Journal Articles

Adoptive T cell therapy

T cell therapies based on tumor infiltrating T lymphocytes and chimeric antigen receptor or T cell receptor engineered T cells

Glycogen Synthase Kinase 3 Inhibition Lowers PD-1 Expression, Promotes Long-term Survival and Memory Generation in Antigen-specific CAR-T cells

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Successful remission in hematological cancers by CAR-T cell immunotherapy has yet to be replicated in solid tumors like GBM. A significant impediment of CAR-T immunotherapy in solid tumors is poor exposure of T cells to tumor antigens resulting in suboptimal CAR-T cell activation, which ultimately fails to induce a robust anti-tumor immune response. Costimulatory moieties in advanced-generation CARs, along with additional IL2 therapy has been shown to be insufficient to overcome this hurdle and have its cytotoxic limitations. GSK3 is constitutively active in naive T cells and is transiently inactivated during T cell activation resulting in rapid T cell proliferation. Pharmacologic inhibition of GSK3 in GBM-specific CAR-T cells reduced FasL expression, increased T cell proliferation and reduced exhaustion by lowering PD-1 levels resulting in the development of CAR-T effector memory phenotype. Treatment with GSK3-inhibited CAR-T cells resulted in 100% tumor elimination during the tumor-rechallenge experiment in GBM-bearing animals and increased accumulation of memory CAR-T cells in secondary lymphoid organs. These adjuvant-like effects of GSK3 inhibition on activated CAR-T cells may be a valuable adjunct to a successful implementation of CAR-T immunotherapy against GBM and other solid tumors.

Author Info: (1) Brain Tumor Laboratory, Roger Williams Medical Center, Providence, RI, USA; Department of Neurosurgery, Alpert School of Medicine, Brown University, Providence, RI, USA. Electronic address

Author Info: (1) Brain Tumor Laboratory, Roger Williams Medical Center, Providence, RI, USA; Department of Neurosurgery, Alpert School of Medicine, Brown University, Providence, RI, USA. Electronic address: sadhak_sengupta@brown.edu. (2) Department of Surgery, Roger Williams Medical Center, Providence, RI, USA; Department of Surgery, Boston University School of Medicine, Boston, MA, USA. (3) Brain Tumor Laboratory, Roger Williams Medical Center, Providence, RI, USA. (4) Brain Tumor Laboratory, Roger Williams Medical Center, Providence, RI, USA; Department of Neurosurgery, Alpert School of Medicine, Brown University, Providence, RI, USA.

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Coexpression profile of leukemic stem cell markers for combinatorial targeted therapy in AML

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Targeted immunotherapy in acute myeloid leukemia (AML) is challenged by the lack of AML-specific target antigens and clonal heterogeneity, leading to unwanted on-target off-leukemia toxicity and risk of relapse from minor clones. We hypothesize that combinatorial targeting of AML cells can enhance therapeutic efficacy without increasing toxicity. To identify target antigen combinations specific for AML and leukemic stem cells, we generated a detailed protein expression profile based on flow cytometry of primary AML (n = 356) and normal bone marrow samples (n = 34), and a recently reported integrated normal tissue proteomic data set. We analyzed antigen expression levels of CD33, CD123, CLL1, TIM3, CD244 and CD7 on AML bulk and leukemic stem cells at initial diagnosis (n = 302) and relapse (n = 54). CD33, CD123, CLL1, TIM3 and CD244 were ubiquitously expressed on AML bulk cells at initial diagnosis and relapse, irrespective of genetic characteristics. For each analyzed target, we found additional expression in different populations of normal hematopoiesis. Analyzing the coexpression of our six targets in all dual combinations (n = 15), we found CD33/TIM3 and CLL1/TIM3 to be highly positive in AML compared with normal hematopoiesis and non-hematopoietic tissues. Our findings indicate that combinatorial targeting of CD33/TIM3 or CLL1/TIM3 may enhance therapeutic efficacy without aggravating toxicity in immunotherapy of AML.

