90 results on '"Clare Y. Slaney"'
Search Results
2. Genetic Redirection of T Cells for the Treatment of Pancreatic Cancer
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Aesha I. Ali, Amanda J. Oliver, Tinaz Samiei, Jack D. Chan, Michael H. Kershaw, and Clare Y. Slaney
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chimeric antigen receptor ,pancreatic cancer ,tumor microenvironment ,pancreatic ductal adenocarcinoma ,adoptive cell transfer ,immunotherapy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Conventional treatments for pancreatic cancer are largely ineffective, and the prognosis for the vast majority of patients is poor. Clearly, new treatment options are desperately needed. Immunotherapy offers hope for the development of treatments for pancreatic cancer. A central requirement for the efficacy of this approach is the existence of cancer antigen-specific T cells, but these are often not present or difficult to isolate for most pancreatic tumors. Nevertheless, specific T cells can be generated using genetic modification to express chimeric antigen receptors (CAR), which can enable T cell responses against pancreatic tumor cells. CAR T cells can be produced ex vivo and expanded in vitro for infusion into patients. Remarkable responses have been documented using CAR T cells against several malignancies, including leukemias and lymphomas. Based on these successes, the extension of CAR T cell therapy for pancreatic cancer holds great promise. However, there are a number of challenges that limit the full potential of CAR T cell therapies for pancreatic cancer, including the highly immunosuppressive tumor microenvironment (TME). In this article, we will review the recent progress in using CAR T cells in pancreatic cancer preclinical and clinical settings, discuss hurdles for utilizing the full potential of CAR T cell therapy and propose research strategies and future perspectives. Research into the use of CAR T cell therapy in pancreatic cancer setting is rapidly gaining momentum and understanding strategies to overcome the current challenges in the pancreatic cancer setting will allow the development of effective CAR T cell therapies, either alone or in combination with other treatments to benefit pancreatic cancer patients.
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- 2019
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3. Tissue-Dependent Tumor Microenvironments and Their Impact on Immunotherapy Responses
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Amanda J. Oliver, Peter K. H. Lau, Ashleigh S. Unsworth, Sherene Loi, Phillip K. Darcy, Michael H. Kershaw, and Clare Y. Slaney
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tumor microenvironment ,tissue-specific microenvironment ,immunotherapy ,immunosuppression ,anticancer therapy ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Recent advances in cancer immunology have led to a better understanding of the role of the tumor microenvironment (TME) in tumor initiation, progression, and metastasis. Tumors can occur at many locations within the body and coevolution between malignant tumor cells and non-malignant cells sculpts the TME at these sites. It has become increasingly clear that there are specific differences of the TMEs at different anatomical locations, and these tissue-specific TMEs regulate tumor growth, determine metastatic progression, and impact on the outcome of therapy responses. Herein, we review the scientific advances in understanding tissue-specific TMEs, discuss their impact on immunotherapeutic response, and assess the current clinical knowledge in this emerging field. A deeper understanding of the tissue-specific TME will help to develop effective immunotherapies against tumors and their metastases and assist in predicting clinical outcomes.
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- 2018
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4. Novel combination immunotherapy for pancreatic cancer: potent anti‐tumor effects with CD40 agonist and interleukin‐15 treatment
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Jonas RM Van Audenaerde, Elly Marcq, Bianca vonScheidt, Ashleigh S Davey, Amanda J Oliver, Jorrit De Waele, Delphine Quatannens, Jinthe Van Loenhout, Patrick Pauwels, Geert Roeyen, Filip Lardon, Clare Y Slaney, Marc Peeters, Michael H Kershaw, Phillip K Darcy, and Evelien LJM Smits
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CD40 agonist ,combination immunotherapy ,interleukin‐15 ,natural killer cells ,pancreatic cancer ,T cells ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Abstract Objectives With the poorest 5‐year survival of all cancers, improving treatment for pancreatic cancer is one of the biggest challenges in cancer research. We sought to explore the potential of combining both priming and activation of the immune system. To achieve this, we combined a CD40 agonist with interleukin‐15 and tested its potential in pancreatic cancer. Methods Response to this combination regimen was assessed in pancreatic ductal adenocarcinoma mouse models, and a thorough analysis of the tumor microenvironment was performed. Results We demonstrated profound reduction in tumor growth and increased survival of mice with the majority of mice being cured when both agents were combined, including an unprecedented 8‐fold dose reduction of CD40 agonist without losing any efficacy. RNAseq analysis showed involvement of natural killer (NK) cell‐ and T‐cell‐mediated anti‐tumor responses and the importance of antigen‐presenting cell pathways. This combination resulted in enhanced infiltration of tumors by both T cells and NK cells, as well as a striking increase in the ratio of CD8+ T cells over Tregs. We also observed a significant increase in numbers of dendritic cells (DCs) in tumor‐draining lymph nodes, particularly CD103+ DCs with cross‐presentation potential. A critical role for CD8+ T cells and involvement of NK cells in the anti‐tumor effect was highlighted. Importantly, strong immune memory was established, with an increase in memory CD8+ T cells only when both interleukin‐15 and the CD40 agonist were combined. Conclusion These novel preclinical data support initiation of a first‐in‐human clinical trial with this combination immunotherapy strategy in pancreatic cancer.
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- 2020
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5. Supplementary Figure Legend from Loss of Host Type-I IFN Signaling Accelerates Metastasis and Impairs NK-cell Antitumor Function in Multiple Models of Breast Cancer
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Belinda S. Parker, Andreas Möller, Daniel M. Andrews, Paul J. Hertzog, Robin L. Anderson, Weisan Chen, Christina S. Wong, Peter Lock, Edwin D. Hawkins, Erin C. Lucas, Bradley N. Bidwell, Kun Xiao, Krishnath M. Jayatilleke, Clare Y. Slaney, Nikola Baschuk, and Jai Rautela
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Supplementary Figure Legend from Loss of Host Type-I IFN Signaling Accelerates Metastasis and Impairs NK-cell Antitumor Function in Multiple Models of Breast Cancer
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- 2023
6. Figure S2 from Dual PD-1 and CTLA-4 Checkpoint Blockade Promotes Antitumor Immune Responses through CD4+Foxp3− Cell–Mediated Modulation of CD103+ Dendritic Cells
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Phillip K. Darcy, Nicole M. Haynes, Michael H. Kershaw, Sherene Loi, Joseph A. Trapani, Clare Y. Slaney, Sherly Mardiana, Liza B. John, Nicole Milenkovski, Kevin Sek, Junyun Lai, Imran G. House, Emma V. Petley, Alexander J. Davenport, Lauren Giuffrida, Melissa A. Henderson, and Paul A. Beavis
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Supplementary Figure 2
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- 2023
7. Supplementary Figure 2 from Loss of Host Type-I IFN Signaling Accelerates Metastasis and Impairs NK-cell Antitumor Function in Multiple Models of Breast Cancer
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Belinda S. Parker, Andreas Möller, Daniel M. Andrews, Paul J. Hertzog, Robin L. Anderson, Weisan Chen, Christina S. Wong, Peter Lock, Edwin D. Hawkins, Erin C. Lucas, Bradley N. Bidwell, Kun Xiao, Krishnath M. Jayatilleke, Clare Y. Slaney, Nikola Baschuk, and Jai Rautela
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IL-2 stimulated NK cells derived from Ifnar1-/- or WT mice have comparable cytotoxicity against syngeneic breast tumor lines.
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- 2023
8. Supplementary Figure 3 from Loss of Host Type-I IFN Signaling Accelerates Metastasis and Impairs NK-cell Antitumor Function in Multiple Models of Breast Cancer
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Belinda S. Parker, Andreas Möller, Daniel M. Andrews, Paul J. Hertzog, Robin L. Anderson, Weisan Chen, Christina S. Wong, Peter Lock, Edwin D. Hawkins, Erin C. Lucas, Bradley N. Bidwell, Kun Xiao, Krishnath M. Jayatilleke, Clare Y. Slaney, Nikola Baschuk, and Jai Rautela
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Immune suppressor cell and T lymphocyte accumulation in the peripheral blood of WT and Ifnar1-/- mice.
