13 results on '"Caitlin D Lemke-Miltner"'
Search Results
2. 1125 In vitro characterization of cellular responses elicited by endosomal TLR agonists encapsulated in Qβ virus-like particles
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George J Weiner, Caitlin D Lemke-Miltner, Andrean L Simons, MM Hasibuzzaman, Briana Ibarra, and Ishrat Khan
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2023
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3. 1122 Vidutolimod, an immunostimulatory virus-like particle, reduces proliferation but enhances the activation of tumor-specific T cells
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George J Weiner, Caitlin D Lemke-Miltner, and Travis D Fischer
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2023
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4. In situ immunization of a TLR9 agonist virus-like particle enhances anti-PD1 therapy
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Yinwen Cheng, Caitlin D Lemke-Miltner, Wattawan Wongpattaraworakul, Carlos H F Chan, and Andrean L Simons
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background CMP-001 is a novel Toll-like receptor-9 agonist that consists of an unmethylated CpG-A motif-rich G10 oligodeoxynucleotide (ODN) encapsulated in virus-like particles. In situ vaccination of CMP-001 is believed to activate local tumor-associated plasmacytoid dendritic cells (pDCs) leading to type I interferon secretion and tumor antigen presentation to T cells and systemic antitumor T cell responses. This study is designed to investigate if CMP-001 would enhance head and neck squamous cell carcinoma (HNSCC) tumor response to anti-programmed cell death protein-1 (anti-PD-1) therapy in a human papilloma virus-positive (HPV+) tumor mouse model.Methods Immune cell activation in response to CMP-001±anti-Qβ was performed using co-cultures of peripheral blood mononuclear cells and HPV+/HPV- HNSCC cells and then analyzed by flow cytometry. In situ vaccination with CMP-001 alone and in combination with anti-PD-1 was investigated in C57BL/6 mice-bearing mEERL HNSCC tumors and analyzed for anti-Qβ development, antitumor response, survival and immune cell recruitment. The role of antitumor immune response due to CMP-001+anti-PD-1 treatment was investigated by the depletion of natural killer (NK), CD4+ T, and CD8+ T cells.Results Results showed that the activity of CMP-001 on immune cell (pDCs, monocytes, CD4+/CD8+ T cells and NK cells) activation depends on the presence of anti-Qβ. A 2-week ‘priming’ period after subcutaneous administration of CMP-001 was required for robust anti-Qβ development in mice. In situ vaccination of CMP-001 was superior to unencapsulated G10 CpG-A ODN at suppressing both injected and uninjected (distant) tumors. In situ vaccination of CMP-001 in combination with anti-PD-1 therapy induced durable tumor regression at injected and distant tumors and significantly prolonged mouse survival compared with anti-PD-1 therapy alone. The antitumor effect of CMP-001+anti-PD-1 was accompanied by increased interferon gamma (IFNγ)+ CD4+/CD8+ T cells compared with control-treated mice. The therapeutic and abscopal effect of CMP-001+ anti-PD-1 therapy was completely abrogated by CD8+ T cell depletion.Conclusions These results demonstrate that in situ vaccination with CMP-001 can induce both local and abscopal antitumor immune responses. Additionally, the antitumor efficacy of CMP-001 combined with α-PD-1 therapy warrants further study as a novel immunotherapeutic strategy for the treatment of HNSCC.