Author Info: (1) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. Translational Cancer Immunology, Gene Center, LMU Munich, Munich, Germany. Center for Cell Engineering and

Author Info: (1) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. Translational Cancer Immunology, Gene Center, LMU Munich, Munich, Germany. Center for Cell Engineering and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (2) Center for Cell Engineering and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (3) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. Translational Cancer Immunology, Gene Center, LMU Munich, Munich, Germany. (4) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. Translational Cancer Immunology, Gene Center, LMU Munich, Munich, Germany. (5) Center for Cell Engineering and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (6) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. Translational Cancer Immunology, Gene Center, LMU Munich, Munich, Germany. (7) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. Translational Cancer Immunology, Gene Center, LMU Munich, Munich, Germany. (8) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. Translational Cancer Immunology, Gene Center, LMU Munich, Munich, Germany. (9) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. Translational Cancer Immunology, Gene Center, LMU Munich, Munich, Germany. (10) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. Translational Cancer Immunology, Gene Center, LMU Munich, Munich, Germany. (11) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. German Cancer Consortium (DKTK), Heidelberg, Germany. German Cancer Research Center (DKFZ), Heidelberg, Germany. (12) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. (13) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. (14) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. (15) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. (16) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. German Cancer Consortium (DKTK), Heidelberg, Germany. German Cancer Research Center (DKFZ), Heidelberg, Germany. (17) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. (18) Center for Cell Engineering and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (19) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. marion.subklewe@med.uni-muenchen.de. Translational Cancer Immunology, Gene Center, LMU Munich, Munich, Germany. marion.subklewe@med.uni-muenchen.de. German Cancer Consortium (DKTK), Heidelberg, Germany. marion.subklewe@med.uni-muenchen.de. German Cancer Research Center (DKFZ), Heidelberg, Germany. marion.subklewe@med.uni-muenchen.de.

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CD19-targeted immunotherapies for treatment of patients with non-Hodgkin B-cell lymphomas

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INTRODUCTION: Ubiquitous expression of CD19 on B cell non-Hodgkin lymphoma identified it as a potential target for immune-based therapies. Areas covered: This article reviews the current literature on anti-CD19 therapies currently in clinical trials including monoclonal antibodies (mAb), antibody targeted cytotoxic drug conjugates (ADC), bispecific antibodies, and chimeric antigen receptor (CAR) modified T cells. Expert opinion: Naked anti-CD19 mAbs, have shown little clinical benefit in B cell lymphomas. Despite unusual toxicity profiles with many anti-CD19 ADCs slowing development, the durable remissions in a substantial minority of patients with refractory aggressive lymphomas should encourage continued efforts in this area. Blinatumomab, an anti-CD19 bispecific T cell engagers, has shown impressive responses in relapse/refractory (rel/ref) diffuse large B cell lymphoma (DLBCL), but is plagued by neurotoxicity issues and the need for continuous infusion. CD19 targeting CAR-T cell therapies are the most promising, with the potential for curing a third of refractory DLBCL patients. There is still much work to be done to address potentially life-threatening cytokine release syndrome and neurotoxicity, an extended production time precluding patients with rapidly progressive disease, and the expense of treatment. However, if the promise of CAR-T cell technology is confirmed, this will likely change the approach and prognosis for rel/ref aggressive lymphoma. Article highlights CD19, a B cell specific member of the immunoglobulin family and highly expressed in nearly all B cell malignancies, making it an attractive receptor for novel targeted therapies for B cell lymphoma. Current naked anti-CD19 monoclonal antibodies have modest activity in B cell lymphomas as single agents. Combination studies of MEDI-551 with chemotherapy have shown no benefit over existing CD20 monoclonal antibody combinations, although additional combination studies with other anti-CD19 mAbs are pending. Bispecific antibodies directed against CD19 and CD3, as well as anti-CD19 antibody drug conjugates have shown encouraging results in early clinical trials, however unique toxicity profiles still need to be addressed. Chimeric antigen receptor (CAR)-T cell therapy directed against CD19 was recently FDA-approved for treatment of refractory diffuse large B cell lymphoma based on high response rates and the potential for durable remissions in approximately one third of patients.