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- 2023
9. Data from Dual PD-1 and CTLA-4 Checkpoint Blockade Promotes Antitumor Immune Responses through CD4+Foxp3− Cell–Mediated Modulation of CD103+ Dendritic Cells
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Phillip K. Darcy, Nicole M. Haynes, Michael H. Kershaw, Sherene Loi, Joseph A. Trapani, Clare Y. Slaney, Sherly Mardiana, Liza B. John, Nicole Milenkovski, Kevin Sek, Junyun Lai, Imran G. House, Emma V. Petley, Alexander J. Davenport, Lauren Giuffrida, Melissa A. Henderson, and Paul A. Beavis
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Immunotherapy is widely accepted as a powerful new treatment modality for the treatment of cancer. The most successful form of immunotherapy to date has been the blockade of the immune checkpoints PD-1 and CTLA-4. Combining inhibitors of both PD-1 and CTLA-4 increases the proportion of patients who respond to immunotherapy. However, most patients still do not respond to checkpoint inhibitors, and prognostic biomarkers are currently lacking. Therefore, a better understanding of the mechanism by which these checkpoint inhibitors enhance antitumor immune responses is required to more accurately predict which patients are likely to respond and further enhance this treatment modality. Our current study of two mouse tumor models revealed that CD4+Foxp3− cells activated by dual PD-1/CTLA-4 blockade modulated the myeloid compartment, including activation of conventional CD103+ dendritic cells (DC) and expansion of a myeloid subset that produces TNFα and iNOS (TIP-DCs). CD4+Foxp3− T cell–mediated activation of CD103+ DCs resulted in enhanced IL12 production by these cells and IL12 enhanced the therapeutic effect of dual PD-1/CTLA-4 blockade. Given the importance of these myeloid subsets in the antitumor immune response, our data point to a previously underappreciated role of CD4+Foxp3− cells in modulating this arm of the antitumor immune response. Cancer Immunol Res; 6(9); 1069–81. ©2018 AACR.
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- 2023
10. Data from Loss of Host Type-I IFN Signaling Accelerates Metastasis and Impairs NK-cell Antitumor Function in Multiple Models of Breast Cancer
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Belinda S. Parker, Andreas Möller, Daniel M. Andrews, Paul J. Hertzog, Robin L. Anderson, Weisan Chen, Christina S. Wong, Peter Lock, Edwin D. Hawkins, Erin C. Lucas, Bradley N. Bidwell, Kun Xiao, Krishnath M. Jayatilleke, Clare Y. Slaney, Nikola Baschuk, and Jai Rautela
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Metastatic progression is the major cause of breast cancer–related mortality. By examining multiple syngeneic preclinical breast cancer models in mice lacking a functional type-I interferon receptor (Ifnar1−/− mice), we show that host-derived type-I interferon (IFN) signaling is a critical determinant of metastatic spread that is independent of primary tumor growth. In particular, we show that bone metastasis can be accelerated in Balb/c Ifnar1−/− mice bearing either 4T1 or 66cl4 orthotopic tumors and, for the first time, present data showing the development of bone metastasis in the C57Bl/6 spontaneous MMTV-PyMT–driven model of tumorigenesis. Further exploration of these results revealed that endogenous type-I IFN signaling to the host hematopoietic system is a key determinant of metastasis-free survival and critical to the responsiveness of the circulating natural killer (NK)–cell population. We find that in vivo–stimulated NK cells derived from wild-type, but not Ifnar1−/−, mice can eliminate the 4T1 and 66cl4 breast tumor lines with varying kinetics in vitro. Together, this study indicates that the dysregulated immunity resulting from a loss of host type-I IFN signaling is sufficient to drive metastasis, and provides a rationale for targeting the endogenous type-I IFN pathway as an antimetastatic strategy. Cancer Immunol Res; 3(11); 1207–17. ©2015 AACR.
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- 2023
11. Supplementary Figure 4 from Loss of Host Type-I IFN Signaling Accelerates Metastasis and Impairs NK-cell Antitumor Function in Multiple Models of Breast Cancer
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Belinda S. Parker, Andreas Möller, Daniel M. Andrews, Paul J. Hertzog, Robin L. Anderson, Weisan Chen, Christina S. Wong, Peter Lock, Edwin D. Hawkins, Erin C. Lucas, Bradley N. Bidwell, Kun Xiao, Krishnath M. Jayatilleke, Clare Y. Slaney, Nikola Baschuk, and Jai Rautela
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Anti-proliferative effects and production of type-I IFN by balb/c syngeneic breast tumor cell lines.
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- 2023
12. Supplementary Figure 1 from Loss of Host Type-I IFN Signaling Accelerates Metastasis and Impairs NK-cell Antitumor Function in Multiple Models of Breast Cancer
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Belinda S. Parker, Andreas Möller, Daniel M. Andrews, Paul J. Hertzog, Robin L. Anderson, Weisan Chen, Christina S. Wong, Peter Lock, Edwin D. Hawkins, Erin C. Lucas, Bradley N. Bidwell, Kun Xiao, Krishnath M. Jayatilleke, Clare Y. Slaney, Nikola Baschuk, and Jai Rautela
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Loss of hematopoietic Ifnar1 reduces metastasis-free survival in the 4T1.2 model.
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- 2023
13. Supplementary Figure 5 from Dual-specific Chimeric Antigen Receptor T Cells and an Indirect Vaccine Eradicate a Variety of Large Solid Tumors in an Immunocompetent, Self-antigen Setting
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Michael H. Kershaw, Phillip K. Darcy, Paul Neeson, Nicholas P. Restifo, Steven A. Rosenberg, Zhiya Yu, Aesha Ali, Michele W. Teng, Mark J. Smyth, Ricky W. Johnstone, Joseph A. Trapani, H. Miles Prince, Sarah Ellis, David C. Tscharke, Sherly Mardiana, Jennifer A. Westwood, Paul A. Beavis, Alexander J. Davenport, Bianca von Scheidt, and Clare Y. Slaney
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CARaMEL T cells persist in long term surviving mice.
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- 2023
14. Supplementary Figure 3 from A Histone Deacetylase Inhibitor, Panobinostat, Enhances Chimeric Antigen Receptor T-cell Antitumor Effect Against Pancreatic Cancer
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Clare Y. Slaney, Michael H. Kershaw, Phillip K. Darcy, Ricky W. Johnstone, Belinda Lee, Yuchen Bai, Xin Du, Jack D. Chan, Amanda J. Oliver, Jian Kang, Daniela G.M. Tantalo, Aaron J. Harrison, Pilar M. Dominguez, Bianca von Scheidt, Minyu Wang, and Aesha I. Ali
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Supplementary Figure 3. Pano induced pancreatic tumor cell apoptosis.
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- 2023
15. Supplementary Figure 2 from A Histone Deacetylase Inhibitor, Panobinostat, Enhances Chimeric Antigen Receptor T-cell Antitumor Effect Against Pancreatic Cancer
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Clare Y. Slaney, Michael H. Kershaw, Phillip K. Darcy, Ricky W. Johnstone, Belinda Lee, Yuchen Bai, Xin Du, Jack D. Chan, Amanda J. Oliver, Jian Kang, Daniela G.M. Tantalo, Aaron J. Harrison, Pilar M. Dominguez, Bianca von Scheidt, Minyu Wang, and Aesha I. Ali
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Supplementary Figure 2. Pancreatic cells are resistant to VV-gp100 oncolysis but sensitive to CAR T cell-mediated cytotoxicity.
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- 2023
16. Supplementary Figure 4 from A Histone Deacetylase Inhibitor, Panobinostat, Enhances Chimeric Antigen Receptor T-cell Antitumor Effect Against Pancreatic Cancer
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Clare Y. Slaney, Michael H. Kershaw, Phillip K. Darcy, Ricky W. Johnstone, Belinda Lee, Yuchen Bai, Xin Du, Jack D. Chan, Amanda J. Oliver, Jian Kang, Daniela G.M. Tantalo, Aaron J. Harrison, Pilar M. Dominguez, Bianca von Scheidt, Minyu Wang, and Aesha I. Ali
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Supplementary Figure 4. Pano did not enhance the cytotoxicity of CARaMEL cells nor oncolysis of VV-gp100.
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- 2023
17. Supplementary Figure 1 from A Histone Deacetylase Inhibitor, Panobinostat, Enhances Chimeric Antigen Receptor T-cell Antitumor Effect Against Pancreatic Cancer
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Clare Y. Slaney, Michael H. Kershaw, Phillip K. Darcy, Ricky W. Johnstone, Belinda Lee, Yuchen Bai, Xin Du, Jack D. Chan, Amanda J. Oliver, Jian Kang, Daniela G.M. Tantalo, Aaron J. Harrison, Pilar M. Dominguez, Bianca von Scheidt, Minyu Wang, and Aesha I. Ali
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Supplementary Figure 1. Panc02-Her2, KPC-Her2 and 24JK-Her2 cells express comparable levels of Her2.
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- 2023
18. Supplementary Figure 5 from A Histone Deacetylase Inhibitor, Panobinostat, Enhances Chimeric Antigen Receptor T-cell Antitumor Effect Against Pancreatic Cancer
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Clare Y. Slaney, Michael H. Kershaw, Phillip K. Darcy, Ricky W. Johnstone, Belinda Lee, Yuchen Bai, Xin Du, Jack D. Chan, Amanda J. Oliver, Jian Kang, Daniela G.M. Tantalo, Aaron J. Harrison, Pilar M. Dominguez, Bianca von Scheidt, Minyu Wang, and Aesha I. Ali
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Supplementary Figure 5. Pano did not alter Her2 or H2-Db expression on Panc02-Her2 tumor cells in vivo and CARaMEL cells were detectable over 100 days in ACTIV+ Pano treated mice.
