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

Induction of Neoantigen-specific Cytotoxic T Cells and Construction of T-cell Receptor-engineered T cells for Ovarian Cancer

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PURPOSE: Current evolution of cancer immunotherapies, such as immune checkpoint blockade, has implicated neoantigens as major targets of anti-cancer cytotoxic T cells. Adoptive T cell therapy with neoantigen-specific T cell receptor (TCR)-engineered T cells would be an attractive therapeutic option for advanced cancers where the host anti-tumor immune function is strongly inhibited. We previously developed a rapid and efficient pipeline for production of neoantigen-specific TCR-engineered T cells using peripheral blood from an HLA-matched healthy donor. Our protocol required only two weeks from stimulation of T cells with neoantigen-loaded dendritic cells to the identification of neoantigen-specific TCRs. We conducted the pilot study to validate our protocol. EXPERIMENTAL DESIGN: We used tumors from 7 ovarian cancer patients to validate our protocol. RESULTS: We chose 14 candidate neoantigens from 7 ovarian tumors (1-3 candidates for each patient), and then successfully induced 3 neoantigen-specific T cells from one healthy donor and identified their TCR sequences. Moreover, we validated functional activity of the three identified TCRs by generating TCR-engineered T cells which recognized the corresponding neoantigens and showed cytotoxic activity in an antigen-dose-dependent manner. However, one case of neoantigen-specific TCR-engineered T cells showed cross-reactivity against the corresponding wild-type peptide. Conclusion/Discussions: This pilot study demonstrated the feasibility of our efficient process from identification of neoantigen to production of the neoantigen-targeting cytotoxic TCR-engineered T cells for ovarian cancer and revealed the importance of careful validation of neoantigen-specific-TCR-engineered T cells to avoid severe immune-related adverse events.

Author Info: (1) Department of Medicine, University of Chicago. (2) Institute of Immunology, Charite. (3) Department of Medicine, University of Chicago. (4) Department of Medicine, University of

Author Info: (1) Department of Medicine, University of Chicago. (2) Institute of Immunology, Charite. (3) Department of Medicine, University of Chicago. (4) Department of Medicine, University of Chicago. (5) Medicine, University of Chicago. (6) Department of Obstetrics and Gynecology, Faculty of Medicine, Nihon University. (7) Department of Medicine, University of Chicago. (8) Cancer Precision Medicine Center, Japanese Foundation for Cancer Research. (9) Medicine, University of Chicago. (10) Department of Medicine, University of Chicago. (11) Department of Medicine, University of Chicago ynakamura@medicine.bsd.uchicago.edu.

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CAR-T Cells Surface-Engineered with Drug-Encapsulated Nanoparticles Can Ameliorate Intratumoral T Cell Hypofunction

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One limiting factor of CAR T-cell therapy for treatment of solid cancers is the suppressive tumor microenvironment, which inactivates the function of tumor infiltrating lymphocytes (TILs) through the production of immunosuppressive molecules such as adenosine. Adenosine inhibits the function of CD4+ and CD8+ T cells by binding to and activating the A2a adenosine receptor (A2aR) expressed on their surface. This suppression pathway can be blocked using the A2aR-specific small molecule antagonist SCH-58261 (SCH), but its applications have been limited owing to difficulties delivering this drug to immune cells within the tumor microenvironment (TME). To overcome this limitation, we used CAR-engineered T cells as active chaperones to deliver SCH-loaded cross-linked, multilamellar liposomal vesicles (cMLVs) to tumor-infiltrating T cells deep within the immune suppressive TME. Through in vitro and in vivo studies, we have demonstrated that this system can be used to effectively deliver SCH to the TME. This treatment may prevent or rescue the emergence of hypofunctional CAR-T cells within the TME.

Author Info: (1) Chemical Engineering and Materials Science, University of Southern California. (2) Pharmacology and Pharmaceutical Sciences, University of Southern California. (3) Biomedical Engineering, University of Southern

Author Info: (1) Chemical Engineering and Materials Science, University of Southern California. (2) Pharmacology and Pharmaceutical Sciences, University of Southern California. (3) Biomedical Engineering, University of Southern California. (4) Pharmacology and Pharmaceutical Sciences, University of Southern California. (5) Biomedical Engineering, University of Southern California. (6) R&D, HRAIN Biotechnology Co. Ltd. (7) Chemical Engineering and Materials Science, University of Southern California pinwang@usc.edu.

