IL-15 mediated expansion of rare durable memory T cells following adoptive cellular therapy
| Autor: | 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, Robin L. Jones |
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| Rok vydání: | 2021 |
| Předmět: |
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 |
| Zdroj: | Journal for ImmunoTherapy of Cancer, Vol 9, Iss 5 (2021) Journal for immunotherapy of cancer, vol 9, iss 5 Journal for Immunotherapy of Cancer |
| ISSN: | 2051-1426 |
| DOI: | 10.1136/jitc-2020-002232 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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