Programming CAR-T cells to kill cancer

Abstract

T cells engineered to express chimeric antigen receptors (CARs) that are specific for tumour antigens have led to high complete response rates in patients with haematologic malignancies. Despite this early success, major challenges to the broad application of CAR-T cells as cancer therapies remain, including treatment-associated toxicities and cancer relapse with antigen-negative tumours. Targeting solid tumours with CAR-T cells poses additional obstacles because of the paucity of tumourspecific antigens and the immunosuppressive effects of the tumour microenvironment. To overcome these challenges, T cells can be programmed with genetic modules that increase their therapeutic potency and specificity. In this Review Article, we survey major advances in the engineering of next-generation CAR-T therapies for haematologic cancers and solid cancers, with particular emphasis on strategies for the control of CAR specificity and activity and on approaches for improving CAR-T-cell persistence and overcoming immunosuppression. We also lay out a roadmap for the development of off-the-shelf CAR-T cells.

T-cells “à la CAR-T(e)” – Genetically engineering T-cell response against cancer

“…Beyond specificity, the use of non-scFv based CAR EC domains may help solving the CAR immunogenicity issue we just described as well as problems of tonic signaling and exhaustion induction observed with certain scFv's due to their predisposition to oligomerization [132,152].…”

“…Adoptive transfer of engineered T cells is an effective treatment for certain hematological malignancies [152] but it faces many challenges when targeting solid tumors [153,154]. A large number of CAR clinical sutides are attempting to replicate the success of α-CD19 and α-BCMA CARs against the solid neoplasms, but the preliminary outcome of more than 100 trials are less encouraging.…”

“…The recent success obtained with anti-CD19 CAR T cells for the treatment of several hematological malignancies [152] have motivated the immunotherapeutic community to look for additional targeting moieties specific for other antigens. Beyond specificity, the use of non-scFv based CAR EC domains may help solving the CAR immunogenicity issue we just described as well as problems of tonic signaling and exhaustion induction observed with certain scFv's due to their predisposition to oligomerization [132,152].…”

“…To ensure safer T-cell engineering implementation and precise activation, several strategies have been developed [152]. As for other types of gene therapy approaches, a suicide gene could be included in the therapeutic vector to mediate the elimination of gene-engineered cells.…”

The FDA’s Regulatory Framework for Chimeric Antigen Receptor‐T Cell Therapies

“…The cells are then expanded in culture and further formulated and characterized for quality control prior to their administration back to the patient. Other novel chimeric constructs, additional genetic alterations to the T cells, and other viral and nonviral methods for introducing the constructs are under investigation . It should be noted that the manufacturing and logistic obstacles that had to be overcome to successfully develop consistently made quality products were formidable, and both the chimeric constructs and manufacturing processes continue to evolve …”