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CD44v6 as innovative sarcoma target for CAR-redirected CIK cells

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Purpose of our study was to explore a new immunotherapy for high grade soft tissue sarcomas (STS) based on cytokine-induced killer cells (CIK) redirected with a chimeric antigen receptor (CAR) against the tumor-promoting antigen CD44v6. We aimed at generating bipotential killers, combining the CAR specificity with the intrinsic tumor-killing ability of CIK cells (CAR(+).CIK). We set a patient-derived experimental platform. CAR(+).CIK were generated by transduction of CIK precursors with a lentiviral vector encoding for anti-CD44v6-CAR. CAR(+).CIK were characterized and assessed in vitro against multiple histotypes of patient-derived STS. The anti-sarcoma activity of CAR(+).CIK was confirmed in a STS xenograft model. CD44v6 was expressed by 40% (11/27) of patient-derived STS. CAR(+).CIK were efficiently expanded from patients (n = 12) and killed multiple histotypes of STS (including autologous targets, n = 4). The killing activity was significantly higher compared with unmodified CIK, especially at low effector/target (E/T) ratios: 98% vs 82% (E/T = 10:1) and 68% vs 26% (1:4), (p<0.0001). Specificity of tumor killing was confirmed by blocking with anti-CD44v6 antibody. CAR(+).CIK produced higher amounts of IL6 and IFN-gamma compared to control CIK. CAR(+).CIK were highly active in mice bearing subcutaneous STS xenografts, with significant delay of tumor growth (p<0.0001) without toxicities. We report first evidence of CAR(+).CIK's activity against high grade STS and propose CD44v6 as an innovative target in this setting. CIK are a valuable platform for the translation of CAR-based strategies to challenging field of solid tumors. Our findings support the exploration of CAR(+).CIK in clinical trials against high grade STS.

Author Info: (1) Department of Oncology, University of Torino, Torino, Italy. Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo (TO), Italy. (2) Innovative Immunotherapies Unit, IRCCS

Author Info: (1) Department of Oncology, University of Torino, Torino, Italy. Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo (TO), Italy. (2) Innovative Immunotherapies Unit, IRCCS San Raffaele Hospital Scientific Institute, Milano, Italy. (3) Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo (TO), Italy. (4) Department of Oncology, University of Torino, Torino, Italy. (5) Department of Oncology, University of Torino, Torino, Italy. (6) Department of Oncology, University of Torino, Torino, Italy. Laboratory of Gene Transfer, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino, Italy. (7) Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo (TO), Italy. (8) Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo (TO), Italy. (9) Department of Oncology, University of Torino, Torino, Italy. (10) Department of Oncology, University of Torino, Torino, Italy. (11) Pathology Unit, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, (TO), Italy. (12) Department of Oncology, University of Torino, Torino, Italy. Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo (TO), Italy. (13) Department of Oncology, University of Torino, Torino, Italy. Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo (TO), Italy. (14) Department of Oncology, University of Torino, Torino, Italy. Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo (TO), Italy. (15) Innovative Immunotherapies Unit, IRCCS San Raffaele Hospital Scientific Institute, Milano, Italy. Vita-Salute San Raffaele University, Milano, Italy. (16) Department of Oncology, University of Torino, Torino, Italy. Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo (TO), Italy.

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Checkpoints and beyond - Immunotherapy in colorectal cancer

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Immunotherapy is the latest revolution in cancer therapy. It continues to show impressive results in malignancies like melanoma and others. At least so far, effects are modest in colorectal cancer (CRC) and only a subset of patients benefits from already approved checkpoint inhibitors. In this review, we discuss major hurdles of immunotherapy like the immunosuppressive niche and low immunogenicity of CRC next to current achievements of checkpoint inhibitors, interleukin treatment and adoptive cell transfer (dendritic cells/cytokine induced killer cells, tumor infiltrating lymphocytes, chimeric antigen receptor cells, T cell receptor transfer) in pre-clinical models and clinical trials. We intensively examine approaches to overcome low immunogenicity by combination of different therapies and address future strategies of therapy as well as the need of predictive factors in this emerging field of precision medicine.

