Baumeister SH, Werner L, Daley H, Trébéden-Negre H, Reder J, Sentman CL, Gilham D, Lehmann F, Snykers S, Sentman ML, Wade T, Schmucker A, Fanger MW, Dranoff G, Ritz J, and Nikiforow S
- Subjects
- Cell Line, Tumor, Cell Proliferation, Clinical Trials as Topic, Cytokines metabolism, Humans, Ligands, Phenotype, Receptors, Antigen, T-Cell immunology, T-Lymphocytes cytology, Transplantation, Autologous, Immunotherapy, Adoptive, NK Cell Lectin-Like Receptor Subfamily K metabolism, Receptors, Chimeric Antigen metabolism, T-Lymphocytes immunology
- Abstract
Background Aims: Adoptive cell therapy employing natural killer group 2D (NKG2D) chimeric antigen receptor (CAR)-modified T cells has demonstrated preclinical efficacy in several model systems, including hematological and solid tumors. We present comprehensive data on manufacturing development and clinical production of autologous NKG2D CAR T cells for treatment of acute myeloid leukemia and multiple myeloma (ClinicalTrials.gov Identifier: NCT02203825). An NKG2D CAR was generated by fusing native full-length human NKG2D to the human CD3ζ cytoplasmic signaling domain. NKG2D naturally associates with native costimulatory molecule DAP10, effectively generating a second-generation CAR against multiple ligands upregulated during malignant transformation including MIC-A, MIC-B and the UL-16 binding proteins., Methods: CAR T cells were infused fresh after a 9-day process wherein OKT3-activated T cells were genetically modified with replication-defective gamma-retroviral vector and expanded ex vivo for 5 days with recombinant human interleukin-2., Results: Despite sizable interpatient variation in originally collected cells, release criteria, including T-cell expansion and purity (median 98%), T-cell transduction (median 66% CD8
+ T cells), and functional activity against NKG2D ligand-positive cells, were met for 100% of healthy donors and patients enrolled and collected. There was minimal carryover of non-T cells, particularly malignant cells; both effector memory and central memory cells were generated, and inflammatory cytokines such as granulocyte colony-stimulating factor, RANTES, interferon-γ and tumor necrosis factor-α were selectively up-regulated., Conclusions: The process resulted in production of required cell doses for the first-in-human phase I NKG2D CAR T clinical trial and provides a robust, flexible base for further optimization of NKG2D CAR T-cell manufacturing., (Copyright © 2018 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)- Published
- 2018
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85. PPARγ Contributes to Immunity Induced by Cancer Cell Vaccines That Secrete GM-CSF.
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Goyal G, Wong K, Nirschl CJ, Souders N, Neuberg D, Anandasabapathy N, and Dranoff G
- Subjects
- Animals, Cancer Vaccines therapeutic use, Cell Line, Tumor, Cytokines metabolism, Dendritic Cells immunology, Dendritic Cells metabolism, Female, Gene Expression Regulation, Neoplastic, Humans, Immunomodulation, Immunotherapy, Leukocytes, Mononuclear immunology, Leukocytes, Mononuclear metabolism, Melanoma, Experimental, Mice, Neoplasms pathology, Neoplasms therapy, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory metabolism, Treatment Outcome, Cancer Vaccines immunology, Granulocyte-Macrophage Colony-Stimulating Factor biosynthesis, Neoplasms immunology, Neoplasms metabolism, PPAR gamma metabolism
- Abstract
Peroxisome proliferator activated receptor-γ (PPARγ) is a lipid-activated nuclear receptor that promotes immune tolerance through effects on macrophages, dendritic cells (DCs), and regulatory T cells (Tregs). Granulocyte-macrophage colony stimulating factor (GM-CSF) induces PPARγ expression in multiple myeloid cell types. GM-CSF contributes to both immune tolerance and protection, but the role of PPARγ in these pathways is poorly understood. Here, we reveal an unexpected stimulatory role for PPARγ in the generation of antitumor immunity with irradiated, GM-CSF-secreting tumor-cell vaccines (GVAX). Mice harboring a deletion of pparg in lysozyme M (LysM)-expressing myeloid cells (KO) showed a decreased ratio of CD8
+ T effectors to Tregs and impaired tumor rejection with GVAX. Diminished tumor protection was associated with altered DC responses and increased production of the Treg attracting chemokines CCL17 and CLL22. Correspondingly, the systemic administration of PPARγ agonists to vaccinated mice elevated the CD8+ T effector to Treg ratio through effects on myeloid cells and intensified the antitumor activity of GVAX combined with cytotoxic T lymphocyte-associated antigen-4 antibody blockade. PPARγ agonists similarly attenuated Treg induction and decreased CCL17 and CCL22 levels in cultures of human peripheral blood mononuclear cells with GM-CSF-secreting tumor cells. Together, these results highlight a key role for myeloid cell PPARγ in GM-CSF-stimulated antitumor immunity and suggest that PPARγ agonists might be useful in cancer immunotherapy. Cancer Immunol Res; 6(6); 723-32. ©2018 AACR ., (©2018 American Association for Cancer Research.)- Published
- 2018
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86. Immunophenotyping of pediatric brain tumors: correlating immune infiltrate with histology, mutational load, and survival and assessing clonal T cell response.