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- 2023
19. Supplementary Figure 3 from Dual-specific Chimeric Antigen Receptor T Cells and an Indirect Vaccine Eradicate a Variety of Large Solid Tumors in an Immunocompetent, Self-antigen Setting
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Michael H. Kershaw, Phillip K. Darcy, Paul Neeson, Nicholas P. Restifo, Steven A. Rosenberg, Zhiya Yu, Aesha Ali, Michele W. Teng, Mark J. Smyth, Ricky W. Johnstone, Joseph A. Trapani, H. Miles Prince, Sarah Ellis, David C. Tscharke, Sherly Mardiana, Jennifer A. Westwood, Paul A. Beavis, Alexander J. Davenport, Bianca von Scheidt, and Clare Y. Slaney
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CAR T cells lacking the pMEL TCR are less effective than CARaMEL T cells at inhibiting tumor growth.
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- 2023
20. Supplementary Figure 1 from Dual-specific Chimeric Antigen Receptor T Cells and an Indirect Vaccine Eradicate a Variety of Large Solid Tumors in an Immunocompetent, Self-antigen Setting
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Michael H. Kershaw, Phillip K. Darcy, Paul Neeson, Nicholas P. Restifo, Steven A. Rosenberg, Zhiya Yu, Aesha Ali, Michele W. Teng, Mark J. Smyth, Ricky W. Johnstone, Joseph A. Trapani, H. Miles Prince, Sarah Ellis, David C. Tscharke, Sherly Mardiana, Jennifer A. Westwood, Paul A. Beavis, Alexander J. Davenport, Bianca von Scheidt, and Clare Y. Slaney
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Dual-specific T cells respond against both gp100 and Her2.
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- 2023
21. Supplementary Figures 1 through 8 from A Multifunctional Role for Adjuvant Anti-4-1BB Therapy in Augmenting Antitumor Response by Chimeric Antigen Receptor T Cells
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Phillip K. Darcy, Paul A. Beavis, Michael H. Kershaw, Nicole M. Haynes, Sherene Loi, Paul J. Neeson, Joseph A. Trapani, Alexander J. Davenport, Lauren Giuffrida, Bianca von Scheidt, Clare Y. Slaney, Melissa A. Henderson, Liza B. John, and Sherly Mardiana
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Supplementary Figure S1. Expression of activation and memory markers on transduced mouse T cells. Supplementary Figure S2. CAR T cell cytotoxic responses are not modulated by anti-4-1BB mAb therapy. Supplementary Figure S3. Her2 expression level on the mouse breast cancer cell line e0771-Her2 is comparable to the Her2-overexpressing human breast cancer cell line SKBR3. Supplementary Figure S4. Tumor weight is significantly reduced following CAR T cell and alpha-4-1BB therapy. Supplementary Figure S5. Anti-4-1BB therapy does not modulate the frequency of transferred or endogenous CD8+ tumor-infiltrating T cells. Supplementary Figure S6. Anti-4-1BB therapy modulates the frequency of mature dendritic cells in tumors and draining lymph nodes. Supplementary Figure S7. Anti-4-1BB does not modulate the frequency of MDSCs and DCs in RAG -/- mice. Supplementary Figure S8. Anti-4-1BB therapy drives maturation of NK cells.
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- 2023
22. Supplementary Figure 2 from Dual-specific Chimeric Antigen Receptor T Cells and an Indirect Vaccine Eradicate a Variety of Large Solid Tumors in an Immunocompetent, Self-antigen Setting
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Michael H. Kershaw, Phillip K. Darcy, Paul Neeson, Nicholas P. Restifo, Steven A. Rosenberg, Zhiya Yu, Aesha Ali, Michele W. Teng, Mark J. Smyth, Ricky W. Johnstone, Joseph A. Trapani, H. Miles Prince, Sarah Ellis, David C. Tscharke, Sherly Mardiana, Jennifer A. Westwood, Paul A. Beavis, Alexander J. Davenport, Bianca von Scheidt, and Clare Y. Slaney
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High dose IL-2 enables durable tumor regression and proliferation of T cells.
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- 2023
23. Supplementary Figure 6 from Dual-specific Chimeric Antigen Receptor T Cells and an Indirect Vaccine Eradicate a Variety of Large Solid Tumors in an Immunocompetent, Self-antigen Setting
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Michael H. Kershaw, Phillip K. Darcy, Paul Neeson, Nicholas P. Restifo, Steven A. Rosenberg, Zhiya Yu, Aesha Ali, Michele W. Teng, Mark J. Smyth, Ricky W. Johnstone, Joseph A. Trapani, H. Miles Prince, Sarah Ellis, David C. Tscharke, Sherly Mardiana, Jennifer A. Westwood, Paul A. Beavis, Alexander J. Davenport, Bianca von Scheidt, and Clare Y. Slaney
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Cytokines present in serum of ACTIV-treated mice.
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- 2023
24. Supplementary Figure 8 from A Histone Deacetylase Inhibitor, Panobinostat, Enhances Chimeric Antigen Receptor T-cell Antitumor Effect Against Pancreatic Cancer
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Clare Y. Slaney, Michael H. Kershaw, Phillip K. Darcy, Ricky W. Johnstone, Belinda Lee, Yuchen Bai, Xin Du, Jack D. Chan, Amanda J. Oliver, Jian Kang, Daniela G.M. Tantalo, Aaron J. Harrison, Pilar M. Dominguez, Bianca von Scheidt, Minyu Wang, and Aesha I. Ali
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Supplementary Figure 8. Proposed mechanisms and clinical application for the ACTIV+Pano treatment.
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- 2023
25. Data from A Multifunctional Role for Adjuvant Anti-4-1BB Therapy in Augmenting Antitumor Response by Chimeric Antigen Receptor T Cells
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Phillip K. Darcy, Paul A. Beavis, Michael H. Kershaw, Nicole M. Haynes, Sherene Loi, Paul J. Neeson, Joseph A. Trapani, Alexander J. Davenport, Lauren Giuffrida, Bianca von Scheidt, Clare Y. Slaney, Melissa A. Henderson, Liza B. John, and Sherly Mardiana
- Abstract
Adoptive immunotherapy utilizing chimeric antigen receptor (CAR) T cells has demonstrated high success rates in hematologic cancers, but results against solid malignancies have been limited to date, due in part to the immunosuppressive tumor microenvironment. Activation of the 4-1BB (CD137) pathway using an agonistic α-4-1BB antibody is known to provide strong costimulatory signals for augmenting and diversifying T-cell responses. We therefore hypothesized that a combination of α-4-1BB and CAR T-cell therapy would result in improved antitumor responses. Using a human-Her2 self-antigen mouse model, we report here that α-4-1BB significantly enhanced CAR T-cell efficacy directed against the Her2 antigen in two different established solid tumor settings. Treatment also increased the expression of IFNγ and the proliferation marker Ki67 in tumor-infiltrating CAR T cells when combined with α-4-1BB. Strikingly, α-4-1BB significantly reduced host immunosuppressive cells at the tumor site, including regulatory T cells and myeloid-derived suppressor cells, correlating with an increased therapeutic response. We conclude that α-4-1BB has a multifunctional role for enhancing CAR T-cell responses and that this combination therapy has high translational potential, given current phase I/II clinical trials with α-4-1BB against various types of cancer. Cancer Res; 77(6); 1296–309. ©2017 AACR.
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- 2023
26. Supplementary Figure 7 from A Histone Deacetylase Inhibitor, Panobinostat, Enhances Chimeric Antigen Receptor T-cell Antitumor Effect Against Pancreatic Cancer
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Clare Y. Slaney, Michael H. Kershaw, Phillip K. Darcy, Ricky W. Johnstone, Belinda Lee, Yuchen Bai, Xin Du, Jack D. Chan, Amanda J. Oliver, Jian Kang, Daniela G.M. Tantalo, Aaron J. Harrison, Pilar M. Dominguez, Bianca von Scheidt, Minyu Wang, and Aesha I. Ali
- Abstract
Supplementary Figure 7. No cytokine storm was observed in WAP- and MMTV-Her2 mice post the ACTIV+Pano treatment.
