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CAR T Cells REPORT by CLINSCIENCE Clinscience Sp CAR T cells REPORT BY CLINSCIENCE Clinscience Sp. z o.o. ul. Erazma Ciołka 10 01-402 Warszawa KRS 0000720389 REGON 369551560 NIP 5272839995 [email protected] clinscience.com 2 CAR T CELLS / REPORT BY CLINSCIENCE INTRODUCTION One type of cells which are Chimeric antigen receptor T cells, known also present in the blood are as CAR T cells are the T cells produced by our leukocytes. Leukocytes are cells body’s white blood cells, which have been of the immune system and are genetically engineered to produce an artificial involved in protecting the body T-cell receptor for use in immunotherapy. against both infectious disease Those chimeric antigen receptors (CAR) are and foreign invaders. Among the receptors for proteins that have been the white blood cells, are engineered to give T cells the new ability to distinguished specific types of target the specific proteins i.e. the proteins of cells i.e. neutrophils, eosinophils, the cancer cells or dysfunctional proteins, which basophils, and lymphocytes, are produced by the dysfunctional organ of which are divided into three the body. The receptors are chimeric, because main subpopulations: B cells, T they combine both antigen-binding and T cell cells and NK cells. activating functions into a single receptor. The production process of CAR T cells is complicated. The first step is to gather and isolate the T cells from human blood. It can be done from the patient’s own blood (autologous treatment) or from healthy donor’s blood (allogenic treatment). The manufacturing process is the same, but the blood is either taken from the patient or from a donor. First, leukocytes are isolated by a blood cell separator in a process known as leukocyte apheresis. The products of leukocyte apheresis are then transferred to a cell-processing center, where specific T cells are stimulated, so they will actively proliferate and expand in large numbers. Then, the large number of T cells are purified and transduced with a gene encoding the engineered CAR via a retroviral vector. Scientists use gammaretroviral or lentiviral vectors. These specific vectors are very safe, because of partial deletion of the U3 region, which is responsible for the transcription of viral genetic material. CAR T CELLS / REPORT BY CLINSCIENCE 3 1. T Cell 2. T Cell 3. T Cell Adoptive 4. Patient Collection Transfection Transfer Monitoring a. Disease response - CT scans 1. Binding - Bone marrow biopsies CD3 - Peripheral blood flow cytometry T Cells 2. Fusion b. CART-T Cell persistence - Immunohistochemistry of bone marrow biopsy 3. Integration - RT-PCR and flow cytometry of blood and bone marrow aspirate +/- Lymphodepleting conditioning 5. CAR cell 4. Transcription and membrane protein expression insertion The first engineered T cell with a chimeric Research into CAR T cells has been a focus since molecule was developed in 1989-1993 by Israeli the beginning of cancer treatment, especially immunologists Zelig Eshar and Gideon Gross blood cancers and now, several therapies, in the Department of Chemical Immunology which use CAR T cells has been approved in the of Weizmann Institute of Science in Rehovot, following indications: Israel. These first-generation CARs were not yet acute lymphoblastic leukaemia (ALL), clinically effective. Over next thirty years, CARs diffuse large B-cell lymphoma (DLBCL). were immunologically and technologically modernized and sophisticated as first, second, third and currently fourth generation, depending on their composition. The second-generation CARs had improved antitumor activity of T cells: improved T cells proliferation, resistance to aptososis, cytokine secretion, and in-vivo persistance. The third-generation CARs in comparison with second-generation CARs, had improved effector functions and in-vivo persistence. Fourth generation CARs, the so- called TRUCKs (CAR redirected T cells that deliver a transgenic product to the targeted tumor tissue) or armored CARs, present further enhancement in antitumoral potency, cytokine activity and costimulatory ligands and enzymes that can degrade the extracellular matrix in solid tumors. 4 CAR T CELLS / REPORT BY CLINSCIENCE There are also two potential CAR T cells therapies, COMPLETED which are expected be approved shortly but currently pending approval by U.S. Food and Drug TRIALS Administration. These will be used to treat the following indications: Hodgkin’s lymphoma (HL), acute myeloid leukaemia (AML). There are many ongoing clinical trials, targeting There are many ongoing clinical trials, targeting blood cancers specifically, but also in solid blood cancers specifically, but also in solid tumours i.e. brain cancer, breast cancer, lung tumours i.e. brain cancer, breast cancer, lung cancer, multiple myeloma, ovarian cancer and cancer, multiple myeloma, ovarian cancer and many others. These clinical trials in solid tumours many others. These clinical trials in solid tumours followed soon after those in hematologic cancers. followed soon after those in hematologic cancers. More than 100 clinical trials of CAR T cells in solid More than 100 clinical trials of CAR T cells in solid tumours have so far been initiated, most using tumours have so far been initiated, most using a second- or third- generation of CARs. At least a second- or third- generation of CARs. At least 20 studies have now had their results published. 