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Plant AS, Koyama S, Sinai C, Solomon IH, Griffin GK, Ligon KL, Bandopadhayay P, Betensky R, Emerson R, Dranoff G, Kieran MW, and Ritz J
- Subjects
- Adolescent, B7-H1 Antigen metabolism, Biomarkers, Tumor blood, Biomarkers, Tumor genetics, Biomarkers, Tumor immunology, Brain immunology, Brain pathology, Brain Neoplasms blood, Brain Neoplasms genetics, Brain Neoplasms pathology, Child, Child, Preschool, Humans, Immunophenotyping, Infant, Mutation, Neoplasm Grading, Programmed Cell Death 1 Receptor metabolism, Receptors, Antigen, T-Cell metabolism, T-Lymphocytes, Regulatory pathology, Brain Neoplasms immunology
- Abstract
There is little known regarding the immune infiltrate present in pediatric brain tumors and how this compares to what is known about histologically similar adult tumors and its correlation with survival. Here, we provide a descriptive analysis of the immune infiltrate of 22 fresh pediatric brain tumor tissue samples of mixed diagnoses and 40 peripheral blood samples. Samples were analyzed using a flow cytometry panel containing markers for immune cell subtypes, costimulatory markers, inhibitory signals, and markers of activation. This was compared to the standard method of immunohistochemistry (IHC) for immune markers for 89 primary pediatric brain tumors. Both flow cytometry and IHC data did not correlate with the grade of tumor or mutational load and IHC data was not significantly associated with survival for either low grade or high grade gliomas. There is a trend towards a more immunosuppressive phenotype in higher grade tumors with more regulatory T cells present in these tumor types. Both PD1 and PDL1 were present in only a small percentage of the tumor infiltrate. T cell receptor sequencing revealed up to 10% clonality of T cells in tumor infiltrates and no significant difference in clonality between low and high grade gliomas. We have shown the immune infiltrate of pediatric brain tumors does not appear to correlate with grade or survival for a small sample of patients. Further research and larger studies are needed to fully understand the interaction of pediatric brain tumors and the immune system.
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- 2018
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87. Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell-driven tumor immunity.
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Ferrari de Andrade L, Tay RE, Pan D, Luoma AM, Ito Y, Badrinath S, Tsoucas D, Franz B, May KF Jr, Harvey CJ, Kobold S, Pyrdol JW, Yoon C, Yuan GC, Hodi FS, Dranoff G, and Wucherpfennig KW
- Subjects
- Animals, Antibodies, Blocking immunology, Antibodies, Monoclonal immunology, Histocompatibility Antigens Class I chemistry, Humans, Immunocompetence, Ligands, Melanoma immunology, Melanoma pathology, Melanoma, Experimental immunology, Melanoma, Experimental pathology, Melanoma, Experimental therapy, Mice, Mice, Inbred C57BL, NK Cell Lectin-Like Receptor Subfamily K immunology, Neoplasm Metastasis, Protein Domains immunology, Receptors, IgG immunology, Antibodies, Blocking therapeutic use, Antibodies, Monoclonal therapeutic use, Histocompatibility Antigens Class I immunology, Killer Cells, Natural immunology, Melanoma therapy
- Abstract
MICA and MICB are expressed by many human cancers as a result of cellular stress, and can tag cells for elimination by cytotoxic lymphocytes through natural killer group 2D (NKG2D) receptor activation. However, tumors evade this immune recognition pathway through proteolytic shedding of MICA and MICB proteins. We rationally designed antibodies targeting the MICA α3 domain, the site of proteolytic shedding, and found that these antibodies prevented loss of cell surface MICA and MICB by human cancer cells. These antibodies inhibited tumor growth in multiple fully immunocompetent mouse models and reduced human melanoma metastases in a humanized mouse model. Antitumor immunity was mediated mainly by natural killer (NK) cells through activation of NKG2D and CD16 Fc receptors. This approach prevents the loss of important immunostimulatory ligands by human cancers and reactivates antitumor immunity., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2018
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88. IAP Antagonists Enhance Cytokine Production from Mouse and Human iNKT Cells.
