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1. IL-15 mediated expansion of rare durable memory T cells following adoptive cellular therapy

Author

Robin L Jones, Erik A Farrar, Jianhong Cao, Venu G Pillarisetty, Stanley R Riddell, Jean Campbell, Brett A Schroeder, Ralph Graeme Black, Shihong Zhang, Karan Kohli, Robert H Pierce, Lu Yao, Theodore Scott Nowicki, Heather Sloan, Dawn Stief, Lee D Cranmer, Douglas S Hawkins, and Edward Y Kim

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background Synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) are ideal solid tumors for the development of adoptive cellular therapy (ACT) targeting NY-ESO-1, as a high frequency of tumors homogeneously express this cancer-testes antigen. Data from early phase clinical trials have shown antitumor activity after the adoptive transfer of NY-ESO-1–specific T cells. In these studies, persistence of NY-ESO-1 specific T cells is highly correlated with response to ACT, but patients often continue to have detectable transferred cells in their peripheral blood following progression.Method We performed a phase I clinical trial evaluating the safety of NY-ESO-1–specific endogenous T cells (ETC) following cyclophosphamide conditioning. Peripheral blood mononuclear cells (PBMCs) from treated patients were evaluated by flow cytometry and gene expression analysis as well as through ex vivo culture assays with and without IL-15.Results Four patients were treated in a cohort using ETC targeting NY-ESO-1 following cyclophosphamide conditioning. Treatment was well tolerated without significant toxicity, but all patients ultimately had disease progression. In two of four patients, we obtained post-treatment tumor tissue and in both, NY-ESO-1 antigen was retained despite clear detectable persisting NY-ESO-1–specific T cells in the peripheral blood. Despite a memory phenotype, these persisting cells lacked markers of proliferation or activation. However, in ex vivo culture assays, they could be induced to proliferate and kill tumor using IL-15. These results were also seen in PBMCs from two patients who received gene-engineered T-cell receptor–based products at other centers.Conclusions ETC targeting NY-ESO-1 with single-agent cyclophosphamide alone conditioning was well tolerated in patients with SS and those with MRCL. IL-15 can induce proliferation and activity in persisting NY-ESO-1–specific T cells even in patients with disease progression following ACT. These results support future work evaluating whether IL-15 could be incorporated into ACT trials post-infusion or at the time of progression.

Published
2021
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2. IL-15 mediated expansion of rare durable memory T cells following adoptive cellular therapy

Author

Theodore S. Nowicki, Antoni Ribas, Venu G. Pillarisetty, Cassian Yee, Brett Schroeder, Lee D. Cranmer, Jianhong Cao, Michael J. Wagner, Karan Kohli, Ralph Graeme Black, Lu Yao, Erik A. Farrar, Douglas S. Hawkins, Dawn Stief, Jean S. Campbell, Stanley R. Riddell, Edward Y. Kim, Heather L. Sloan, Seth M. Pollack, Shihong Zhang, Robert H. Pierce, and Robin L. Jones

Subjects
Cytotoxicity, Immunologic, Cancer Research, Adoptive cell transfer, Transplantation Conditioning, Time Factors, Cytotoxicity, medicine.medical_treatment, Adoptive, Pilot Projects, Lymphocyte Activation, Immunotherapy, Adoptive, Immunologic, antigens, Tumor Microenvironment, Immunology and Allergy, Medicine, Neoplasm, RC254-282, Cancer, Interleukin-15, Tumor, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Sarcoma, Liposarcoma, Middle Aged, Liposarcoma, Myxoid, Treatment Outcome, Oncology, Interleukin 15, Molecular Medicine, immunotherapy, Development of treatments and therapeutic interventions, Biotechnology, medicine.drug, Adult, Cyclophosphamide, Clinical Trials and Supportive Activities, Immunology, cell engineering, adoptive, Peripheral blood mononuclear cell, Cell Line, Vaccine Related, Sarcoma, Synovial, Memory T Cells, Rare Diseases, Antigen, Antigens, Neoplasm, Clinical Research, Cell Line, Tumor, Genetics, Humans, Cell Proliferation, Pharmacology, Immune Cell Therapies and Immune Cell Engineering, Synovial, 5.2 Cellular and gene therapies, business.industry, Membrane Proteins, Immunotherapy, Myeloablative Agonists, medicine.disease, immunity, Coculture Techniques, cytokines, Orphan Drug, Cancer research, Myxoid, business, Immunologic Memory, cellular, neoplasm, Ex vivo
Abstract

Author(s): Kohli, Karan; Yao, Lu; Nowicki, Theodore Scott; Zhang, Shihong; Black, Ralph Graeme; Schroeder, Brett A; Farrar, Erik A; Cao, Jianhong; Sloan, Heather; Stief, Dawn; Cranmer, Lee D; Wagner, Michael J; Hawkins, Douglas S; Pillarisetty, Venu G; Ribas, Antoni; Campbell, Jean; Pierce, Robert H; Kim, Edward Y; Jones, Robin L; Riddell, Stanley R; Yee, Cassian; Pollack, Seth M | Abstract: BackgroundSynovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) are ideal solid tumors for the development of adoptive cellular therapy (ACT) targeting NY-ESO-1, as a high frequency of tumors homogeneously express this cancer-testes antigen. Data from early phase clinical trials have shown antitumor activity after the adoptive transfer of NY-ESO-1-specific T cells. In these studies, persistence of NY-ESO-1 specific T cells is highly correlated with response to ACT, but patients often continue to have detectable transferred cells in their peripheral blood following progression.MethodWe performed a phase I clinical trial evaluating the safety of NY-ESO-1-specific endogenous T cells (ETC) following cyclophosphamide conditioning. Peripheral blood mononuclear cells (PBMCs) from treated patients were evaluated by flow cytometry and gene expression analysis as well as through ex vivo culture assays with and without IL-15.ResultsFour patients were treated in a cohort using ETC targeting NY-ESO-1 following cyclophosphamide conditioning. Treatment was well tolerated without significant toxicity, but all patients ultimately had disease progression. In two of four patients, we obtained post-treatment tumor tissue and in both, NY-ESO-1 antigen was retained despite clear detectable persisting NY-ESO-1-specific T cells in the peripheral blood. Despite a memory phenotype, these persisting cells lacked markers of proliferation or activation. However, in ex vivo culture assays, they could be induced to proliferate and kill tumor using IL-15. These results were also seen in PBMCs from two patients who received gene-engineered T-cell receptor-based products at other centers.ConclusionsETC targeting NY-ESO-1 with single-agent cyclophosphamide alone conditioning was well tolerated in patients with SS and those with MRCL. IL-15 can induce proliferation and activity in persisting NY-ESO-1-specific T cells even in patients with disease progression following ACT. These results support future work evaluating whether IL-15 could be incorporated into ACT trials post-infusion or at the time of progression.

Published
2021

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