20 studies have now had their results published. The most positive trials to date have included the The most positive trials to date have included the targeting of GD2 in neuroblastoma (3 of 11 patients targeting of GD2 in neuroblastoma (3 of 11 patients with complete remissions), human epidermal with complete remissions), human epidermal growth factor receptor 2 (HER2) in sarcoma (4 growth factor receptor 2 (HER2) in sarcoma (4 of 17 patients with stable disease) and prostate- of 17 patients with stable disease) and prostate- specific membrane antigen (PSMA) in prostate specific membrane antigen (PSMA) in prostate cancer (partial response in two of five patients with cancer (partial response in two of five patients with minimal response in one of five patients). minimal response in one of five patients). Regarding safety, CAR T cells are theoretically more precise and potentially less toxic than conventional systemic chemotherapy. However, there are several serious adverse events associated with their use, including cytokine release syndrome (CRS), neurotoxicity and on-target off-tumour toxicity. Both CRS and neurotoxicity are thought to be related to the massive cytokine release that occurs when T cells are activated in the setting of a high tumour burden. CRS have proven quite common src: https://qtxasset.com/FiercePharma-1509455918/kymriah.jpg/ with anti-CD19 therapy in B-cell malignancies, kymriah.jpg?nwzZudSnfHm5SGe1OQsMZGtVtHl8xyUv occurring in 19-43% of patients, although treatments such as systemic corticosteroids and anti-IL-6 monoclonal antibodies are often rapidly effective in reversing these reactions. CAR T CELLS / REPORT BY CLINSCIENCE 5 ONGOING CLINICAL TRIALS Right now, there are over 2,300 clinical trials concerned with CAR T cells. Most of them (1099) are in Phase I, 753 are in Phase I/II and only 248 are completed. Most of them are focused on blood cancers, although over 100 are concerned with solid tumors and autoimmunological diseases i.e. multiple sclerosis, type-1 diabetes, colitis, rheumatoid arthritis and pemphigus vulgaris. 181 in Phase 0 753 1099 in Phase I/II in Phase I 235 in Phase II 10 in Phase II/III 8 in Phase III 271 248 20 planned of clinical trials in Phase IV are completed 6 CAR T CELLS / REPORT BY CLINSCIENCE MULTIPLE GLIOBLASTOMA MYELOMA MULTIFORME Idecaptagene vicleucel (Ide-cel) is the first CAR Despite the established efficacy of CAR T cells T cell therapy which has been submitted for therapy in hematologic malignancies, translating regulatory approval to target the antigen for this therapy to solid tumours has remained multiple myeloma. It is a drug developed by investigational. Glioblastoma (GB), the most Bristol Myers Squibb (BMS) and Bluebird Bio. aggressive and lethal form of primary brain tumour, Ide-cel is a B-cell maturation antigen (BCMA)- has recently been among the malignancies being second generation chimeric antigen receptor trialled clinically with CAR T cells. Glioblastoma T cell therapy. It binds to BCMA on the surface holds several unique features that have hindered of multiple myeloma cells leading to CAR T cell clinical translation, including its vast intertumoural growth, cytokine secretion, and subsequent and intratumoral heterogeneity, associated cytolytic killing of BCMA-expressing cells. In March immunosuppressive environment and lack of clear 2020 the BMS and Bluebird Bio submitted the experimental models to predict response and Biological License Application for Ide-cel. The analyse resistant phenotypes. companies asked for approval to treat adults with relapsed and refractory multiple myeloma, who had undergone at least three prior lines of therapy. Furthermore, during the ASCO20, t scientists from Juno Therapeutics and BMS, who developing orvacaptagene autoleucel (orva-cel) presented updated results of the EVOLVE clinical trial. Orva- src: cel is an autologous B-cell maturation antigen C. Michael Gibson, M.S., M.D., Wikimedia (BCMA) - directed CAR T cell therapy in refractory multiple myeloma. They reported the safety One of the major problems in treating solid tumours update which concerns the adverse event profile like glioblastoma is fact the that conventional cancer of orva-cel as most patients had neutropenia, drugs have molecules too large to cross the blood- thrombocytopenia and anemia (above 50%), but brain barrier. Because of this one of the biggest only 13% had some form of neurotoxicity. chances of success is immunotherapy. Scientists from McMaster University and the University of Toronto have developed CAR T cell therapy for GB which helped to reduce tumour burden and improved survival in mouse models. The team has tested three types of treatments in vitro and in mice. The first was a human IgG antibody that binds to CD133 on glioblastoma cells.
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