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Clancy-Thompson E, Ali L, Bruck PT, Exley MA, Blumberg RS, Dranoff G, Dougan M, and Dougan SK
- Subjects
- Animals, Apoptosis drug effects, Apoptosis immunology, Cells, Cultured, Disease Models, Animal, Humans, Lung Neoplasms immunology, Lung Neoplasms metabolism, Lung Neoplasms secondary, Lung Neoplasms therapy, Lymphocyte Activation immunology, Mice, Mice, Knockout, Natural Killer T-Cells drug effects, Neoplasm Metastasis, Organ Culture Techniques, Thymus Gland cytology, Thymus Gland metabolism, Cytokines biosynthesis, Inhibitor of Apoptosis Proteins antagonists & inhibitors, Natural Killer T-Cells immunology, Natural Killer T-Cells metabolism
- Abstract
Inhibitor of apoptosis protein (IAP) antagonists are in clinical trials for a variety of cancers, and mouse models show synergism between IAP antagonists and anti-PD-1 immunotherapy. Although IAP antagonists affect the intrinsic signaling of tumor cells, their most pronounced effects are on immune cells and the generation of antitumor immunity. Here, we examined the effects of IAP antagonism on T-cell development using mouse fetal thymic organ culture and observed a selective loss of iNKT cells, an effector cell type of potential importance for cancer immunotherapy. Thymic iNKT-cell development probably failed due to increased strength of TCR signal leading to negative selection, given that mature iNKT cells treated with IAP antagonists were not depleted, but had enhanced cytokine production in both mouse and human ex vivo cultures. Consistent with this, mature mouse primary iNKT cells and iNKT hybridomas increased production of effector cytokines in the presence of IAP antagonists. In vivo administration of IAP antagonists and α-GalCer resulted in increased IFNγ and IL-2 production from iNKT cells and decreased tumor burden in a mouse model of melanoma lung metastasis. Human iNKT cells also proliferated and increased IFNγ production dramatically in the presence of IAP antagonists, demonstrating the utility of these compounds in adoptive therapy of iNKT cells. Cancer Immunol Res; 6(1); 25-35. ©2017 AACR ., (©2017 American Association for Cancer Research.)
- Published
- 2018
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89. Genomic Analysis of Nasopharyngeal Carcinoma Reveals TME-Based Subtypes.
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Zhang L, MacIsaac KD, Zhou T, Huang PY, Xin C, Dobson JR, Yu K, Chiang DY, Fan Y, Pelletier M, Wang Y, Jaeger S, Krishnamurthy Radhakrishnan V, JeBailey L, Skewes-Cox P, Zhang J, Fang W, Huang Y, Zhao H, Zhao Y, Li E, Peng B, Huang A, Dranoff G, Hammerman PS, Engelman J, Bitter H, Zeng YX, and Yao Y
- Subjects
- Adult, Aged, Carcinoma pathology, Carcinoma virology, Cell Proliferation genetics, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinase Inhibitor p18 genetics, Disease-Free Survival, Female, Gene Expression Regulation, Neoplastic, Genomics, Herpesvirus 4, Human genetics, Herpesvirus 4, Human pathogenicity, Humans, Lymphocytes, Tumor-Infiltrating metabolism, Lymphocytes, Tumor-Infiltrating pathology, Male, Middle Aged, Mutation, NF-kappa B genetics, Nasopharyngeal Carcinoma, Nasopharyngeal Neoplasms pathology, Nasopharyngeal Neoplasms virology, Transforming Growth Factor beta genetics, Wnt Signaling Pathway genetics, Carcinoma genetics, Genome, Human genetics, Nasopharyngeal Neoplasms genetics, Prognosis, Tumor Microenvironment genetics
- Abstract
Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV) associated cancer characterized by a poor prognosis and a high level of lymphocyte infiltrate. Genetic hallmarks of NPC are not completely known but include deletion of the p16 ( CDKN2A ) locus and mutations in NF-κB pathway components, with a relatively low total mutational load. To better understand the genetic landscape, an integrated genomic analysis was performed using a large clinical cohort of treatment-naïve NPC tumor specimens. This genomic analysis was generally concordant with previous studies; however, three subtypes of NPC were identified by differences in immune cell gene expression, prognosis, tumor cell morphology, and genetic characteristics. A gene expression signature of proliferation was poorly prognostic and associated with either higher mutation load or specific EBV gene expression patterns in a subtype-specific manner. Finally, higher levels of stromal tumor-infiltrating lymphocytes associated with good prognosis and lower expression of a WNT and TGFβ pathway activation signature. Implications: This study represents the first integrated analysis of mutation, copy number, and gene expression data in NPC and suggests how tumor genetics and EBV infection influence the tumor microenvironment in this disease. These insights should be considered for guiding immunotherapy treatment strategies in this disease. Mol Cancer Res; 15(12); 1722-32. ©2017 AACR ., (©2017 American Association for Cancer Research.)
- Published
- 2017
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90. Vaccination with autologous myeloblasts admixed with GM-K562 cells in patients with advanced MDS or AML after allogeneic HSCT.