Author Info: (1) Department of Medicine II, Universitatsmedizin Mannheim, Medical Faculty Mannheim, University Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. (2) Department of Medicine II, Universitatsmedizin Mannheim, Medical

Author Info: (1) Department of Medicine II, Universitatsmedizin Mannheim, Medical Faculty Mannheim, University Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. (2) Department of Medicine II, Universitatsmedizin Mannheim, Medical Faculty Mannheim, University Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. (3) Department of Medicine II, Universitatsmedizin Mannheim, Medical Faculty Mannheim, University Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany; Heilig-Geist Hospital Bensheim, Rodensteinstrasse 94, 64625 Bensheim, Germany. (4) Department of Medicine II, Universitatsmedizin Mannheim, Medical Faculty Mannheim, University Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. Electronic address: matthias.ebert@umm.de.

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Durable regression of Medulloblastoma after regional and intravenous delivery of anti-HER2 chimeric antigen receptor T cells

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BACKGROUND: Standard-of-care therapies for treating pediatric medulloblastoma have long-term side effects, even in children who are cured. One emerging modality of cancer therapy that could be equally effective without such side effects would be chimeric antigen receptor (CAR) T cells. Knowing that human epidermal growth factor receptor 2 (HER2) is overexpressed in many medulloblastomas and has been used as a CAR T target before, we sought to evaluate the efficacy of more sophisticated anti-HER2 CAR T cells, as well as the feasibility and efficacy of different routes of delivering these cells, for the treatment of pediatric medulloblastoma. METHODS: Daoy, D283 and D425 medulloblastoma cell lines were characterized by flow cytometry to evaluate HER2 expression. Anti-tumor efficacy of HER2-BBz-CAR T cells in vitro was performed using cytokine release and immune cytotoxicity assays compared to control CD19 CAR T cells. In vivo, Daoy and D283 tumor cells were orthotopically implanted in the posterior fossa of NOD.Cg-Prkdc (scid) Il2rg (tm1Wjl) /SzJ (NSG) mice and treated with regional or intravenous HER2-BBz-CAR T cells or control CD19 CAR T cells. Non-human primates (NHPs) bearing ventricular and lumbar reservoirs were treated with target autologous cells bearing extracellular HER2 followed by autologous HER2-CAR T cells intraventricularly. Cerebrospinal fluid and blood were collected serially to measure the persistence of delivered cells and cytokines. RESULTS: HER2-BBz-CAR T cells effectively clear medulloblastoma orthotopically implanted in the posterior fossa of NSG mice via both regional and intravenous delivery in xenograft models. Intravenous delivery requires a log higher dose compared to regional delivery. NHPs tolerated intraventricular delivery of autologous cells bearing extracellular HER2 followed by HER2-BBz-CAR T cells without experiencing any systemic toxicity. CONCLUSIONS: HER2-BBz-CAR T cells show excellent pre-clinical efficacy in vitro and in mouse medulloblastoma models, and their intraventricular delivery is feasible and safe in NHPs. A clinical trial of HER2-BBz-CAR T cells directly delivered into cerebrospinal fluid should be designed for patients with relapsed medulloblastoma.

Author Info: (1) Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora

Author Info: (1) Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, CO, USA. (2) Division of Medical Sciences, Harvard Medical School, Harvard University, Boston, MA, USA. (3) Division of Pediatric Hematology and Oncology, Department of Pediatrics, Stanford University, Stanford, CA, USA. (4) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (5) Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, CO, USA. (6) Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, CO, USA. (7) Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, CO, USA. (8) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (9) Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Virginia, PO Box 800386, Charlottesville, VA, 22908, USA. dwl4q@hscmail.mcc.virginia.edu.

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Noninvasive PET Imaging of T cells

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The rapidly evolving field of cancer immunotherapy recently saw the approval of several new therapeutic antibodies. Several cell therapies, for example, chimeric antigen receptor-expressing T cells (CAR-T), are currently in clinical trials for a variety of cancers and other diseases. However, approaches to monitor changes in the immune status of tumors or to predict therapeutic responses are limited. Monitoring lymphocytes from whole blood or biopsies does not provide dynamic and spatial information about T cells in heterogeneous tumors. Positron emission tomography (PET) imaging using probes specific for T cells can noninvasively monitor systemic and intratumoral immune alterations during experimental therapies and may have an important and expanding value in the clinic.