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- 2020
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5. Monocytes Exposed to Immune Complexes Reduce pDC Type 1 Interferon Response to Vidutolimod
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Shakoora A. Sabree, Caitlin D. Lemke-Miltner, Sue E. Blackwell, Chaobo Yin, Aaron Bossler, Kareem Ebeid, Aliasger K. Salem, and George J. Weiner
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vidutolimod ,Fc gamma receptor ,TLR9 ,pDCs ,Type 1 Interferon ,monocytes ,Medicine - Abstract
Vidutolimod, also known as CMP-001, is a virus-like particle composed of the Qβ bacteriophage coat protein encasing a TLR9 agonist. Vidutolimod injected intratumorally is showing promise in early phase clinical trials based on its ability to alter the tumor microenvironment and induce an anti-tumor immune response. We previously demonstrated that the in vivo efficacy of vidutolimod is dependent on the presence of anti-Qβ antibodies that enhance opsonization and uptake of vidutolimod by TLR9-expressing plasmacytoid dendritic cells (pDCs). Here, we evaluated the effect of immune complexes, including anti-Qβ-coated vidutolimod, on induction of Type 1 Interferon production by peripheral blood mononuclear cells in response to vidutolimod and soluble TLR9 agonists. Immune complexes, including but not limited to anti-Qβ-coated vidutolimod, indirectly suppressed TLR9-mediated Type 1 Interferon production by pDCs in a monocyte-dependent manner. These findings indicate that anti-Qβ-coated vidutolimod has effects in addition to those mediated by TLR9 that could have important clinical implications for understanding the mechanism of action of this exciting new approach to in situ immunization and cancer immunotherapy.
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- 2021
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6. Abstract 4: A novel humanized mouse model for study of T cells and NK cells in the tumor microenvironment
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Jyoti Arora, Caitlin D. Lemke-Miltner, and George J. Weiner
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Cancer Research ,Oncology - Abstract
Humanized mouse models can be useful for in vivo preclinical evaluation of mechanisms underlying cancer immunotherapy. Most such models involve systemic engraftment of immunocompromised mice with human lymphoid and hematopoietic cells, often using normal donor peripheral blood mononuclear cells (PBMCs), followed by inoculation with human tumor. The ability to control and modify immune cells within the tumor microenvironment (TME), especially human NK cells, is limited in such models. Here, we report the development of a mouse model designed to control the number of human T cells and NK cells in the TME. 18 mice and pre-validated PBMCs were obtained from Charles River. Six groups of 3 mice each were inoculated with Raji lymphoma cells. Group 1 was inoculated with Raji cells only and received no PBMCs. Raji cells were mixed PBMCs for groups 2-4. Group 5 was systemically engrafted with PBMCs 12 days prior to Raji inoculation and Group 6 was systemically engrafted with PBMCs 10 days after Raji inoculation. All mice developed tumors with similar growth characteristics. Serial fine needle aspirates (FNAs) of the resulting tumors were evaluated by flow cytometry. Results of FNAs are summarized below. Tumors were harvested at the end of experiment, typically 27 days after tumor inoculation, and evaluated by immunohistochemistry. Both T cells and NK cells were evenly distributed within tumors at the time of harvest. We conclude co-injection of tumor and PBMCs results in engraftment of both T cells and NK cells within the TME for up to 27 days, with T cells and NK cells distributed evenly within the tumor. Mixing higher numbers of PBMCs with tumor cells resulted in increased numbers of T cells and NK cells in the TME throughout the experiment. Matrigel did not improve engraftment or persistence of T or NK cells in the TME. We conclude mixing PBMCs with Raji tumor cells prior to tumor inoculation into immunocompromised mice is an effective approach when a humanized model with human T cells and NK cells within the TME is desired. Group Description % T cells in tumor at 17 days % NK cells in tumor at 17 days 1 No PBMCs 0 0 2 PBMCs mixed with Raji at 10:1 ratio 8.6 1.5 3 PBMCs mixed with Raji at 2:1 ratio 20.3 2.7 4 PBMCs and Raji in matrigel 9.2 0.6 5 PBMCs systemically engrafted 12 days before Raji inoculation 23.2 0.1 6 PBMCs systemically engrafted 10 days after Raji inoculation 19.6 0.2 Citation Format: Jyoti Arora, Caitlin D. Lemke-Miltner, George J. Weiner. A novel humanized mouse model for study of T cells and NK cells in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4.