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Ho VT, Kim HT, Bavli N, Mihm M, Pozdnyakova O, Piesche M, Daley H, Reynolds C, Souders NC, Cutler C, Koreth J, Alyea EP, Antin JH, Ritz J, Dranoff G, and Soiffer RJ
- Abstract
We report a clinical trial testing vaccination of autologous myeloblasts admixed with granulocyte-macrophage colony-stimulating factor secreting K562 cells after allogeneic hematopoietic stem cell transplantation (HSCT). Patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) with ≥5% marrow blasts underwent myeloblast collection before HSCT. At approximately day +30, 6 vaccines composed of irradiated autologous myeloblasts mixed with GM-K562 were administered. Tacrolimus-based graft-versus-host disease (GVHD) prophylaxis was not tapered until vaccine completion (∼day 100). Thirty-three patients with AML (25) and MDS (8) enrolled, 16 (48%) had ≥5% marrow blasts at transplantation. The most common vaccine toxicity was injection site reactions. One patient developed severe eosinophilia and died of eosinophilic myocarditis. With a median follow-up of 67 months, cumulative incidence of grade 2-4 acute and chronic GVHD were 24% and 33%, respectively. Relapse and nonrelapse mortality were 48% and 9%, respectively. Progression-free survival (PFS) and overall survival (OS) at 5 years were 39% and 39%. Vaccinated patients who were transplanted with active disease (≥5% marrow blasts) had similar OS and PFS at 5 years compared with vaccinated patients transplanted with <5% marrow blasts (OS, 44% vs 35%, respectively, P = .81; PFS, 44% vs 35%, respectively, P = .34). Postvaccination antibody responses to angiopoietin-2 was associated with superior OS (hazard ratio [HR], 0.43; P = .031) and PFS (HR, 0.5; P = .036). Patients transplanted with active disease had more frequent angiopoeitin-2 antibody responses (62.5% vs 20%, P = .029) than those transplanted in remission. GM-K562/leukemia cell vaccination induces biologic activity, even in patients transplanted with active MDS/AML. This study is registered at www.clinicaltrials.gov as #NCT 00809250., Competing Interests: Conflict-of-interest disclosure: The authors declare no competing financial interests.
- Published
- 2017
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91. Role of Granulocyte-Macrophage Colony-Stimulating Factor Production by T Cells during Mycobacterium tuberculosis Infection.
- Author
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Rothchild AC, Stowell B, Goyal G, Nunes-Alves C, Yang Q, Papavinasasundaram K, Sassetti CM, Dranoff G, Chen X, Lee J, and Behar SM
- Subjects
- Animals, Granulocyte-Macrophage Colony-Stimulating Factor genetics, Humans, Interferon-gamma biosynthesis, Interferon-gamma immunology, Lung immunology, Lung microbiology, Macrophages immunology, Macrophages microbiology, Mice, PPAR gamma metabolism, Tuberculosis prevention & control, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Granulocyte-Macrophage Colony-Stimulating Factor biosynthesis, Granulocyte-Macrophage Colony-Stimulating Factor immunology, Mycobacterium tuberculosis immunology, T-Lymphocyte Subsets immunology, Tuberculosis immunology
- Abstract
Mice deficient for granulocyte-macrophage colony-stimulating factor (GM-CSF
-/- ) are highly susceptible to infection with Mycobacterium tuberculosis , and clinical data have shown that anti-GM-CSF neutralizing antibodies can lead to increased susceptibility to tuberculosis in otherwise healthy people. GM-CSF activates human and murine macrophages to inhibit intracellular M. tuberculosis growth. We have previously shown that GM-CSF produced by iNKT cells inhibits growth of M. tuberculosis However, the more general role of T cell-derived GM-CSF during infection has not been defined and how GM-CSF activates macrophages to inhibit bacterial growth is unknown. Here we demonstrate that, in addition to nonconventional T cells, conventional T cells also produce GM-CSF during M. tuberculosis infection. Early during infection, nonconventional iNKT cells and γδ T cells are the main source of GM-CSF, a role subsequently assumed by conventional CD4+ T cells as the infection progresses. M. tuberculosis -specific T cells producing GM-CSF are also detected in the peripheral blood of infected people. Under conditions where nonhematopoietic production of GM-CSF is deficient, T cell production of GM-CSF is protective and required for control of M. tuberculosis infection. However, GM-CSF is not required for T cell-mediated protection in settings where GM-CSF is produced by other cell types. Finally, using an in vitro macrophage infection model, we demonstrate that GM-CSF inhibition of M. tuberculosis growth requires the expression of peroxisome proliferator-activated receptor gamma (PPARγ). Thus, we identified GM-CSF production as a novel T cell effector function. These findings suggest that a strategy augmenting T cell production of GM-CSF could enhance host resistance against M. tuberculosis IMPORTANCE Mycobacterium tuberculosis is the bacterium that causes tuberculosis, the leading cause of death by any infection worldwide. T cells are critical components of the immune response to Mycobacterium tuberculosis While gamma interferon (IFN-γ) is a key effector function of T cells during infection, a failed phase IIb clinical trial and other studies have revealed that IFN-γ production alone is not sufficient to control M. tuberculosis In this study, we demonstrate that CD4+ , CD8+ , and nonconventional T cells produce GM-CSF during Mycobacterium tuberculosis infection in mice and in the peripheral blood of infected humans. Under conditions where other sources of GM-CSF are absent, T cell production of GM-CSF is protective and is required for control of infection. GM-CSF activation of macrophages to limit bacterial growth requires host expression of the transcription factor PPARγ. The identification of GM-CSF production as a T cell effector function may inform future host-directed therapy or vaccine designs., (Copyright © 2017 Rothchild et al.)- Published
- 2017
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92. Interleukin-17A Promotes Lung Tumor Progression through Neutrophil Attraction to Tumor Sites and Mediating Resistance to PD-1 Blockade.