Author Info: (1) Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China; Department of Radiology, Department of Medical Physics, University of

Author Info: (1) Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China; Department of Radiology, Department of Medical Physics, University of Wisconsin, Madison, WI 53705, USA; These authors contributed equally to this work. (2) Department of Radiology, Department of Medical Physics, University of Wisconsin, Madison, WI 53705, USA; These authors contributed equally to this work. (3) Department of Medical Physics, University of Wisconsin, Madison, WI 53705, USA. (4) Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China. Electronic address: lqyn@sh163.net. (5) Department of Radiology, Department of Medical Physics, University of Wisconsin, Madison, WI 53705, USA; Department of Medical Physics, University of Wisconsin, Madison, WI 53705, USA; University of Wisconsin Carbone Cancer Center, Madison, Wisconsin 53705, USA. Electronic address: wcai@uwhealth.org.

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Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia

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Tolerance to self-antigens prevents the elimination of cancer by the immune system(1,2). We used synthetic chimeric antigen receptors (CARs) to overcome immunological tolerance and mediate tumor rejection in patients with chronic lymphocytic leukemia (CLL). Remission was induced in a subset of subjects, but most did not respond. Comprehensive assessment of patient-derived CAR T cells to identify mechanisms of therapeutic success and failure has not been explored. We performed genomic, phenotypic and functional evaluations to identify determinants of response. Transcriptomic profiling revealed that CAR T cells from complete-responding patients with CLL were enriched in memory-related genes, including IL-6/STAT3 signatures, whereas T cells from nonresponders upregulated programs involved in effector differentiation, glycolysis, exhaustion and apoptosis. Sustained remission was associated with an elevated frequency of CD27(+)CD45RO(-)CD8(+) T cells before CAR T cell generation, and these lymphocytes possessed memory-like characteristics. Highly functional CAR T cells from patients produced STAT3-related cytokines, and serum IL-6 correlated with CAR T cell expansion. IL-6/STAT3 blockade diminished CAR T cell proliferation. Furthermore, a mechanistically relevant population of CD27(+)PD-1(-)CD8(+) CAR T cells expressing high levels of the IL-6 receptor predicts therapeutic response and is responsible for tumor control. These findings uncover new features of CAR T cell biology and underscore the potential of using pretreatment biomarkers of response to advance immunotherapies.

Author Info: (1) Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA. Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. Parker Institute

Author Info: (1) Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA. Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA. (2) Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA. Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA. (3) Novartis Institutes for BioMedical Research, Cambridge, MA, USA. (4) Novartis Institutes for BioMedical Research, Cambridge, MA, USA. (5) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. (6) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. (7) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. (8) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. (9) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. (10) Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA. (11) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. (12) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. (13) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. (14) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. (15) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. (16) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. (17) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. (18) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. (19) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. (20) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. (21) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. (22) Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA. (23) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. (24) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. (25) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. (26) Novartis Institutes for BioMedical Research, Cambridge, MA, USA. (27) Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA. Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. (28) Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA. Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. (29) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. Division of Hematology-Oncology, Department of Internal Medicine, University of Pennsylvania, Philadelphia, PA, USA. (30) Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA. Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. Division of Transfusion Medicine and Therapeutic Pathology, University of Pennsylvania, Philadelphia, PA, USA. (31) Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA. Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (32) Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA. Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (33) Novartis Institutes for BioMedical Research, Cambridge, MA, USA. (34) Novartis Institutes for BioMedical Research, Cambridge, MA, USA. (35) Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA. Division of Hematology-Oncology, Department of Internal Medicine, University of Pennsylvania, Philadelphia, PA, USA. (36) Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA. Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA. (37) Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA. mej@upenn.edu. Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. mej@upenn.edu. Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA. mej@upenn.edu.