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- 2023
27. Data from Dual-specific Chimeric Antigen Receptor T Cells and an Indirect Vaccine Eradicate a Variety of Large Solid Tumors in an Immunocompetent, Self-antigen Setting
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Michael H. Kershaw, Phillip K. Darcy, Paul Neeson, Nicholas P. Restifo, Steven A. Rosenberg, Zhiya Yu, Aesha Ali, Michele W. Teng, Mark J. Smyth, Ricky W. Johnstone, Joseph A. Trapani, H. Miles Prince, Sarah Ellis, David C. Tscharke, Sherly Mardiana, Jennifer A. Westwood, Paul A. Beavis, Alexander J. Davenport, Bianca von Scheidt, and Clare Y. Slaney
- Abstract
Purpose: While adoptive transfer of T cells bearing a chimeric antigen receptor (CAR) can eliminate substantial burdens of some leukemias, the ultimate challenge remains the eradication of large solid tumors for most cancers. We aimed to develop an immunotherapy approach effective against large tumors in an immunocompetent, self-antigen preclinical mouse model.Experimental Design: In this study, we generated dual-specific T cells expressing both a CAR specific for Her2 and a TCR specific for the melanocyte protein (gp100). We used a regimen of adoptive cell transfer incorporating vaccination (ACTIV), with recombinant vaccinia virus expressing gp100, to treat a range of tumors including orthotopic breast tumors and large liver tumors.Results: ACTIV therapy induced durable complete remission of a variety of Her2+ tumors, some in excess of 150 mm2, in immunocompetent mice expressing Her2 in normal tissues, including the breast and brain. Vaccinia virus induced extensive proliferation of T cells, leading to massive infiltration of T cells into tumors. Durable tumor responses required the chemokine receptor CXCR3 and exogenous IL2, but were independent of IFNγ. Mice were resistant to tumor rechallenge, indicating immune memory involving epitope spreading. Evidence of limited neurologic toxicity was observed, associated with infiltration of cerebellum by T cells, but was only transient.Conclusions: This study supports a view that it is possible to design a highly effective combination immunotherapy for solid cancers, with acceptable transient toxicity, even when the target antigen is also expressed in vital tissues. Clin Cancer Res; 23(10); 2478–90. ©2016 AACR.
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- 2023
28. Supplementary Figure 4 from Dual-specific Chimeric Antigen Receptor T Cells and an Indirect Vaccine Eradicate a Variety of Large Solid Tumors in an Immunocompetent, Self-antigen Setting
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Michael H. Kershaw, Phillip K. Darcy, Paul Neeson, Nicholas P. Restifo, Steven A. Rosenberg, Zhiya Yu, Aesha Ali, Michele W. Teng, Mark J. Smyth, Ricky W. Johnstone, Joseph A. Trapani, H. Miles Prince, Sarah Ellis, David C. Tscharke, Sherly Mardiana, Jennifer A. Westwood, Paul A. Beavis, Alexander J. Davenport, Bianca von Scheidt, and Clare Y. Slaney
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ACTIV therapy induces cytokine secretion and apoptosis of tumor cells.
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- 2023
29. Data from BMP4 Inhibits Breast Cancer Metastasis by Blocking Myeloid-Derived Suppressor Cell Activity
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Robin L. Anderson, Bedrich L. Eckhardt, Jai Rautela, Cameron N. Johnstone, Belinda S. Parker, Bradley N. Bidwell, Clare Y. Slaney, and Yuan Cao
- Abstract
The TGFβ growth factor family member BMP4 is a potent suppressor of breast cancer metastasis. In the mouse, the development of highly metastatic mammary tumors is associated with an accumulation of myeloid-derived suppressor cells (MDSC), the numbers of which are reduced by exogenous BMP4 expression. MDSCs are undetectable in naïve mice but can be induced by treatment with granulocyte colony-stimulating factor (G-CSF/Csf3) or by secretion of G-CSF from the tumor. Both tumor-induced and G-CSF–induced MDSCs effectively suppress T-cell activation and proliferation, leading to metastatic enhancement. BMP4 reduces the expression and secretion of G-CSF by inhibiting NF-κB (Nfkb1) activity in human and mouse tumor lines. Because MDSCs correlate with poor prognosis in patients with breast cancer, therapies based on activation of BMP4 signaling may offer a novel treatment strategy for breast cancer. Cancer Res; 74(18); 5091–102. ©2014 AACR.
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- 2023
30. Data Supplement from BMP4 Inhibits Breast Cancer Metastasis by Blocking Myeloid-Derived Suppressor Cell Activity
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Robin L. Anderson, Bedrich L. Eckhardt, Jai Rautela, Cameron N. Johnstone, Belinda S. Parker, Bradley N. Bidwell, Clare Y. Slaney, and Yuan Cao
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Supplementary Figure 4. Differential suppression of CD4+ and CD8+ T cell activation by granulocytic and monocytic MDSC isolated from 4T1.2 or 4T1.2-BMP4 tumor bearing mice
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- 2023
31. Cellular networks controlling T cell persistence in adoptive cell therapy
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Clare Y Slaney, Jack D Chan, Junyun Lai, Axel Kallies, Phillip K. Darcy, and Paul A. Beavis
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0301 basic medicine ,History ,Effector ,medicine.medical_treatment ,T cell ,Context (language use) ,Immunotherapy ,Biology ,Chimeric antigen receptor ,Computer Science Applications ,Education ,Cell therapy ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,T cell differentiation ,Cancer research ,medicine ,Epigenetics ,030215 immunology - Abstract
The antitumour activity of endogenous or adoptively transferred tumour-specific T cells is highly dependent on their differentiation status. It is now apparent that less differentiated T cells compared with fully differentiated effector T cells have better antitumour therapeutic effects owing to their enhanced capacity to expand and their long-term persistence. In patients with cancer, the presence of endogenous or adoptively transferred T cells with stem-like memory or precursor phenotype correlates with improved therapeutic outcomes. Advances in our understanding of T cell differentiation states at the epigenetic and transcriptional levels have led to the development of novel methods to generate tumour-specific T cells - namely, chimeric antigen receptor T cells - that are more persistent and resistant to the development of dysfunction. These include the use of novel culture methods before infusion, modulation of transcriptional, metabolic and/or epigenetic programming, and strategies that fine-tune antigen receptor signalling. This Review discusses existing barriers and strategies to overcome them for successful T cell expansion and persistence in the context of adoptive T cell immunotherapy for solid cancers.
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- 2021
32. Tissue-specific tumour microenvironments are an emerging determinant of immunotherapy responses
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Clare Y Slaney, Amanda J Oliver, Phillip K. Darcy, and Michael H. Kershaw
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Pulmonary and Respiratory Medicine ,business.industry ,medicine.medical_treatment ,Cancer research ,MEDLINE ,Medicine ,Tissue specific ,Cancer ,Immunotherapy ,Editorial on Immunotherapy and Tumor Microenvironment ,Nivolumab ,business ,medicine.disease - Published
- 2020
33. Cross‐talk between tumors at anatomically distinct sites
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Phillip K. Darcy, Michael H. Kershaw, Joseph A. Trapani, Amanda J Oliver, and Clare Y Slaney
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0301 basic medicine ,Cell type ,Cell Communication ,Biology ,T-Lymphocytes, Regulatory ,Biochemistry ,Extracellular Vesicles ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,Tumor Microenvironment ,medicine ,Animals ,Humans ,Neoplasm Metastasis ,Molecular Biology ,Tumor microenvironment ,Tumor Necrosis Factor-alpha ,Myeloid-Derived Suppressor Cells ,fungi ,Granulocyte-Macrophage Colony-Stimulating Factor ,food and beverages ,Abscopal effect ,Cancer ,Cell Biology ,Neoplastic Cells, Circulating ,medicine.disease ,Primary tumor ,Microvesicles ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer cell ,Neoplastic Stem Cells ,Myeloid-derived Suppressor Cell ,Cancer research ,Immunotherapy ,Signal Transduction - Abstract
Cancer tissue is not homogenous, and individual metastases at different anatomical locations can differ from the primary tumor and from one another in both their morphology and cellular composition, even within an individual patient. Tumors are composed of cancer cells and a range of other cell types, which, together with a variety of secreted molecules, collectively comprise the tumor microenvironment (TME). Cells of the TME can communicate with each other and with distant tissues in a form of molecular cross-talk to influence their growth and function. Cross-talk between cancer cells and local immune cells is well described and can lead to the induction of local immunosuppression. Recently, it has become apparent that tumors located remotely from each other, can engage in cross-talk that can influence their responsiveness to various therapies, including immunotherapy. In this article, we review studies that describe how tumors systemically communicate with distant tissues through motile cells, extracellular vesicles, and secreted molecules that can affect their function. In addition, we summarize evidence from mouse studies and the clinic that indicate an ability of some tumors to influence the progression and therapeutic responses of other tumors in different anatomical locations.
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- 2020
34. Insights into Cancer Immunotherapies: Recent Breakthroughs, Opportunities, and Challenges
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Evan G. Pappas, Michael H. Kershaw, and Clare Y. Slaney
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Cancer Research ,Oncology - Abstract
This Special Issue reminds us that, although incredible developments have occurred in the field of cancer immunotherapy, there is still plenty of room for improvement [...]