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- 2023
7. Intraperitoneal CMP-001: A Novel Immunotherapy for Treating Peritoneal Carcinomatosis of Gastrointestinal and Pancreaticobiliary Cancer
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Sue E. Blackwell, Ann M. Miller, Ann Tomanek-Chalkley, Kristen L Coleman, George J. Weiner, Carlos H. F. Chan, Katherine N Gibson-Corely, and Caitlin D Lemke-Miltner
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Chemokine ,medicine.medical_treatment ,030230 surgery ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,In vivo ,Cytidine Monophosphate ,Tumor Microenvironment ,Animals ,Humans ,Medicine ,Peritoneal Neoplasms ,Tumor microenvironment ,biology ,business.industry ,Dendritic Cells ,Immunotherapy ,Interleukin-12 ,Oncology ,030220 oncology & carcinogenesis ,Interleukin 12 ,Cancer research ,biology.protein ,Cytokines ,Surgery ,business ,Ex vivo ,CD8 - Abstract
BACKGROUND. The treatment options for patients with peritoneal carcinomatosis (PC) of gastrointestinal and pancreaticobiliary origins are limited. The virus-like particle, CMP-001, composed of the Qβ bacteriophage capsid protein encapsulating a CpG-A oligodeoxynucleotide, activates plasmacytoid dendritic cells (pDCs) and triggers interferon alpha (IFNα) release, leading to a cascade of anti-tumor immune effects. METHODS. To evaluate the ability of CMP-001 to trigger an immune response in patients with PC, peritoneal cells were isolated and stimulated ex vivo with CMP-001. Both IFNα release and percentage of pDC were quantified using enzyme-linked immunosorbent assay (ELISA) and flow cytometry, respectively. To evaluate the anti-tumor response in vivo, murine PC models were generated using mouse cancer cell lines (Panc02 and MC38) in immunocompetent mice treated with intraperitoneal CMP-001 or saline control. Survival was followed, and the immunophenotype of cells in the peritoneal tumor microenvironment was evaluated. RESULTS. The pDCs accounted for 1% (range 0.1–3.9%; n = 17) of the isolated peritoneal cells. Ex vivo CMP-001 stimulation of the peritoneal cells released an average of 0.77 ng/ml of IFNα (range, 0–4700 pg/ml; n = 14). The IFNα concentration was proportional to the percentage of pDCs present in the peritoneal cell mixture (r = 0.6; p = 0.037). In murine PC models, intraperitoneal CMP-001 treatment elicited an anti-tumor immune response including an increase in chemokines (RANTES and MIP-1β), pro-inflammatory cytokines (IFNγ, interleukin 6 [IL-6], and IL-12), and peritoneal/tumor immune infiltration (CD4(+)/CD8(+) T and natural killer [NK] cells). The CMP-001 treatment improved survival in both the Panc02 (median, 35 vs 28 days) and the MC38 (median: 57 vs 35 days) PC models (p < 0.05). CONCLUSIONS. As a novel immunotherapeutic agent, CMP-001 may be effective for treating patients with PC.
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- 2020
8. Antibody Opsonization of a TLR9 Agonist–Containing Virus-like Particle Enhances In Situ Immunization
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Aaron Morris, Anna E Krug, Sue E. Blackwell, George J. Weiner, Caitlin D Lemke-Miltner, Arthur M. Krieg, and Chaobo Yin
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Lymphoma ,Antibodies, Neoplasm ,medicine.medical_treatment ,T cell ,Immunology ,Article ,Mice ,In vivo ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Immunology and Allergy ,Vaccines, Virus-Like Particle ,B-cell lymphoma ,Mice, Knockout ,Immunity, Cellular ,biology ,Chemistry ,TLR9 ,Immunotherapy ,medicine.disease ,carbohydrates (lipids) ,Cytokine ,medicine.anatomical_structure ,Oligodeoxyribonucleotides ,Toll-Like Receptor 9 ,biology.protein ,Cancer research ,Female ,Immunization ,Antibody - Abstract
The immunologic and therapeutic effects of intratumoral (IT) delivery of a novel virus-like particle as a lymphoma immunotherapy were evaluated in preclinical studies with human cells and a murine model. CMP-001 is a virus-like particle composed of the Qβ bacteriophage capsid protein encapsulating an immunostimulatory CpG-A oligodeoxynucleotide TLR9 agonist. In vitro, CMP-001 induced cytokine production, including IFN-α from plasmacytoid dendritic cells, but only in the presence of anti-Qβ Ab. In vivo, IT CMP-001 treatment of murine A20 lymphoma enhanced survival and reduced growth of both injected and contralateral noninjected tumors in a manner dependent on both the ability of mice to generate anti-Qβ Ab and the presence of T cells. The combination of IT CMP-001 with systemic anti–PD-1 enhanced antitumor responses in both injected and noninjected tumors. IT CMP-001 alone or combined with anti–PD-1 augmented T cell infiltration in tumor-draining lymph nodes. We conclude IT CMP-001 induces a robust antitumor T cell response in an anti-Qβ Ab–dependent manner and results in systemic antitumor T cell effects that are enhanced by anti–PD-1 in a mouse model of B cell lymphoma. Early-phase clinical evaluation of CMP-001 and anti–PD-1 combination therapy in lymphoma will begin shortly, based in part on these results.