- Author
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Akbay EA, Koyama S, Liu Y, Dries R, Bufe LE, Silkes M, Alam MM, Magee DM, Jones R, Jinushi M, Kulkarni M, Carretero J, Wang X, Warner-Hatten T, Cavanaugh JD, Osa A, Kumanogoh A, Freeman GJ, Awad MM, Christiani DC, Bueno R, Hammerman PS, Dranoff G, and Wong KK
- Subjects
- Animals, Disease Progression, Gene Expression, Humans, Interleukin-17 immunology, Lung Neoplasms genetics, Lung Neoplasms pathology, Mice, Mice, Transgenic, Mutation, Neutrophils pathology, Programmed Cell Death 1 Receptor antagonists & inhibitors, Proto-Oncogene Proteins p21(ras) genetics, Proto-Oncogene Proteins p21(ras) immunology, Interleukin-17 biosynthesis, Lung Neoplasms immunology, Neutrophils immunology, Programmed Cell Death 1 Receptor immunology
- Abstract
Introduction: Proinflammatory cytokine interleukin-17A (IL-17A) is overexpressed in a subset of patients with lung cancer. We hypothesized that IL-17A promotes a protumorigenic inflammatory phenotype and inhibits antitumor immune responses., Methods: We generated bitransgenic mice expressing a conditional IL-17A allele along with conditional Kras
G12D and performed immune phenotyping of mouse lungs, a survival analysis, and treatment studies with antibodies either blocking programmed cell death 1 (PD-1) or IL-6 or depleting neutrophils. To support the preclinical findings, we analyzed human gene expression data sets and immune profiled patient lung tumors., Results: Tumors in IL-17:KrasG12D mice grew more rapidly, resulting in a significantly shorter survival as compared with that of KrasG12D mice. IL-6, granulocyte colony-stimulating factor (G-CSF), milk fat globule-EGF factor 8 protein, and C-X-C motif chemokine ligand 1 were increased in the lungs of IL17:Kras mice. Time course analysis revealed that levels of tumor-associated neutrophils were significantly increased, and lymphocyte recruitment was significantly reduced in IL17:KrasG12D mice as compared with in KrasG12D mice. In therapeutic studies PD-1 blockade was not effective in treating IL-17:KrasG12D tumors. In contrast, blocking IL-6 or depleting neutrophils with an anti-Ly-6G antibody in the IL17:KrasG12D tumors resulted in a clinical response associated with T-cell activation. In tumors from patients with lung cancer with KRAS mutation we found a correlation between higher levels of IL-17A and colony- stimulating factor 3 and a significant correlation among high neutrophil and lower T-cell numbers., Conclusions: Here we have shown that an increase in a single cytokine, IL-17A, without additional mutations can promote lung cancer growth by promoting inflammation, which contributes to resistance to PD-1 blockade and sensitizes tumors to cytokine and neutrophil depletion., (Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)- Published
- 2017
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93. Adoptive Transfer of Invariant NKT Cells as Immunotherapy for Advanced Melanoma: A Phase I Clinical Trial.