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- 2023
35. Embryonic Lethality in Homozygous Human Her-2 Transgenic Mice Due to Disruption of the Pds5b Gene.
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Carmen S M Yong, Janelle Sharkey, Belinda Duscio, Ben Venville, Wei-Zen Wei, Richard F Jones, Clare Y Slaney, Gisela Mir Arnau, Anthony T Papenfuss, Jan Schröder, Phillip K Darcy, and Michael H Kershaw
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Medicine ,Science - Abstract
The development of antigen-targeted therapeutics is dependent on the preferential expression of tumor-associated antigens (TAA) at targetable levels on the tumor. Tumor-associated antigens can be generated de novo or can arise from altered expression of normal basal proteins, such as the up-regulation of human epidermal growth factor receptor 2 (Her2/ErbB2). To properly assess the development of Her2 therapeutics in an immune tolerant model, we previously generated a transgenic mouse model in which expression of the human Her2 protein was present in both the brain and mammary tissue. This mouse model has facilitated the development of Her2 targeted therapies in a clinically relevant and suitable model. While heterozygous Her2+/- mice appear to develop in a similar manner to wild type mice (Her2-/-), it has proven difficult to generate homozygous Her2+/+ mice, potentially due to embryonic lethality. In this study, we performed whole genome sequencing to determine if the integration site of the Her2 transgene was responsible for this lethality. Indeed, we report that the Her2 transgene had integrated into the Pds5b (precocious dissociation of sisters) gene on chromosome 5, as a 162 copy concatemer. Furthermore, our findings demonstrate that Her2+/+ mice, similar to Pds5b-/- mice, are embryonic lethal and confirm the necessity for Pds5b in embryonic development. This study confirms the value of whole genome sequencing in determining the integration site of transgenes to gain insight into associated phenotypes.
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- 2015
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36. Enterotoxins can support CAR T cells against solid tumors
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Phillip K. Darcy, Amanda J Oliver, Clare Y Slaney, Jack D Chan, Fiona Clow, Bianca von Scheidt, John D. Fraser, Michael H. Kershaw, Aesha I. Ali, Kylie M. Quinn, Metta K. Jana, and Minyu Wang
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0301 basic medicine ,T-Lymphocytes ,T cell ,Lymphocyte ,Receptors, Antigen, T-Cell ,Antigen-Presenting Cells ,Immunotherapy, Adoptive ,Enterotoxins ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,Neoplasms ,medicine ,Animals ,Humans ,CD40 Antigens ,Antigen-presenting cell ,Cell Proliferation ,Multidisciplinary ,CD40 ,biology ,Chemistry ,T-cell receptor ,Cross-presentation ,Biological Sciences ,Chimeric antigen receptor ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,human activities - Abstract
Responses of solid tumors to chimeric antigen receptor (CAR) T cell therapy are often minimal. This is potentially due to a lack of sustained activation and proliferation of CAR T cells when encountering antigen in a profoundly immunosuppressive tumor microenvironment. In this study, we investigate if inducing an interaction between CAR T cells and antigen-presenting cells (APCs) in lymphoid tissue, away from an immunosuppressive microenvironment, could enhance solid-tumor responses. We combined CAR T cell transfer with the bacterial enterotoxin staphylococcal enterotoxin-B (SEB), which naturally links a proportion of T cell receptor (TCR) Vβ subtypes to MHC-II, present on APCs. CAR T cell proliferation and function was significantly enhanced by SEB. Solid tumor-growth inhibition in mice was increased when CAR T cells were administered in combination with SEB. CAR T cell expansion in lymphoid tissue was demonstrated, and inhibition of lymphocyte egress from lymph nodes using FTY720 abrogated the benefit of SEB. We also demonstrate that a bispecific antibody, targeting a c-Myc tag on CAR T cells and cluster of differentiation 40 (CD40), could also enhance CAR T cell activity and mediate increased antitumor activity of CAR T cells. These model systems serve as proof-of-principle that facilitating the interaction of CAR T cells with APCs can enhance their ability to mediate antitumor activity.
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- 2019
37. Enhancing co-stimulation of CAR T cells to improve treatment outcomes in solid cancers
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Michael H. Kershaw, Xin Du, Bianca von Scheidt, Aaron J Harrison, and Clare Y Slaney
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biology ,Effector ,business.industry ,T cell ,medicine.medical_treatment ,Cancer ,General Medicine ,Immunotherapy ,medicine.disease ,Chimeric antigen receptor ,medicine.anatomical_structure ,Co-stimulation ,Lymphocyte costimulation ,medicine ,Cancer research ,biology.protein ,Antibody ,business ,human activities - Abstract
Summary Co-stimulation is a fundamental component of T cell biology and plays a key role in determining the quality of T cell proliferation, differentiation, and memory formation. T cell-based immunotherapies, such as chimeric antigen receptor (CAR) T cell immunotherapy, are no exception. Solid tumours have largely been refractory to CAR T cell therapy owing to an immunosuppressive microenvironment which limits CAR T cell persistence and effector function. In order to eradicate solid cancers, increasingly sophisticated strategies are being developed to deliver these vital co-stimulatory signals to CAR T cells, often specifically within the tumour microenvironment. These include designing novel co-stimulatory domains within the CAR or other synthetic receptors, arming CAR T cells with cytokines or using CAR T cells in combination with agonist antibodies. This review discusses the evolving role of co-stimulation in CAR T cell therapies and the strategies employed to target co-stimulatory pathways in CAR T cells, with a view to improve responses in solid tumours.
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- 2021
38. A Histone Deacetylase Inhibitor, Panobinostat, Enhances Chimeric Antigen Receptor T-cell Antitumor Effect Against Pancreatic Cancer
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Daniela Gm Tantalo, Clare Y Slaney, Amanda J Oliver, Jack D Chan, Aaron J Harrison, Belinda Lee, Minyu Wang, Jian Kang, Bianca von Scheidt, Aesha I. Ali, Michael H. Kershaw, Phillip K. Darcy, Yuchen Bai, Ricky W. Johnstone, Pilar M. Dominguez, and Xin Du
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Cancer Research ,medicine.drug_class ,T cell ,T-Lymphocytes ,Receptors, Antigen, T-Cell ,Biology ,Immunotherapy, Adoptive ,chemistry.chemical_compound ,Mice ,Pancreatic cancer ,Panobinostat ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Receptors, Chimeric Antigen ,Histone deacetylase inhibitor ,T-cell receptor ,Cancer ,medicine.disease ,Xenograft Model Antitumor Assays ,Tumor antigen ,Chimeric antigen receptor ,Histone Deacetylase Inhibitors ,Pancreatic Neoplasms ,medicine.anatomical_structure ,Oncology ,chemistry ,Cancer research - Abstract
Purpose: In this article, we describe a combination chimeric antigen receptor (CAR) T-cell therapy that eradicated the majority of tumors in two immunocompetent murine pancreatic cancer models and a human pancreatic cancer xenograft model. Experimental Design: We used a dual-specific murine CAR T cell that expresses a CAR against the Her2 tumor antigen, and a T-cell receptor (TCR) specific for gp100. As gp100 is also known as pMEL, the dual-specific CAR T cells are thus denoted as CARaMEL cells. A vaccine containing live vaccinia virus coding a gp100 minigene (VV-gp100) was administered to the recipient mice to stimulate CARaMEL cells. The treatment also included the histone deacetylase inhibitor panobinostat (Pano). Results: The combination treatment enabled significant suppression of Her2+ pancreatic cancers leading to the eradication of the majority of the tumors. Besides inducing cancer cell apoptosis, Pano enhanced CAR T-cell gene accessibility and promoted CAR T-cell differentiation into central memory cells. To test the translational potential of this approach, we established a method to transduce human T cells with an anti-Her2 CAR and a gp100-TCR. The exposure of the human T cells to Pano promoted a T-cell central memory phenotype and the combination treatment of human CARaMEL cells and Pano eradicated human pancreatic cancer xenografts in mice. Conclusions: We propose that patients with pancreatic cancer could be treated using a scheme that contains dual-specific CAR T cells, a vaccine that activates the dual-specific CAR T cells through their TCR, and the administration of Pano.