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- 2020
9. The anti-tumor effects of cetuximab in combination with VTX-2337 are T cell dependent
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Allen B. Choi, Nicholas Borcherding, Andrean L. Simons, George J. Weiner, Wattawan Wongpattaraworakul, Aliasger K. Salem, Caitlin D Lemke-Miltner, Carlos H. F. Chan, Ayomide Ogunsakin, Yinwen Cheng, Anand Rajan, and Katherine N. Gibson-Corley
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0301 basic medicine ,Male ,Cancer therapy ,medicine.medical_treatment ,T-Lymphocytes ,Cetuximab ,Gene Expression ,CD8-Positive T-Lymphocytes ,Biomarkers, Pharmacological ,Mice ,0302 clinical medicine ,Neoplasms ,Databases, Genetic ,Receptor ,Head and neck cancer ,Mice, Inbred BALB C ,Mice, Inbred C3H ,Multidisciplinary ,Oral cancer ,Gene Expression Regulation, Neoplastic ,Killer Cells, Natural ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Medicine ,Tumour immunology ,Cytokines ,Female ,Adjuvant ,medicine.drug ,T cell ,Science ,Antineoplastic Agents ,Article ,03 medical and health sciences ,Immune system ,Cell Line, Tumor ,medicine ,Animals ,Humans ,business.industry ,Squamous Cell Carcinoma of Head and Neck ,Antibody-Dependent Cell Cytotoxicity ,Dendritic cell ,Benzazepines ,medicine.disease ,Head and neck squamous-cell carcinoma ,Mice, Inbred C57BL ,030104 developmental biology ,Toll-Like Receptor 8 ,Cancer research ,business ,CD8 - Abstract
The Toll-like receptor 8 (TLR8) agonist VTX-2337 (motolimod) is an anti-cancer immunotherapeutic agent that is believed to augment natural killer (NK) and dendritic cell (DC) activity. The goal of this work is to examine the role of TLR8 expression/activity in head and neck squamous cell carcinoma (HNSCC) to facilitate the prediction of responders to VTX-2337-based therapy. The prognostic role of TLR8 expression in HNSCC patients was assessed by TCGA and tissue microarray analyses. The anti-tumor effect of VTX-2337 was determined in SCCVII/C3H, mEERL/C57Bl/6 and TUBO-human EGFR/BALB/c syngeneic mouse models. The effect of combined VTX-2337 and cetuximab treatment on tumor growth, survival and immune cell recruitment was assessed. TLR8 expression was associated with CD8+ T cell infiltration and favorable survival outcomes. VTX-2337 delayed tumor growth in all 3 syngeneic mouse models and significantly increased the survival of cetuximab-treated mice. The anti-tumor effects of VTX-2337+ cetuximab were accompanied by increased splenic lymphoid DCs and IFNγ+ CD4+ and tumor-specific CD8+ T cells. Depletion of CD4+ T cells, CD8+ T cells and NK cells were all able to abolish the anti-tumor effect of VTX-2337+ cetuximab. Altogether, VTX-2337 remains promising as an adjuvant for cetuximab-based therapy however patients with high TLR8 expression may be more likely to derive benefit from this drug combination compared to patients with low TLR8 expression.