Author Info: (1) a Washington University School of Medicine , St. Louis , MO. (2) a Washington University School of Medicine , St. Louis , MO.

Author Info: (1) a Washington University School of Medicine , St. Louis , MO. (2) a Washington University School of Medicine , St. Louis , MO.

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Expansion and Antitumor Cytotoxicity of T-Cells Are Augmented by Substrate-Bound CCL21 and Intercellular Adhesion Molecule 1

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Adoptive immunotherapy is based on ex vivo expansion and stimulation of T-cells, followed by their transfer into patients. The need for the ex vivo culturing step provides opportunities for modulating the properties of transferred T-cells, enhancing their antitumor abilities, and increasing their number. Here, we present a synthetic immune niche (SIN) that increases the number and antitumor activity of cytotoxic CD8(+) T-cells. We first evaluated the effect of various SIN compositions that mimic the physiological microenvironment encountered by T-cells during their activation and expansion in the lymph node. We found that substrates coated with the chemokine CCL21 together with the adhesion molecule intercellular adhesion molecule 1 significantly increase the number of ovalbumin-specific murine CD8(+) T-cells activated by antigen-loaded dendritic cells or activation microbeads. Notably, cells cultured on these substrates also displayed augmented cytotoxic activity toward ovalbumin-expressing melanoma cells, both in culture and in vivo. This increase in specific cytotoxic activity was associated with a major increase in the cellular levels of the killing-mediator granzyme B. Our results suggest that this SIN may be used for generating T-cells with augmented cytotoxic function, for use in cancer immunotherapy.

Author Info: (1) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (2) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. (3) Department of

Author Info: (1) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (2) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. (3) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.

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A novel AXL chimeric antigen receptor endows T cells with anti-tumor effects against triple negative breast cancers

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Identifying targets for chimeric antigen receptor-modulated T lymphocyte (CAR-T) therapy against solid tumors is an urgent problem to solve. In this study, we showed for the first time that the receptor tyrosine kinase, AXL, is overexpressed in various tumor cell lines and patient tumor tissues including triple negative breast cancer (TNBC) cell lines and patient samples, making AXL a potent novel target for cancer therapy, specifically for TNBC treatment. We also engineered T cells with a CAR consisting of a novel single-chain variable fragment against AXL and revealed its antigen-specific cytotoxicity and ability to release cytokines in a TNBC cell line and other AXL-positive tumors in vitro. Furthermore, AXL-CAR-T cells displayed a significant anti-tumor effect and in vivo persistence in a TNBC xenograft model. Taken together, our findings indicate that AXL-CAR-T cells can represent a promising therapeutic strategy against TNBC.

Author Info: (1) Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850, PR China. (2) Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing

Author Info: (1) Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850, PR China. (2) Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850, PR China. (3) Pathology Department Weifang Heart Hospital, Shandong Province, PR China. (4) Department of Urology, General Hospital of Chinese People's Armed Police Forces, Beijing 100039, PR China. (5) Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850, PR China. (6) College of Basic Medicine, The Fourth Military Medical University, Xi'an, Shannxi 710000, PR China. (7) State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, PR China. (8) Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850, PR China. (9) Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850, PR China; Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing 100850, PR China. (10) State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, PR China. Electronic address: lm62033@163.com. (11) Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850, PR China; School of Nursing, Jilin University, Changchun, Jilin 130021, PR China; Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing 100850, PR China. Electronic address: lishengwang@ymail.com. (12) Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850, PR China; Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing 100850, PR China. Electronic address: 13910026365@163.com.