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- 2021
39. Cellular networks controlling T cell persistence in adoptive cell therapy
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Jack D, Chan, Junyun, Lai, Clare Y, Slaney, Axel, Kallies, Paul A, Beavis, and Phillip K, Darcy
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Neoplasms ,T-Lymphocytes ,Cell- and Tissue-Based Therapy ,Animals ,Humans ,Lymphocyte Activation ,Immunotherapy, Adoptive - Abstract
The antitumour activity of endogenous or adoptively transferred tumour-specific T cells is highly dependent on their differentiation status. It is now apparent that less differentiated T cells compared with fully differentiated effector T cells have better antitumour therapeutic effects owing to their enhanced capacity to expand and their long-term persistence. In patients with cancer, the presence of endogenous or adoptively transferred T cells with stem-like memory or precursor phenotype correlates with improved therapeutic outcomes. Advances in our understanding of T cell differentiation states at the epigenetic and transcriptional levels have led to the development of novel methods to generate tumour-specific T cells - namely, chimeric antigen receptor T cells - that are more persistent and resistant to the development of dysfunction. These include the use of novel culture methods before infusion, modulation of transcriptional, metabolic and/or epigenetic programming, and strategies that fine-tune antigen receptor signalling. This Review discusses existing barriers and strategies to overcome them for successful T cell expansion and persistence in the context of adoptive T cell immunotherapy for solid cancers.
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- 2021
40. 453 Novel combination immunotherapy for boosting and priming immune responses in pancreatic cancer: strong anti-tumour effects with interleukin-15 and CD40 agonist treatment
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Bianca von Scheidt, Clare Y Slaney, Geert Roeyen, Michael H. Kershaw, Jorrit De Waele, Delphine Quatannens, Marc Peeters, Amanda J Oliver, Phillip K. Darcy, Elly Marcq, Filip Lardon, Jinthe Van Loenhout, Patrick Pauwels, Ashleigh S Davey, Jonas Van Audenaerde, and Evelien Smits
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CD40 ,biology ,business.industry ,T cell ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,lcsh:RC254-282 ,Natural killer cell ,medicine.anatomical_structure ,Immune system ,Interleukin 15 ,Pancreatic cancer ,medicine ,Cancer research ,biology.protein ,Cytotoxic T cell ,business ,CD8 - Abstract
Background With the poorest 5-year survival of all cancers, improving treatment for pancreatic cancer is one of the biggest challenges in cancer research. In this era of combination immunotherapies, we sought to explore the potential of combining both priming and activation of the immune system. To achieve this, we combined a CD40 agonist with interleukin-15 and tested its potential in pancreatic cancer. Methods Two different mouse models of pancreatic cancer were used to assess the potential of this combination regimen. Therefore, effects on tumour growth kinetics and survival were charted. Differential effects on immune signatures was investigated using RNA sequencing. Functional immune subset involvement was tested using different immune depletion experiments and multicolour flow cytometry in different relevant immune sites. Immune memory was checked using re-challenge experiments. Results We demonstrated profound reduction in tumour growth and increased survival of mice with the majority of mice being cured when both agents were combined, including an unprecedented dose reduction of CD40 agonist without losing any efficacy (fig 1). RNA sequencing analysis showed involvement of natural killer cell and T cell mediated anti-tumour responses and the importance of antigen-presenting cell pathways. This combination resulted in enhanced infiltration of tumours by both cytotoxic T cells and natural killer cells, as well as a striking increase in the ratio of CD8+ T cells over T regulatory cells. We also observed a significant increase in numbers of dendritic cells in tumour draining lymph nodes, particularly CD103+ dendritic cells with cross-presentation potential. A critical role for CD8+ T cells and involvement of natural killer cells in the anti-tumour effect was highlighted. Importantly, strong immune memory was established, with an increase in memory CD8+ T cells only when both interleukin-15 and the CD40 agonist were combined. Conclusions We demonstrated profound synergistic anti-tumour effects upon combination of CD40 agonist and interleukin-15 treatment in mouse models of pancreatic cancer. This preclinical data supports initiation of a first-in-human clinical trial with this combination immunotherapy strategy in pancreatic cancer.
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- 2020
41. Chimeric antigen receptor T cell therapies for thoracic cancers-challenges and opportunities
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Clare Y Slaney, Jack D Chan, Michael H. Kershaw, Phillip K. Darcy, and Aaron J Harrison
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Pulmonary and Respiratory Medicine ,medicine.anatomical_structure ,Text mining ,business.industry ,T cell ,medicine.medical_treatment ,Cancer research ,medicine ,Immunotherapy ,Editorial on Immunotherapy and Tumor Microenvironment ,business ,Chimeric antigen receptor - Published
- 2020
42. Enhancing chimeric antigen receptor T‐cell immunotherapy against cancer using a nanoemulsion‐based vaccine targeting cross‐presenting dendritic cells
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Joseph A. Trapani, Riccardo Dolcetti, Jack D Chan, Ashleigh S Davey, Michael H. Kershaw, Bianca von Scheidt, Phillip K. Darcy, Aesha I. Ali, Clare Y Slaney, Bijun Zeng, Ranjeny Thomas, and Amanda J Oliver
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0301 basic medicine ,lcsh:Immunologic diseases. Allergy ,Adoptive cell transfer ,medicine.medical_treatment ,Immunology ,Antigen presentation ,nanoemulsion ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Cancer immunotherapy ,Clec9A ,vaccine ,medicine ,Immunology and Allergy ,dendritic cells ,General Nursing ,CAR T cells ,biology ,business.industry ,Cross-presentation ,Chimeric antigen receptor ,Ovalbumin ,030104 developmental biology ,cross‐presentation ,030220 oncology & carcinogenesis ,biology.protein ,Cytokine secretion ,Original Article ,business ,lcsh:RC581-607 - Abstract
Objectives Adoptive transfer of chimeric antigen receptor (CAR)‐modified T cells is a form of cancer immunotherapy that has achieved remarkable efficacy in patients with some haematological cancers. However, challenges remain in CAR T‐cell treatment of solid tumours because of tumour‐mediated immunosuppression. Methods We have demonstrated that CAR T‐cell stimulation through T‐cell receptors (TCRs) in vivo can generate durable responses against solid tumours in a variety of murine models. Since Clec9A‐targeting tailored nanoemulsion (Clec9A‐TNE) vaccine enhances antitumour immune responses through selective activation of Clec9A+ cross‐presenting dendritic cells (DCs), we hypothesised that Clec9A‐TNE could prime DCs for antigen presentation to CAR T cells through TCRs and thus improve CAR T‐cell responses against solid tumours. To test this hypothesis, we used CAR T cells expressing transgenic TCRs specific for ovalbumin (OVA) peptides SIINFEKL (CAROTI) or OVA323‐339 (CAROTII). Results We demonstrated that the Clec9A‐TNEs encapsulating full‐length recombinant OVA protein (OVA‐Clec9A‐TNE) improved CAROT T‐cell proliferation and inflammatory cytokine secretion in vitro. Combined treatment using the OVA‐Clec9A‐TNE and CAROT cells resulted in durable responses and some rejections of tumours in immunocompetent mice. Tumour regression was accompanied by enhanced CAROT cell proliferation and infiltration into the tumours. Conclusion Our study presents Clec9A‐TNE as a prospective avenue to enhance CAR T‐cell efficacy for solid cancers., Clec9A‐targeting tailored nanoemulsion (Clec9A‐TNE) induced extensive proliferation, persistence and activation of chimeric antigen receptor (CAR) T cells, leading to the eradication of solid tumours in murine models. This novel approach could lead to the development of new CAR T‐cell therapies against some common solid tumour types in patients.
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- 2020
43. Primary and metastatic breast tumors cross-talk to influence immunotherapy responses
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Aaron J Harrison, Phillip K. Darcy, Amanda J Oliver, Michael H. Kershaw, Simon P. Keam, Bianca von Scheidt, Damien Zanker, Clare Y Slaney, and Daniela Gm Tantalo
- Subjects
0301 basic medicine ,Lung Neoplasms ,T cell ,medicine.medical_treatment ,Immunology ,CD8-Positive T-Lymphocytes ,Lymphocyte Depletion ,Metastasis ,Mice ,03 medical and health sciences ,breast cancer ,0302 clinical medicine ,Breast cancer ,Tumor Microenvironment ,Animals ,metastasis ,Immunology and Allergy ,Medicine ,Lung cancer ,RC254-282 ,Tumor microenvironment ,Lung ,business.industry ,Brief Report ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Immunotherapy ,RC581-607 ,medicine.disease ,tumor cross-talk ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,immunotherapy ,Immunologic diseases. Allergy ,business ,CD8 - Abstract
The presence of a tumor can alter host immunity systematically. The immune-tumor interaction in one site may impact the local immune microenvironment in distal tissues through the circulation, and therefore influence the efficacy of immunotherapies to distant metastases. Improved understanding of the immune-tumor interactions during immunotherapy treatment in a metastatic setting may enhance the efficacy of current immunotherapies. Here we investigate the response to αPD-1/αCTLA4 and trimAb (αDR5, α4-1BB, αCD40) of 67NR murine breast tumors grown simultaneously in the mammary fat pad (MFP) and lung, a common site of breast cancer metastasis, and compared to tumors grown in isolation. Lung tumors present in isolation were resistant to both therapies. However, in MFP and lung tumor-bearing mice, the presence of a MFP tumor could increase lung tumor response to immunotherapy and decrease the number of lung metastases, leading to complete eradication of lung tumors in a proportion of mice. The MFP tumor influence on lung metastases was mediated by CD8+ T cells, as CD8+ T cell depletion abolished the difference in lung metastases. Furthermore, mice with concomitant MFP and lung tumors had increased tumor specific, effector CD8+ T cells infiltration in the lungs. Thus, we propose a model where tumors in an immunogenic location can give rise to systemic anti-tumor CD8+ T cell responses that could be utilized to target metastatic tumors. These results highlight the requirement for clinical consideration of cross-talk between primary and metastatic tumors for effective immunotherapy for cancers otherwise resistant to immunotherapy.