- Author
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Exley MA, Friedlander P, Alatrakchi N, Vriend L, Yue S, Sasada T, Zeng W, Mizukami Y, Clark J, Nemer D, LeClair K, Canning C, Daley H, Dranoff G, Giobbie-Hurder A, Hodi FS, Ritz J, and Balk SP
- Subjects
- Adoptive Transfer methods, Adult, Aged, CD3 Complex immunology, Female, Galactosylceramides immunology, Humans, Interferon-gamma immunology, Interferon-gamma therapeutic use, Interleukin-10 immunology, Interleukin-2 immunology, Interleukin-4 immunology, Kaplan-Meier Estimate, Lymphocyte Activation immunology, Male, Melanoma immunology, Melanoma pathology, Middle Aged, Natural Killer T-Cells immunology, T-Lymphocyte Subsets immunology, Cell- and Tissue-Based Therapy methods, Immunotherapy, Melanoma therapy, Natural Killer T-Cells transplantation, T-Lymphocyte Subsets transplantation
- Abstract
Purpose: Invariant NKT cells (iNKT) are innate-like CD1d-restricted T cells with immunoregulatory activity in diseases including cancer. iNKT from advanced cancer patients can have reversible defects including IFNγ production, and iNKT IFNγ production may stratify for survival. Previous clinical trials using iNKT cell activating ligand α-galactosylceramide have shown clinical responses. Therefore, a phase I clinical trial was performed of autologous in vitro expanded iNKT cells in stage IIIB-IV melanoma. Experimental Design: Residual iNKT cells [<0.05% of patient peripheral blood mononuclear cell (PBMC)] were purified from autologous leukapheresis product using an antibody against the iNKT cell receptor linked to magnetic microbeads. iNKT cells were then expanded with CD3 mAb and IL2 in vitro to obtain up to approximately 10
9 cells. Results: Expanded iNKT cells produced IFNγ, but limited or undetectable IL4 or IL10. Three iNKT infusions each were completed on 9 patients, and produced only grade 1-2 toxicities. The 4th patient onward received systemic GM-CSF with their second and third infusions. Increased numbers of iNKT cells were seen in PBMCs after some infusions, particularly when GM-CSF was also given. IFNγ responses to α-galactosylceramide were increased in PBMCs from some patients after infusions, and delayed-type hypersensitivity responses to Candida increased in 5 of 8 evaluated patients. Three patients have died, three were progression-free at 53, 60, and 65 months, three received further treatment and were alive at 61, 81, and 85 months. There was no clear correlation between outcome and immune parameters. Conclusions: Autologous in vitro expanded iNKT cells are a feasible and safe therapy, producing Th1-like responses with antitumor potential. Clin Cancer Res; 23(14); 3510-9. ©2017 AACR ., (©2017 American Association for Cancer Research.)- Published
- 2017
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94. Erratum: Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2.
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Zhang H, Brainson CF, Koyama S, Redig AJ, Chen T, Li S, Gupta M, Garcia-de-Alba C, Paschini M, Herter-Sprie GS, Lu G, Zhang X, Marsh BP, Tuminello SJ, Xu C, Chen Z, Wang X, Akbay EA, Zheng M, Palakurthi S, Sholl LM, Rustgi AK, Kwiatkowski DJ, Alan Diehl J, Bass AJ, Sharpless NE, Dranoff G, Hammerman PS, Ji H, Bardeesy N, Saur D, Watanabe H, Kim CF, and Wong KK
- Abstract
This corrects the article DOI: 10.1038/ncomms14922.
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- 2017
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95. Integrin-targeted cancer immunotherapy elicits protective adaptive immune responses.
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Kwan BH, Zhu EF, Tzeng A, Sugito HR, Eltahir AA, Ma B, Delaney MK, Murphy PA, Kauke MJ, Angelini A, Momin N, Mehta NK, Maragh AM, Hynes RO, Dranoff G, Cochran JR, and Wittrup KD
- Subjects
- Animals, Antibody Formation drug effects, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, CD4-Positive T-Lymphocytes drug effects, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes immunology, Cell Line, Tumor, Colonic Neoplasms pathology, Cross Reactions drug effects, Cross Reactions immunology, Dendritic Cells drug effects, Dendritic Cells metabolism, Disease Models, Animal, Female, Humans, Immune Tolerance drug effects, Inflammation pathology, Interleukin-2 metabolism, Liver drug effects, Liver pathology, Macrophages drug effects, Macrophages metabolism, Mice, Mice, Inbred C57BL, Peptides metabolism, Receptors, IgG metabolism, Serum Albumin metabolism, Species Specificity, Tissue Distribution drug effects, Treatment Outcome, Adaptive Immunity drug effects, Colonic Neoplasms drug therapy, Colonic Neoplasms immunology, Immunotherapy, Integrins metabolism
- Abstract
Certain RGD-binding integrins are required for cell adhesion, migration, and proliferation and are overexpressed in most tumors, making them attractive therapeutic targets. However, multiple integrin antagonist drug candidates have failed to show efficacy in cancer clinical trials. In this work, we instead exploit these integrins as a target for antibody Fc effector functions in the context of cancer immunotherapy. By combining administration of an engineered mouse serum albumin/IL-2 fusion with an Fc fusion to an integrin-binding peptide (2.5F-Fc), significant survival improvements are achieved in three syngeneic mouse tumor models, including complete responses with protective immunity. Functional integrin antagonism does not contribute significantly to efficacy; rather, this therapy recruits both an innate and adaptive immune response, as deficiencies in either arm result in reduced tumor control. Administration of this integrin-targeted immunotherapy together with an anti-PD-1 antibody further improves responses and predominantly results in cures. Overall, this well-tolerated therapy achieves tumor specificity by redirecting inflammation to a functional target fundamental to tumorigenic processes but expressed at significantly lower levels in healthy tissues, and it shows promise for translation., (© 2017 Kwan et al.)