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Cross-talk between T cells and hematopoietic stem cells during adoptive cellular therapy for malignant glioma

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PURPOSE: Adoptive T cell immunotherapy (ACT) has emerged as a viable therapeutic for peripheral and central nervous system (CNS) tumors. In peripheral cancers, optimal efficacy of ACT is reliant on dendritic cells (DCs) in the tumor microenvironment. However, the CNS is largely devoid of resident migratory DCs to function as antigen-presenting cells during immunotherapy. Herein, we demonstrate that cellular interactions between adoptively-transferred tumor-reactive T cells and bone marrow-derived HSPCs lead to the generation of potent intratumoral DCs within the CNS compartment. EXPERIMENTAL DESIGN: We evaluated HSPC differentiation during ACT in vivo in glioma-bearing hosts and HSPC proliferation and differentiation in vitro using a T cell co-culture system. We utilized FACS, ELISAs, and gene expression profiling to study the phenotype and function of HSPC-derived cells ex vivo and in vivo. To demonstrate the impact of HSPC differentiation and function on anti-tumor efficacy, we performed survival experiments. RESULTS: Transfer of HSPCs with concomitant ACT led to the production of activated CD86+CD11c+MHCII+ cells consistent with DC phenotype and function within the brain tumor microenvironment. These intratumoral DCs largely supplanted abundant host myeloid-derived suppressor cells. We determined that during ACT, HSPC-derived cells in gliomas rely on T cell-released IFN-gamma to differentiate into DCs, activate T cells, and reject intracranial tumors. CONCLUSIONS: Our data supports the use of HSPCs as a novel cellular therapy. While DC vaccines induce robust immune responses in the periphery, our data demonstrates that HSPC transfer uniquely generates intratumoral DCs that potentiate T cell responses and promote glioma rejection in situ.

Author Info: (1) Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, McKnight Brain Institute, University of Florida. (2) Preston A

Author Info: (1) Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, McKnight Brain Institute, University of Florida. (2) Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, McKnight Brain Institute, University of Florida. (3) Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, McKnight Brain Institute, University of Florida. (4) Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, McKnight Brain Institute, University of Florida. (5) Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, McKnight Brain Institute, University of Florida. (6) Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, McKnight Brain Institute, University of Florida. (7) Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, McKnight Brain Institute, University of Florida catherine.flores@neurosurgery.ufl.edu. (8) Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, McKnight Brain Institute, University of Florida.

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Biomarkers in chimeric antigen receptor T-cell therapy

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Will biomarkers be helpful in CAR therapy

Author Info: (1) Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA

Author Info: (1) Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia 19104, PA, USA. (2) Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia 19104, PA, USA. (3) Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia 19104, PA, USA. (4) Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia 19104, PA, USA.

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CAR T-cell Therapy: a New Era in Cancer Immunotherapy

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BACKGROUND: Cancer is one of the leading causes of death worldwide. Over the years, a number of conventional cytotoxic approaches for neoplastic diseases has been developed. However, due to their limited effectiveness in accordance with the heterogeneity of cancer cells, there is a constant search for therapeutic approaches with improved outcome, such as immunotherapy that utilizes and enhances the normal capacity of the patient's immune system. METHODS: Chimeric Antigen Receptor (CAR) T-cell therapy involves genetic modification of patient's autologous T-cells to express a CAR specific for a tumor antigen, following by ex vivo cell expansion and re-infusion back to the patient. CARs are fusion proteins of a selected single-chain fragment variable from a specific monoclonal antibody and one or more T-cell receptor intracellular signaling domains. This T-cell genetic modification may occur either via viral-based gene transfer methods or non-viral methods, such as DNA-based transposons, CRISPR/Cas9 technology or direct transfer of in vitro transcribed-mRNA by electroporation. RESULTS: Clinical trials have shown very promising results in end-stage patients with a full recovery of up to 92% in Acute Lymphocytic Leukemia. Despite such results in hematological cancers, the effective translation of CAR T-cell therapy to solid tumors and the corresponding clinical experience is limited due to therapeutic barriers, like CAR T-cell expansion, persistence, trafficking, and fate within tumors. CONCLUSION: In this review, the basic design of CARs, the main genetic modification strategies, the safety matters as well as the initial clinical experience with CAR T-cells are described.

Author Info: (1) Laboratory of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Macedonia. Greece. (2) Laboratory of Pharmacology, School of Pharmacy, Aristotle University of

Author Info: (1) Laboratory of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Macedonia. Greece. (2) Laboratory of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Macedonia. Greece.

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