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- 2020
44. Novel combination immunotherapy for pancreatic cancer: potent anti-tumor effects with CD40 agonist and interleukin-15 treatment
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Clare Y Slaney, Phillip K. Darcy, Patrick Pauwels, Amanda J Oliver, Filip Lardon, Evelien Ljm Smits, Elly Marcq, Delphine Quatannens, Marc Peeters, Jorrit De Waele, Jonas Van Audenaerde, Geert Roeyen, Jinthe Van Loenhout, Michael H. Kershaw, Bianca von Scheidt, and Ashleigh S Davey
- Subjects
0301 basic medicine ,Agonist ,lcsh:Immunologic diseases. Allergy ,medicine.drug_class ,Immunology ,pancreatic cancer ,T cells ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Pancreatic cancer ,interleukin‐15 ,medicine ,Immunology and Allergy ,General Nursing ,Tumor microenvironment ,CD40 ,natural killer cells ,biology ,business.industry ,medicine.disease ,CD40 agonist ,030104 developmental biology ,Interleukin 15 ,030220 oncology & carcinogenesis ,combination immunotherapy ,biology.protein ,Adenocarcinoma ,Original Article ,Human medicine ,business ,lcsh:RC581-607 ,CD8 - Abstract
Objectives With the poorest 5‐year survival of all cancers, improving treatment for pancreatic cancer is one of the biggest challenges in cancer research. We sought to explore the potential of combining both priming and activation of the immune system. To achieve this, we combined a CD40 agonist with interleukin‐15 and tested its potential in pancreatic cancer. Methods Response to this combination regimen was assessed in pancreatic ductal adenocarcinoma mouse models, and a thorough analysis of the tumor microenvironment was performed. Results We demonstrated profound reduction in tumor growth and increased survival of mice with the majority of mice being cured when both agents were combined, including an unprecedented 8‐fold dose reduction of CD40 agonist without losing any efficacy. RNAseq analysis showed involvement of natural killer (NK) cell‐ and T‐cell‐mediated anti‐tumor responses and the importance of antigen‐presenting cell pathways. This combination resulted in enhanced infiltration of tumors by both T cells and NK cells, as well as a striking increase in the ratio of CD8+ T cells over Tregs. We also observed a significant increase in numbers of dendritic cells (DCs) in tumor‐draining lymph nodes, particularly CD103+ DCs with cross‐presentation potential. A critical role for CD8+ T cells and involvement of NK cells in the anti‐tumor effect was highlighted. Importantly, strong immune memory was established, with an increase in memory CD8+ T cells only when both interleukin‐15 and the CD40 agonist were combined. Conclusion These novel preclinical data support initiation of a first‐in‐human clinical trial with this combination immunotherapy strategy in pancreatic cancer., With the poorest 5‐year survival of all cancers, improving treatment for pancreatic cancer is one of the biggest challenges in cancer research. We demonstrate in this study significant tumor reduction and prolonged survival, including complete cures, in two mouse models of pancreatic cancer. This was mediated by a significant increase of natural killer and T cells in the tumors as well as a striking increase in the ratio of CD8+ T cells over Tregs. These data support initiation of a first‐in‐human clinical trial with this combination immunotherapy strategy in pancreatic cancer.
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- 2020
45. Dual PD-1 and CTLA-4 Checkpoint Blockade Promotes Antitumor Immune Responses through CD4+Foxp3− Cell–Mediated Modulation of CD103+ Dendritic Cells
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Lauren Giuffrida, Phillip K. Darcy, Alexander J Davenport, Liza B John, Michael H. Kershaw, Clare Y Slaney, Sherene Loi, Emma V. Petley, Joseph A. Trapani, Nicole Milenkovski, Junyun Lai, Kevin Sek, Sherly Mardiana, Nicole M. Haynes, Imran G House, Melissa A. Henderson, and Paul A. Beavis
- Subjects
0301 basic medicine ,Cancer Research ,Myeloid ,Tumor-infiltrating lymphocytes ,business.industry ,medicine.medical_treatment ,Immunology ,FOXP3 ,hemic and immune systems ,chemical and pharmacologic phenomena ,Immunotherapy ,Blockade ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Immune system ,CTLA-4 ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,Antigen-presenting cell ,business - Abstract
Immunotherapy is widely accepted as a powerful new treatment modality for the treatment of cancer. The most successful form of immunotherapy to date has been the blockade of the immune checkpoints PD-1 and CTLA-4. Combining inhibitors of both PD-1 and CTLA-4 increases the proportion of patients who respond to immunotherapy. However, most patients still do not respond to checkpoint inhibitors, and prognostic biomarkers are currently lacking. Therefore, a better understanding of the mechanism by which these checkpoint inhibitors enhance antitumor immune responses is required to more accurately predict which patients are likely to respond and further enhance this treatment modality. Our current study of two mouse tumor models revealed that CD4+Foxp3− cells activated by dual PD-1/CTLA-4 blockade modulated the myeloid compartment, including activation of conventional CD103+ dendritic cells (DC) and expansion of a myeloid subset that produces TNFα and iNOS (TIP-DCs). CD4+Foxp3− T cell–mediated activation of CD103+ DCs resulted in enhanced IL12 production by these cells and IL12 enhanced the therapeutic effect of dual PD-1/CTLA-4 blockade. Given the importance of these myeloid subsets in the antitumor immune response, our data point to a previously underappreciated role of CD4+Foxp3− cells in modulating this arm of the antitumor immune response. Cancer Immunol Res; 6(9); 1069–81. ©2018 AACR.
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- 2018
46. Enhancing Adoptive Cell Transfer with Combination BRAF-MEK and CDK4/6 Inhibitors in Melanoma
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Peter Kar Han Lau, Carleen Cullinane, Susan Jackson, Rachael Walker, Lorey K. Smith, Alison Slater, Laura Kirby, Riyaben P. Patel, Bianca von Scheidt, Clare Y. Slaney, Grant A. McArthur, and Karen E. Sheppard
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Cancer Research ,endocrine system diseases ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,targeted therapy ,Article ,melanoma ,adoptive cell transfer ,cell cycle ,immuno-oncology ,enzymes and coenzymes (carbohydrates) ,Oncology ,neoplasms ,RC254-282 - Abstract
Simple Summary Adoptive cell transfer (ACT) is a potentially robust treatment option for patients with advanced melanoma that is resistant to immune checkpoint inhibitors. The addition of cyclin-dependent kinase 4/6 inhibitors to combination BRAF-MEK inhibitors can also greatly improve the duration of response against melanoma. The aim of our study was to investigate adoptive cell transfer with combination BRAF-MEK and CDK4/6 inhibitors. We show triplet targeted therapy is highly efficacious against BRAFV600 melanoma in YOVAL1.1 and the BRAFi resistant SM1WT1 model. Combination ACT with BRAF-MEK-CDK4/6i led to prolonged and deep anti-tumor responses in YOVAL1.1. This work provides additional evidence for BRAF-MEK-CDK4/6i in clinical trials and in combination with ACT. Abstract Despite the success of immune checkpoint inhibitors that target cytotoxic lymphocyte antigen-4 (CTLA-4) and programmed-cell-death-1 (PD-1) in the treatment of metastatic melanoma, there is still great need to develop robust options for patients who are refractory to first line immunotherapy. As such there has been a resurgence in interest of adoptive cell transfer (ACT) particularly derived from tumor infiltrating lymphocytes. Moreover, the addition of cyclin dependent kinase 4/6 inhibitors (CDK4/6i) have been shown to greatly extend duration of response in combination with BRAF-MEK inhibitors (BRAF-MEKi) in pre-clinical models of melanoma. We therefore investigated whether combinations of BRAF-MEK-CDK4/6i and ACT were efficacious in murine models of melanoma. Triplet targeted therapy of BRAF-MEK-CDK4/6i with OT-1 ACT led to sustained and robust anti-tumor responses in BRAFi sensitive YOVAL1.1. We also show that BRAF-MEKi but not CDK4/6i enhanced MHC Class I expression in melanoma cell lines in vitro. Paradoxically CDK4/6i in low concentrations of IFN-γ reduced expression of MHC Class I and PD-L1 in YOVAL1.1. Overall, this work provides additional pre-clinical evidence to pursue combination of BRAF-MEK-CDK4/6i and to combine this combination with ACT in the clinic.