- Published
- 2017
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96. Soluble PD-L1 as a Biomarker in Malignant Melanoma Treated with Checkpoint Blockade.
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Zhou J, Mahoney KM, Giobbie-Hurder A, Zhao F, Lee S, Liao X, Rodig S, Li J, Wu X, Butterfield LH, Piesche M, Manos MP, Eastman LM, Dranoff G, Freeman GJ, and Hodi FS
- Subjects
- Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, B7-H1 Antigen genetics, B7-H1 Antigen metabolism, Bevacizumab therapeutic use, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Cell Line, Tumor, Cytokines blood, Humans, Ipilimumab therapeutic use, Melanoma drug therapy, Melanoma genetics, Melanoma metabolism, Protein Isoforms, Antineoplastic Agents, Immunological therapeutic use, B7-H1 Antigen antagonists & inhibitors, B7-H1 Antigen blood, Biomarkers, Tumor blood, CTLA-4 Antigen antagonists & inhibitors, Melanoma blood
- Abstract
Blockade of the pathway including programmed death-ligand 1 (PD-L1) and its receptor programmed cell death protein 1 (PD-1) has produced clinical benefits in patients with a variety of cancers. Elevated levels of soluble PD-L1 (sPD-L1) have been associated with worse prognosis in renal cell carcinoma and multiple myeloma. However, the regulatory roles and function of sPD-L1 particularly in connection with immune checkpoint blockade treatment are not fully understood. We identified four splice variants of PD-L1 in melanoma cells, and all of them are secreted. Secretion of sPD-L1 resulted from alternate splicing activities, cytokine induction, cell stress, cell injury, and cell death in melanoma cells. Pretreatment levels of sPD-L1 were elevated in stage IV melanoma patient sera compared with healthy donors. High pretreatment levels of sPD-L1 were associated with increased likelihood of progressive disease in patients treated by CTLA-4 or PD-1 blockade. Although changes in circulating sPD-L1 early after treatment could not distinguish responders from those with progressive disease, after five months of treatment by CTLA-4 or PD-1 blockade patients who had increased circulating sPD-L1 had greater likelihood of developing a partial response. Induction of sPD-L1 was associated with increased circulating cytokines after CTLA-4 blockade but not following PD-1 blockade. Circulating sPD-L1 is a prognostic biomarker that may predict outcomes for subgroups of patients receiving checkpoint inhibitors. Cancer Immunol Res; 5(6); 480-92. ©2017 AACR ., (©2017 American Association for Cancer Research.)
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- 2017
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97. Combined Anti-VEGF and Anti-CTLA-4 Therapy Elicits Humoral Immunity to Galectin-1 Which Is Associated with Favorable Clinical Outcomes.
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Wu X, Li J, Connolly EM, Liao X, Ouyang J, Giobbie-Hurder A, Lawrence D, McDermott D, Murphy G, Zhou J, Piesche M, Dranoff G, Rodig S, Shipp M, and Hodi FS
- Subjects
- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bevacizumab therapeutic use, Humans, Immunity, Humoral drug effects, Ipilimumab therapeutic use, Leukocyte Common Antigens immunology, Melanoma drug therapy, Antineoplastic Combined Chemotherapy Protocols pharmacology, Bevacizumab pharmacology, CTLA-4 Antigen antagonists & inhibitors, Galectin 1 immunology, Ipilimumab pharmacology, Melanoma immunology, Vascular Endothelial Growth Factor A antagonists & inhibitors
- Abstract
The combination of anti-VEGF blockade (bevacizumab) with immune checkpoint anti-CTLA-4 blockade (ipilimumab) in a phase I study showed tumor endothelial activation and immune cell infiltration that were associated with favorable clinical outcomes in patients with metastatic melanoma. To identify potential immune targets responsible for these observations, posttreatment plasma from long-term responding patients were used to screen human protein arrays. We reported that ipilimumab plus bevacizumab therapy elicited humoral immune responses to galectin-1 (Gal-1), which exhibits protumor, proangiogenesis, and immunosuppressive activities in 37.2% of treated patients. Gal-1 antibodies purified from posttreatment plasma suppressed the binding of Gal-1 to CD45, a T-cell surface receptor that transduces apoptotic signals upon binding to extracellular Gal-1. Antibody responses to Gal-1 were found more frequently in the group of patients with therapeutic responses and correlated with improved overall survival. In contrast, another subgroup of treated patients had increased circulating Gal-1 protein instead, and they had reduced overall survival. Our findings suggest that humoral immunity to Gal-1 may contribute to the efficacy of anti-VEGF and anti-CTLA-4 combination therapy. Gal-1 may offer an additional therapeutic target linking anti-angiogenesis and immune checkpoint blockade. Cancer Immunol Res; 5(6); 446-54. ©2017 AACR ., (©2017 American Association for Cancer Research.)