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Non-viral RNA chimeric antigen receptor modified T cells in patients with Hodgkin lymphoma

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Chimeric antigen receptor (CAR) modified T cells are being investigated in many settings including classical Hodgkin lymphoma (cHL). The unique biology of cHL, characterized by scant Hodgkin and Reed-Sternberg (HRS) cells within an immunosuppressive tumor microenvironment (TME), may pose challenges for cellular therapies directly targeting antigens expressed on HRS. We hypothesized that eradicating CD19 positive (+) B cells within the TME and the putative circulating CD19+ HRS clonotypic cells using anti-CD19 directed CAR modified T cells (CART19) may indirectly affect HRS cells, which do not express CD19. Here we describe our pilot trial using CART19 in patients with relapsed and refractory cHL. To limit potential toxicities, we used non-viral RNA CART19 cells which are expected to express CAR protein only a few days, as opposed to CART19 generated by viral vector transduction, which expand in vivo and retain CAR expression. All 5 enrolled patients underwent successful manufacturing of non-viral RNA CART19 and 4 were infused with protocol specified cell dose. There were no severe toxicities. Responses were seen, but these were transient. To our knowledge, this is the first CART19 clinical trial to use non-viral RNA gene delivery. This trial was registered at www.clinicaltrials.gov as NCT02277522 (adult) and NCT02624258 (pediatric).

Author Info: (1) Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, United States; jakub.svoboda@uphs.upenn.edu. (2) Division of Oncology, Cancer Immunotherapy Program, Children's Hospital of Philadelphia

Author Info: (1) Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, United States; jakub.svoboda@uphs.upenn.edu. (2) Division of Oncology, Cancer Immunotherapy Program, Children's Hospital of Philadelphia, Philadelphia, PA, United States. (3) Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, United States. (4) Division of Oncology, Cancer Immunotherapy Program, Children's Hospital of Philadelphia, Philadelphia, PA, United States. (5) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, United States. (6) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, United States. (7) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, United States. (8) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, United States. (9) Division of Oncology, Cancer Immunotherapy Program, Children's Hospital of Philadelphia, Philadelphia, PA, United States. (10) Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, United States. (11) Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, United States. (12) Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, United States. (13) Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, United States. (14) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, United States. (15) Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, United States. (16) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, United States. (17) Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, United States.

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Translating anti-CD19 CAR T-Cell therapy into clinical practice for relapsed/refractory diffuse large B-Cell lymphoma

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Chimeric antigen receptor (CAR) T-cells demonstrate efficacy in B-cell malignancies, leading to FDA approval of axicaptagene ciloleucel in October 2017 and tisagenlecleucel in May 2018 for large B-cell lymphomas after two prior lines of therapy. Durable remissions are seen in 30-40% of study-treated patients, but unique toxicities of cytokine release syndrome and neurotoxicity require administration in specialized centers. This article reviews the data to-date within the context of current diffuse large B-cell lymphoma management, focusing on axicaptagene ciloleucel, tisagenlecleucel and lisocabtagene maraleucel.

Author Info: (1) Department of Medicine, Division of Medical Oncology, Clinical Research Division, University of Washington, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, Seattle, WA

Author Info: (1) Department of Medicine, Division of Medical Oncology, Clinical Research Division, University of Washington, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, Seattle, WA, United States. (2) Department of Medicine, Division of Medical Oncology, Clinical Research Division, University of Washington, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, Seattle, WA, United States. (3) Department of Medicine, Division of Medical Oncology, Clinical Research Division, University of Washington, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, United States agopal@u.washington.edu.

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Autologous CD19-Targeted CAR T Cells in Patients with Residual CLL following Initial Purine Analog-Based Therapy

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Patients with residual chronic lymphocytic leukemia (CLL) following initial purine analog-based chemoimmunotherapy exhibit a shorter duration of response and may benefit from novel therapeutic strategies. We and others have previously described the safety and efficacy of autologous T cells modified to express anti-CD19 chimeric antigen receptors (CARs) in patients with relapsed or refractory B cell acute lymphoblastic leukemia and CLL. Here we report the use of CD19-targeted CAR T cells incorporating the intracellular signaling domain of CD28 (19-28z) as a consolidative therapy in 8 patients with residual CLL following first-line chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab. Outpatients received low-dose conditioning therapy with cyclophosphamide (600 mg/m(2)), followed by escalating doses of 3 x 10(6), 1 x 10(7), or 3 x 10(7) 19-28z CAR T cells/kg. An objective response was observed in 3 of 8 patients (38%), with a clinically complete response lasting more than 28 months observed in two patients. Self-limited fevers were observed post-CAR T cell infusion in 4 patients, contemporaneous with elevations in interleukin-6 (IL-6), IL-10, IL-2, and TGF-alpha. None developed severe cytokine release syndrome or neurotoxicity. CAR T cells were detectable post-infusion in 4 patients, with a longest observed persistence of 48 days by qPCR. Further strategies to enhance CAR T cell efficacy in CLL are under investigation.