- Published
- 2021
47. Dual-specific Chimeric Antigen Receptor T Cells and an Indirect Vaccine Eradicate a Variety of Large Solid Tumors in an Immunocompetent, Self-antigen Setting
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Michele W.L. Teng, Bianca von Scheidt, David C. Tscharke, Alexander J Davenport, H. Miles Prince, Sherly Mardiana, Clare Y Slaney, Joseph A. Trapani, Aesha I. Ali, Paul A. Beavis, Sarah Ellis, Phillip K. Darcy, Jennifer A. Westwood, Ricky W. Johnstone, Zhiya Yu, Steven A. Rosenberg, Michael H. Kershaw, Mark J. Smyth, Nicholas P. Restifo, and Paul J Neeson
- Subjects
0301 basic medicine ,Interleukin 2 ,Cancer Research ,Adoptive cell transfer ,Receptor, ErbB-2 ,medicine.medical_treatment ,T cell ,Receptors, Antigen, T-Cell ,Breast Neoplasms ,Mice, Transgenic ,Vaccinia virus ,CD8-Positive T-Lymphocytes ,CXCR3 ,Autoantigens ,Cancer Vaccines ,Immunotherapy, Adoptive ,Article ,Interferon-gamma ,Mice ,03 medical and health sciences ,Antigen ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Cell Proliferation ,Brain Neoplasms ,business.industry ,Remission Induction ,T-cell receptor ,Immunotherapy ,Flow Cytometry ,Chimeric antigen receptor ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Immunology ,Female ,business ,gp100 Melanoma Antigen ,medicine.drug - Abstract
Purpose: While adoptive transfer of T cells bearing a chimeric antigen receptor (CAR) can eliminate substantial burdens of some leukemias, the ultimate challenge remains the eradication of large solid tumors for most cancers. We aimed to develop an immunotherapy approach effective against large tumors in an immunocompetent, self-antigen preclinical mouse model. Experimental Design: In this study, we generated dual-specific T cells expressing both a CAR specific for Her2 and a TCR specific for the melanocyte protein (gp100). We used a regimen of adoptive cell transfer incorporating vaccination (ACTIV), with recombinant vaccinia virus expressing gp100, to treat a range of tumors including orthotopic breast tumors and large liver tumors. Results: ACTIV therapy induced durable complete remission of a variety of Her2+ tumors, some in excess of 150 mm2, in immunocompetent mice expressing Her2 in normal tissues, including the breast and brain. Vaccinia virus induced extensive proliferation of T cells, leading to massive infiltration of T cells into tumors. Durable tumor responses required the chemokine receptor CXCR3 and exogenous IL2, but were independent of IFNγ. Mice were resistant to tumor rechallenge, indicating immune memory involving epitope spreading. Evidence of limited neurologic toxicity was observed, associated with infiltration of cerebellum by T cells, but was only transient. Conclusions: This study supports a view that it is possible to design a highly effective combination immunotherapy for solid cancers, with acceptable transient toxicity, even when the target antigen is also expressed in vital tissues. Clin Cancer Res; 23(10); 2478–90. ©2016 AACR.
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- 2017
48. A Multifunctional Role for Adjuvant Anti-4-1BB Therapy in Augmenting Antitumor Response by Chimeric Antigen Receptor T Cells
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Joseph A. Trapani, Michael H. Kershaw, Paul A. Beavis, Clare Y Slaney, Alexander J Davenport, Melissa A. Henderson, Lauren Giuffrida, Bianca von Scheidt, Sherene Loi, Sherly Mardiana, Paul J Neeson, Phillip K. Darcy, Liza B John, and Nicole M. Haynes
- Subjects
Cytotoxicity, Immunologic ,0301 basic medicine ,Cancer Research ,Receptor, ErbB-2 ,T cell ,medicine.medical_treatment ,Receptors, Antigen, T-Cell ,Mice, Transgenic ,CD8-Positive T-Lymphocytes ,Biology ,Lymphocyte Activation ,Immunotherapy, Adoptive ,Mice ,Tumor Necrosis Factor Receptor Superfamily, Member 9 ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,Tumor Cells, Cultured ,Tumor Microenvironment ,medicine ,Animals ,Humans ,Cytotoxic T cell ,IL-2 receptor ,Antigen-presenting cell ,Tumor microenvironment ,Antibodies, Monoclonal ,Mammary Neoplasms, Experimental ,Immunotherapy ,Chimeric antigen receptor ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Colonic Neoplasms ,Immunology ,Female ,Sarcoma, Experimental - Abstract
Adoptive immunotherapy utilizing chimeric antigen receptor (CAR) T cells has demonstrated high success rates in hematologic cancers, but results against solid malignancies have been limited to date, due in part to the immunosuppressive tumor microenvironment. Activation of the 4-1BB (CD137) pathway using an agonistic α-4-1BB antibody is known to provide strong costimulatory signals for augmenting and diversifying T-cell responses. We therefore hypothesized that a combination of α-4-1BB and CAR T-cell therapy would result in improved antitumor responses. Using a human-Her2 self-antigen mouse model, we report here that α-4-1BB significantly enhanced CAR T-cell efficacy directed against the Her2 antigen in two different established solid tumor settings. Treatment also increased the expression of IFNγ and the proliferation marker Ki67 in tumor-infiltrating CAR T cells when combined with α-4-1BB. Strikingly, α-4-1BB significantly reduced host immunosuppressive cells at the tumor site, including regulatory T cells and myeloid-derived suppressor cells, correlating with an increased therapeutic response. We conclude that α-4-1BB has a multifunctional role for enhancing CAR T-cell responses and that this combination therapy has high translational potential, given current phase I/II clinical trials with α-4-1BB against various types of cancer. Cancer Res; 77(6); 1296–309. ©2017 AACR.
- Published
- 2017
49. Current status, challenges and perspectives: immunotherapy and tumour microenvironment in thoracic cancer
- Author
-
Peng Luo, Jian Zhang, and Clare Y Slaney
- Subjects
Pulmonary and Respiratory Medicine ,Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,medicine.medical_treatment ,MEDLINE ,Medicine ,Immunotherapy ,Editorial on Immunotherapy and Tumor Microenvironment ,Current (fluid) ,Thoracic cancer ,business - Published
- 2020
50. Understanding T cell phenotype for the design of effective chimeric antigen receptor T cell therapies
- Author
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Amanda J Oliver, Michael H. Kershaw, Scott N. Mueller, Bianca von Scheidt, Daniela Gm Tantalo, Clare Y Slaney, and Aaron J Harrison
- Subjects
Cytotoxicity, Immunologic ,0301 basic medicine ,Cancer Research ,Adoptive cell transfer ,T-Lymphocytes ,medicine.medical_treatment ,Review ,self-renewal ,Lymphocyte Activation ,Immunotherapy, Adoptive ,memory ,0302 clinical medicine ,Neoplasms ,Immunology and Allergy ,Cell Self Renewal ,RC254-282 ,Receptors, Chimeric Antigen ,chimeric antigen receptor ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Cell Differentiation ,persistence ,Phenotype ,Treatment Outcome ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Molecular Medicine ,Signal Transduction ,T cell ,Immunology ,Biology ,03 medical and health sciences ,Antigen ,trafficking ,exhaustion ,medicine ,Animals ,Humans ,Cell Proliferation ,Pharmacology ,Cancer ,Immunotherapy ,medicine.disease ,Chimeric antigen receptor ,030104 developmental biology ,Cancer cell ,Cancer research ,Immunologic Memory - Abstract
Rapid advances in immunotherapy have identified adoptive cell transfer as one of the most promising approaches for the treatment of cancers. Large numbers of cancer reactive T lymphocytes can be generated ex vivo from patient blood by genetic modification to express chimeric antigen receptors (CAR) specific for tumor-associated antigens. CAR T cells can respond strongly against cancer cells, and adoptive transferred CAR T cells can induce dramatic responses against certain types of cancers. The ability of T cells to respond against disease depends on their ability to localize to sites, persist and exert functions, often in an immunosuppressive microenvironment, and these abilities are reflected in their phenotypes. There is currently intense interest in generating CAR T cells possessing the ideal phenotypes to confer optimal antitumor activity. In this article, we review T cell phenotypes for trafficking, persistence and function, and discuss how culture conditions and genetic makeups can be manipulated to achieve the ideal phenotypes for antitumor activities.
- Published
- 2021
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