Research Techniques Made Simple: CAR T-Cell Therapy

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Research Techniques Made Simple: CAR T-Cell Therapy Haziq F. Siddiqi, BS1,2 Karl W. Staser, MD, PhD3 Vinod E. Nambudiri, MD, MBA1,2 1Harvard Medical School, Boston, Massachusetts 2Department of Dermatology, Brigham and Women’s Hospital, Boston, Massachusetts 3Division of Dermatology, Department of Medicine; Washington University in St. Louis School of Medicine; St. Louis, MO.

What is CAR T Cell Therapy? An adoptive cell immunotherapy using genetically-modified T cells to selectively target disease-causing cells. Chimeric antigen receptors (CARs) and chimeric autoantibody receptors (CAARs) express an antigen recognition domain that allow the engineered T cells to selectively kill disease-causing cells. Anti-CD19 CAR T cell therapy is currently FDA-approved for the treatment of certain treatment-refractory B cell lymphomas.

What is CAR T Cell Therapy? There are 5 stages of CAR T Cell preparation: First, patient T cells are collected by leukapheresis. Once a Chimeric Antigen has been designed ex vivo, the patient T cells are transduced with an expression vector to express the CAR fusion protein. These T cells are then amplified in culture, and are ultimately infused back into the patient.

What is the structure of a CAR? The antigen-recognizing domain is derived from a monoclonal antibody (CAR) or an autoantibody-targeted protein (CAAR). Confers selectivity for a particular antigen or antigen receptor. The intracellular signaling domain promotes T cell activation. Initiates CAR T killing of the target-expressing cell and potentiates the host immune response. 2nd and 3rd generation CARs contain co-stimulatory domains to potentiate the response. The CAR protein consists of a mAb-derived ScFv ectodomain and a signaling endodomain. The endodomain consists of a co-stimulatory domain and a T cell activating domain

What defines CAR generations? The three generations of CARs are defined by the number of signaling domains in the endodomain.

Applications of CAR and CAAR T cells in Dermatology Disease Potential Application Melanoma May circumvent melanoma evasion of the host immune response and resistance to chemotherapy or immunotherapy (e.g. checkpoint inhibitors). CAR-like strategy called TETARs (T cells Expressing Two Additional Receptors) may be even more effective Pemphigus Vulgaris CAAR T cells expressing a Desmoglein 3 fragment can selectively kill pemphigus-specific B cells. Desmoglein 3 CAAR T cells for treatment of pemphigus likely to enter early phase clinical trials soon.

Side Effects of CAR Therapy High levels of inflammatory cytokines may cause cytokine release syndrome (CRS) within days after CAR T cell infusion. Skin-related CAR T cell toxicities Cutaneous eruptions Infections Neoplasia Ongoing observations with increased utilization Features of Cytokine Release Syndrome Hypotension Capillary leak Disseminated Intravascular Coagulopathy Death

Summary CAR T cell therapy involves genetically-engineered T cells that selectively target disease-causing cells. Sophisticated molecular refinements have enhanced CAR T cell specificity, longevity, and cytotoxic abilities. Current FDA-approved CAR T cell therapy has shown great promise in treatment-refractory B cell lymphoma. Potential dermatologic applications of CAR technology include treatment of melanoma and pemphigus vulgaris. More data needed on short- and long-term effects of CAR therapy.