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- 2021
10. Abstract 6641: In situ immunization with the TLR9-agonist CMP-001 enhances anti-PD1 therapy in head and neck tumors
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Aliasger K. Salem, Carlos H. F. Chan, Andrean L. Simons, Caitlin D Lemke-Miltner, George J. Weiner, and Yinwen Cheng
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Cancer Research ,business.industry ,T cell ,medicine.medical_treatment ,Cancer ,Abscopal effect ,Immunotherapy ,medicine.disease ,Head and neck squamous-cell carcinoma ,Tumor antigen ,Immune system ,medicine.anatomical_structure ,Oncology ,medicine ,Cancer research ,business ,CD8 - Abstract
Immunotherapy involving immune checkpoint inhibitors (i.e. anti-PD1) has shown promise for the treatment of head and neck squamous cell carcinoma (HNSCC). However, only a small subset of HNSCC patients respond to these therapies. Therefore, the identification of alternative immunotherapeutic strategies is necessary to improve HNSCC patient outcomes. CMP-001 is a novel toll-like receptor-9 agonist that consists of an unmethylated CpG motif-rich G10 oligonucleotide encapsulated in virus-like particles. In situ vaccination of CMP-001 is believed to activate tumor-associated plasmacytoid dendritic cells (pDCs) leading to tumor antigen presentation to T cells and anti-tumor T cell responses. This study is designed to investigate if CMP-001 would enhance HNSCC tumor response to anti-PD1 therapy in a human papilloma virus-positive (HPV+) tumor mouse model. C57BL/6 mice were subcutaneously inoculated with murine HPV+ mEERL HNSCC cells on both left and right flanks of each mouse. CMP-001 (100 µg/mouse) was administered intratumorally (i.t.) 3 times over the course of 1 week into the left tumor as a single agent and in combination with anti-PD1 (50 µg/mouse, intraperitoneally (i.p.)) 3 times per week for 2 weeks. Succinate buffer i.t. in combination with human IgG i.p. was administered as controls. The role of anti-tumor immune response due to CMP-001+anti-PD1 treatment was investigated by the depletion of NK cells, CD4+ and CD8+ T cells. Tumor growth, survival and immune cell recruitment was monitored and analyzed in response to drug treatment. Results showed that in situ vaccination of CMP-001 alone and in combination with anti-PD1 therapy induced tumor regression in the injected tumors and the regression of CMP-001+anti-PD1-injected tumors was durable. Additionally, CMP-001+anti-PD1 induced tumor regression at the distant sites which was not observed in the other treatment groups. CMP-001+anti-PD1 also significantly prolonged mouse survival compared with other groups. The anti-tumor effect of CMP-001+anti-PD1 was accompanied by increased DCs, macrophages, IFNγ+ CD4+/CD8+ T cells, HPV+ CD8+ T cells and activated NK cells in tumors and lymph nodes near the injected site compared with control. The therapeutic and abscopal effect of CMP-001+anti-PD1 therapy was partially abrogated by NK cell depletion and completely abrogated by CD8+ T cell depletion. These results demonstrate the synergistic anti-tumor efficacy of CMP-001 combined with α-PD1 therapy and warrants further study of this combination as a novel immunotherapeutic strategy for the treatment of HNSCC. Citation Format: Yinwen Cheng, Caitlin D. Lemke-Miltner, Carlos H. Chan, Aliasger Salem, George Weiner, Andrean Simons. In situ immunization with the TLR9-agonist CMP-001 enhances anti-PD1 therapy in head and neck tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6641.