Author Info: (1) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY

Author Info: (1) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (2) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Michael G. Harris Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (3) Michael G. Harris Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (4) Michael G. Harris Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (5) Michael G. Harris Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (6) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (7) Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (8) Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (9) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (10) Department of Medicine, Columbia University, Herbert Irving Comprehensive Cancer Center, New York, NY, USA. (11) Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (12) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (13) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: brentjer@mskcc.org. (14) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

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Bone Marrow-derived CD8+ T Cells From Pediatric Leukemia Patients Express PD1 and Expand Ex Vivo Following Induction Chemotherapy

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Adoptive cell therapy (ACT) of chimeric antigen receptor T cells has demonstrated remarkable success for the treatment of pediatric B-cell leukemia. For patients who are not candidates for chimeric antigen receptor T-cell therapy, ACT using tumor antigen-experienced polyclonal T cells may be a treatment option. Since leukemic blasts reside in the bone marrow and bone marrow is a preferred site for homeostatic proliferation of cytotoxic memory CD8 T cells, we hypothesized that bone marrow would be a source of activated T cells. The aim of this study was to determine the feasibility of using bone marrow-derived T cells following postinduction chemotherapy for use in adoptive cell transfer. Matched patient samples of bone marrow and peripheral blood-derived T cells expanded ex vivo and displayed similar apoptotic profiles. Before activation and expansion, there was a significant increase in the percentage of bone marrow-derived CD8 T cells expressing activation markers PD1, CD45RO, and CD69 as compared with peripheral blood CD8 T cells. Considering, melanoma-reactive CD8 T cells reside in the subset of PD1CD8 T cells, the bone marrow may be an enriched source leukemic-specific T cells that can be used for ACT.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/.

Author Info: (1) Department of Pediatrics, Division of Hematology and Oncology. (2) Department of Pediatrics, Division of Hematology and Oncology. (3) Department of Pediatrics, Division of Hematology

Author Info: (1) Department of Pediatrics, Division of Hematology and Oncology. (2) Department of Pediatrics, Division of Hematology and Oncology. (3) Department of Pediatrics, Division of Hematology and Oncology. Department of Medicine, Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI. (4) Department of Pediatrics, Division of Hematology and Oncology.

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Axicabtagene ciloleucel (KTE-C19), an anti-CD19 CAR T therapy for the treatment of relapsed/refractory aggressive B-cell non-Hodgkin's lymphoma

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Adoptive T-cell immunotherapy is a rapidly growing field and is shifting the paradigm of clinical cancer treatment. Axicabtagene ciloleucel (axi-cel) is an anti-CD19 chimeric antigen receptor T-cell therapy that was initially developed at the National Cancer Institute and has recently been commercially approved by the US Food and Drug Administration for relapsed or refractory aggressive non-Hodgkin's lymphomas including diffuse large B-cell lymphoma and its variants. The ZUMA-1 Phase I and II clinical trials formed the basis of the US Food and Drug Administration approval of this product, and we discuss the particulars of the clinical trials and the pharmacology of axi-cel. In addition, we review the CD19 chimeric antigen receptor T-specific toxicities of cytokine release syndrome and neurotoxicity, which remain the challenges to the safe delivery of this important therapy for aggressive B-cell lymphomas with poor prognosis.

Author Info: (1) Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL, USA. Department of Oncologic Sciences, University of South Florida, Tampa

Author Info: (1) Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL, USA. Department of Oncologic Sciences, University of South Florida, Tampa, FL, USA. (2) Department of Pharmacy, Moffitt Cancer Center, Tampa, FL, USA. (3) Department of Oncologic Sciences, University of South Florida, Tampa, FL, USA. (4) Department of Oncologic Sciences, University of South Florida, Tampa, FL, USA. Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL, USA.

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