Concise Review: Emerging Principles from the Clinical Application of Chimeric Antigen Receptor T Cell Therapies for B Cell Malignancies

Abstract

Gene-engineered T cell therapies are soon to be United States Food and Drug Administration (FDA) approved for at least two types of B cell malignancies in pediatric and adult patients, in the form of CD19 targeted chimeric antigen receptor T (CAR T) cell therapy. This represents a triumph of a true bench to bedside clinical translation of a therapy that was conceived of in the early 1990s. Clinical results have demonstrated efficacious responses in patients with the CD19 positive diseases B cell acute lymphoblastic leukemia and diffuse large B cell lymphoma. However, significant challenges have emerged, including worrisome immune-related toxicities, therapy resistance, and understanding how to administer CD19 CAR T cells in clinical practice. Although much remains to be learned, pioneering clinical trials have led to foundational insights about the clinical translation of this novel therapy. Here, we review the "lessons learned" from the pre-clinical and human experience with CAR T cell therapy. STEM CELLS 2018;36:36-44 SIGNIFICANCE STATEMENTGene-engineered T cells have generated remarkable responses for patients with B cell malignancies. This article reviews the development and clinical application of T cells gene-engineered with chimeric antigen receptors. Lessons learned from the clinical experience and future directions are discussed.

CD22 CAR T-cell therapy in refractory or relapsed B acute lymphoblastic leukemia

“…Loss or mutation of CD19 are frequently observed, which hamper the secondary application of CD19 CAR T-cell therapy [4,[10][11][12][13][14]. Even in some treatment-failure cases which preserves high CD19 expression on leukemia cells, a secondary infusion of CD19 CAR T-cells has not been reproducibly successful, which may be partly due to immune-mediated clearance of murine-derived CARs [15][16][17]. Therefore, new therapeutic methods are required for r/r patients who have failed previous CD19 CAR T-cell therapy.…”

Future prospects for CD8+ regulatory T cells in immune tolerance

“…CAR-T cells targeting CD19 are effective in the treatment of malignant hematological diseases in preclinical and clinical trials. 182,187,188 They were approved by the US food and drug administration for clinical treatments in 2017. This technology has shown its full potential in cancer therapy, it is now extended to therapies using Tregs.…”

Immunotherapy Deriving from CAR-T Cell Treatment in Autoimmune Diseases

“…The application of CAR-T cells to treat B-lineage surface antigen CD19 is a huge forward step in cancer immunotherapy. The classic clinical use of CAR-T cells was to treat relapsed or refractory B cell acute lymphocyte leukemia (ALL), refractory B cell lymphoma, and non-Hodgkin lymphoma [29][30][31][32]. And now, the CAR-T cell is designed to have wider use that is to treat B cell malignancies beyond ALL, like chronic lymphocytic leukemia and multiple myeloma [24,33,34].…”