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- 2020
11. Abstract 6666: Evaluation of the complexity of the immune response to CMP-001, a TLR9 agonist
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Laura Rogers, George J. Weiner, Shakoora A Sabree, Caitlin D Lemke-Miltner, Sue E. Blackwell, and Andrew P. Voigt
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Cancer Research ,CpG Oligodeoxynucleotide ,CD14 ,TLR9 ,Biology ,Peripheral blood mononuclear cell ,carbohydrates (lipids) ,Immune system ,Oncology ,Interferon ,Immunology ,medicine ,biology.protein ,CXCL10 ,Antibody ,medicine.drug - Abstract
CMP-001 is a virus-like particle containing a TLR9 agonist (class A CpG ODN) encapsulated by the Qβ capsid. Preclinical studies and early phase clinical trials of intralesional injection with CMP-001, combined with anti-PD1 antibody, demonstrate promising results. Prior work by our group has demonstrated that the immunostimulatory effects of CMP-001 are dependent on generation of an anti-Qβ antibody response which results in opsonization of CMP-001 by plasmacytoid dendritic cells (pDCs) and production of IFNα. While a variety of cell types including monocytes and B cells can take up CMP-001, the immune response to CMP-001 is based in large part on rapid induction of IFNα production by pDCs. The current studies were designed to assess the downstream effects of CMP-001 and anti-Qβ antibody on various arms of the immune response using normal donor human peripheral blood mononuclear cells (PBMCs) as a model. Stimulation of PBMCs with CMP-001 and anti-Qβ antibody induced production of IFNα from pDCs as previously observed. This IFNα production occurred very rapidly (within 2 hours) and was short lived, but had long term secondary effects, including induction of CXCL10 production by monocytes. Single cell RNA sequencing done 24 hours after stimulation demonstrated additional downstream changes including the following: Upregulation of CXCL10, MIP1-α, IL1-RA and IDO by monocytes. Downregulation of CD14 by monocytes. Upregulation of a broad variety of interferon response genes in various cell types including NK cells and T cells. We conclude the primary effect of in situ immunization with CMP-001 is to induce rapid production of IFNα production by pDCs. This results in significant downstream effects on various cell populations that contribute to the anti-tumor immune response. Understanding these pathways could help identify the most promising combination immunotherapies involving CMP-001. Ongoing studies are exploring the kinetics of these responses and whether similar changes are observed in the tumor microenvironment. Citation Format: Shakoora Sabree, Andrew Voigt, Laura Rogers, Sue Blackwell, Caitlin Lemke-Miltner, George J. Weiner. Evaluation of the complexity of the immune response to CMP-001, a TLR9 agonist [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6666.
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- 2020
12. Abstract 3273: CMP-001, a virus-like particle containing immunostimulatory CpG-A, for treatment of peritoneal carcinomatosis of gastrointestinal and pancreatic cancers
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Ann Tomanek-Chalkley, Kristen L Coleman, Ann M. Miller, George J. Weiner, Carlos H. F. Chan, Sue E. Blackwell, and Caitlin D Lemke-Miltner
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Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,TLR9 ,Cancer ,medicine.disease ,Gastroenterology ,Metastasis ,carbohydrates (lipids) ,Immune system ,Oncology ,Internal medicine ,Pancreatic cancer ,medicine ,business ,Receptor ,Saline ,CD8 - Abstract
Peritoneal carcinomatosis is a common form of metastasis occurring in approximately 10% of gastrointestinal and pancreatic cancers with life expectancy often less than 6-12 months. Due to the limited options for treatment of peritoneal carcinomatosis, there is a significant need for novel therapeutic strategies. We explored the therapeutic potential of CMP-001, a novel virus-like particle composed of the Qβ bacteriophage capsid protein encapsulating an immunostimulatory CpG-A oligodeoxynucleotide (CpG-A ODN) in this cancer. CpG-A ODN is a known activator of toll-like receptor 9 (TLR9), which is expressed by human and murine plasmacytoid dendritic