Chimeric Antigen Receptor T Cell Therapy Targeting CD19-Positive Leukemia and Lymphoma in the Context of Stem Cell Transplantation

Abstract

Novel therapies with chimeric antigen receptor (CAR)-transduced T cells (TCs) sparked new hope for patients with relapsed or refractory CD19-positive leukemia or lymphoma even after stem cell therapies. This review focuses on CARs recognizing the B cell antigen CD19. Both retroviral and lentiviral vectors are used, encoding various anti-CD19 CAR constructs comprising costimulatory molecules such as CD28, CD137/4-1BB, and OX40 either alone (second-generation CARs) or in combination (third-generation CARs). Current, up-to-date published studies on anti-CD19 CAR therapy for acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma (NHL) with observed side effects are discussed and an outlook on 58 ongoing trials is given. Clinical responses were achieved in up to 81% of ALL, 50% of CLL, and 40% of NHL patients. Factors with potential influence on the clinical outcome might be the design of the vector, the preconditioning regimen, and the number and quality of transfused CAR TCs. The applicability of clinical CAR TC therapy might include relapse after allogeneic stem cell transplantation (alloSCT), and ineligibility for or "bridging" until alloSCT. In summary, CAR therapy represents a highly promising treatment option even in heavily pretreated patients.

Idelalisib for optimized CD19‐specific chimeric antigen receptor T cells in chronic lymphocytic leukemia patients

“…Response rates with CD19‐specific CART cells are significantly lower in CLL compared to e.g. B cell ALL patients . Different qualities and phenotypes of T cells from CLL patients compared to relatively young ALL patients may be, at least in part, responsible for this observation.…”

“…B cell ALL patients. 1 Different qualities and phenotypes of T cells from CLL patients compared to relatively young ALL patients may be, at least in part, responsible for this observation. In contrast to ALL, down-regulation of CD19 expression is not a common mechanism of resistance in CLL.…”

“…The remarkable results of anti-CD19 chimeric antigen receptor T (CART) cell therapy sparked new hope for relapsed or refractory patients with B cell malignancies. 1 However, full antitumor activity for complete cancer eradication can be insufficient. 2 Efficacy of CART cell therapy is associated with in vivo proliferative capacity and sustained persistence of the genemodified cells.…”

Clinical translation and regulatory aspects of CAR/TCR-based adoptive cell therapies—the German Cancer Consortium approach

“…This can be effective by the development of new CAR constructs from earlier-generation CARs using the same vector backbone to which additional costimulatory molecules, hinge regions, and spacer elements may be added [72]. Another approach combines a universal CAR with modular adapter proteins for tumor cell recognition (e.g., UniCARs [60]).…”

Future of Chimeric Antigen Receptors (Cars): Could it Drive Solutions Beyond Cancer? Examples in Autoimmune Diseases

“…After expanding these CAR+ T-cells, these cells are infused in the bloodstream of the patient to generate a specific immune response against tumour. CART cells become able to recognize cancerous cells through the specificity of a scFv (single-chain variable fragment) to detect an antigen on the surface of the tumour cells, and after that to kill them [2,3]. The affinity and the avidity of the interaction between a CAR and its ligand are higher than the interaction between T cell receptor (TCR) and its peptide-MHC ligand; however, a CAR (instead of TCRs) is unable to recognize intracellular molecules [4].…”