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- 2017
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98. Prospects for combining targeted and conventional cancer therapy with immunotherapy.
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Gotwals P, Cameron S, Cipolletta D, Cremasco V, Crystal A, Hewes B, Mueller B, Quaratino S, Sabatos-Peyton C, Petruzzelli L, Engelman JA, and Dranoff G
- Subjects
- Animals, Combined Modality Therapy, Humans, Neoplasms drug therapy, Neoplasms genetics, Neoplasms immunology, Immunotherapy trends, Molecular Targeted Therapy trends, Neoplasms therapy
- Abstract
Over the past 25 years, research in cancer therapeutics has largely focused on two distinct lines of enquiry. In one approach, efforts to understand the underlying cell-autonomous, genetic drivers of tumorigenesis have led to the development of clinically important targeted agents that result in profound, but often not durable, tumour responses in genetically defined patient populations. In the second parallel approach, exploration of the mechanisms of protective tumour immunity has provided several therapeutic strategies - most notably the 'immune checkpoint' antibodies that reverse the negative regulators of T cell function - that accomplish durable clinical responses in subsets of patients with various tumour types. The integration of these potentially complementary research fields provides new opportunities to improve cancer treatments. Targeted and immune-based therapies have already transformed the standard-of-care for several malignancies. However, additional insights into the effects of targeted therapies, along with conventional chemotherapy and radiation therapy, on the induction of antitumour immunity will help to advance the design of combination strategies that increase the rate of complete and durable clinical response in patients.
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- 2017
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99. Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2.
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Zhang H, Fillmore Brainson C, Koyama S, Redig AJ, Chen T, Li S, Gupta M, Garcia-de-Alba C, Paschini M, Herter-Sprie GS, Lu G, Zhang X, Marsh BP, Tuminello SJ, Xu C, Chen Z, Wang X, Akbay EA, Zheng M, Palakurthi S, Sholl LM, Rustgi AK, Kwiatkowski DJ, Diehl JA, Bass AJ, Sharpless NE, Dranoff G, Hammerman PS, Ji H, Bardeesy N, Saur D, Watanabe H, Kim CF, and Wong KK
- Subjects
- AMP-Activated Protein Kinases, Adenocarcinoma metabolism, Adenocarcinoma pathology, Animals, Carcinoma, Squamous Cell metabolism, Carcinoma, Squamous Cell pathology, Enhancer of Zeste Homolog 2 Protein genetics, Enhancer of Zeste Homolog 2 Protein metabolism, Gene Expression Profiling methods, Gene Expression Regulation, Neoplastic, Histones metabolism, Kaplan-Meier Estimate, Lung Neoplasms metabolism, Lung Neoplasms pathology, Methylation, Mice, 129 Strain, Mice, Knockout, Polycomb Repressive Complex 2 metabolism, Protein Serine-Threonine Kinases metabolism, Proto-Oncogene Proteins p21(ras) genetics, Proto-Oncogene Proteins p21(ras) metabolism, Tumor Cells, Cultured, Adenocarcinoma genetics, Carcinoma, Squamous Cell genetics, Lung Neoplasms genetics, Polycomb Repressive Complex 2 genetics, Protein Serine-Threonine Kinases genetics
- Abstract
Adenosquamous lung tumours, which are extremely poor prognosis, may result from cellular plasticity. Here, we demonstrate lineage switching of KRAS+ lung adenocarcinomas (ADC) to squamous cell carcinoma (SCC) through deletion of Lkb1 (Stk11) in autochthonous and transplant models. Chromatin analysis reveals loss of H3K27me3 and gain of H3K27ac and H3K4me3 at squamous lineage genes, including Sox2, ΔNp63 and Ngfr. SCC lesions have higher levels of the H3K27 methyltransferase EZH2 than the ADC lesions, but there is a clear lack of the essential Polycomb Repressive Complex 2 (PRC2) subunit EED in the SCC lesions. The pattern of high EZH2, but low H3K27me3 mark, is also prevalent in human lung SCC and SCC regions within ADSCC tumours. Using FACS-isolated populations, we demonstrate that bronchioalveolar stem cells and club cells are the likely cells-of-origin for SCC transitioned tumours. These findings shed light on the epigenetics and cellular origins of lineage-specific lung tumours.
- Published
- 2017
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100. The Cloning of GM-CSF.
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Dranoff G
- Subjects
- Amino Acid Sequence, Cloning, Molecular, Granulocyte-Macrophage Colony-Stimulating Factor genetics
- Published
- 2017
- Full Text
- View/download PDF
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