cells (pDCs). Initial studies evaluated the effect of CMP-001 in vitro on cells obtained from the ascitic fluid of patients with peritoneal carcinomatosis. These studies demonstrated that pDCs are present in the ascitic fluid and produce IFN-α in response to CMP-001 stimulation. A mouse model of peritoneal carcinomatosis was used to further explore the therapeutic potential of CMP-001. C57BL/6 mice were challenged intraperitoneally (i.p.) with Panc02 mouse pancreatic cancer cells. On days 5, 9, and 13 post-tumor challenge mice were treated i.p. with either saline or 100 μg CMP-001. Mice treated with CMP-001 had a median survival of 35 days compared to mice treated with saline alone with a median survival of 28 days (n = 10 per group, p = 0.028). Examination of the immune response demonstrated CMP-001 induced an influx of dendritic cells (CMP- 001 8.99% ± 0.95 vs saline 4.57% ± 0.7, p = 0.0015), NK cells (CMP-001 0.26% ± 0.052 vs saline 0.087% ± 0.0085, p = 0.006), and CD4+ T cells (CMP-001 3.29% ± 0.85 vs saline 0.95% ± 0.097, p = 0.0168) into the ascitic fluid. In addition, CMP-001 induced a significant increase in antigen-experienced, effector and memory, CD11ahiCD44hi CD4+ T cells (CMP-001 54.55% ± 6.52 vs saline 28.12% ± 3.68, p = 0.0028) and CD11ahiCD8αlo CD8+ T cells (CMP-001 58.49% ± 4.47 vs saline 23.04% ± 2.86, p < 0.0001) in the ascites. These data demonstrate that CMP-001 treatment activates pDCs in the peritoneal fluid of patients with carcinomatosis. In addition, CMP-001 stimulates a robust immune response in the peritoneal cavity of mice with peritoneal carcinomatosis. This robust immune response likely contributes to the enhanced survival and decreased disease progression in these mice. Collectively, these promising preclinical results suggest that CMP-001 may have potential as an immunotherapy for the treatment of patients with peritoneal carcinomatosis and is worthy of further evaluation. Citation Format: Ann M. Miller, Caitlin Lemke-Miltner, Sue Blackwell, Ann Tomanek-Chalkley, Kristen Coleman, George Weiner, Carlos Chan. CMP-001, a virus-like particle containing immunostimulatory CpG-A, for treatment of peritoneal carcinomatosis of gastrointestinal and pancreatic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3273.
- Published
- 2019
13. The anti-tumor effects of cetuximab in combination with VTX-2337 are T cell dependent
- Author
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Yinwen Cheng, Nicholas Borcherding, Ayomide Ogunsakin, Caitlin D. Lemke-Miltner, Katherine N. Gibson-Corley, Anand Rajan, Allen B. Choi, Wattawan Wongpattaraworakul, Carlos H. F. Chan, Aliasger K. Salem, George J. Weiner, and Andrean L. Simons
- Subjects
Medicine ,Science - Abstract
Abstract The Toll-like receptor 8 (TLR8) agonist VTX-2337 (motolimod) is an anti-cancer immunotherapeutic agent that is believed to augment natural killer (NK) and dendritic cell (DC) activity. The goal of this work is to examine the role of TLR8 expression/activity in head and neck squamous cell carcinoma (HNSCC) to facilitate the prediction of responders to VTX-2337-based therapy. The prognostic role of TLR8 expression in HNSCC patients was assessed by TCGA and tissue microarray analyses. The anti-tumor effect of VTX-2337 was determined in SCCVII/C3H, mEERL/C57Bl/6 and TUBO-human EGFR/BALB/c syngeneic mouse models. The effect of combined VTX-2337 and cetuximab treatment on tumor growth, survival and immune cell recruitment was assessed. TLR8 expression was associated with CD8+ T cell infiltration and favorable survival outcomes. VTX-2337 delayed tumor growth in all 3 syngeneic mouse models and significantly increased the survival of cetuximab-treated mice. The anti-tumor effects of VTX-2337+ cetuximab were accompanied by increased splenic lymphoid DCs and IFNγ+ CD4+ and tumor-specific CD8+ T cells. Depletion of CD4+ T cells, CD8+ T cells and NK cells were all able to abolish the anti-tumor effect of VTX-2337+ cetuximab. Altogether, VTX-2337 remains promising as an adjuvant for cetuximab-based therapy however patients with high TLR8 expression may be more likely to derive benefit from this drug combination compared to patients with low TLR8 expression.
- Published
- 2021
- Full Text
- View/download PDF
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