Abstract
Chimeric antigen receptor (CAR)-engineered T lymphocytes (CAR Ts) produced impressive clinical results against selected hematological malignancies, but the extension of CAR T cell therapy to the challenging field of solid tumors has not, so far, replicated similar clinical outcomes. Many efforts are currently dedicated to improve the efficacy and safety of CAR-based adoptive immunotherapies, including application against solid tumors. A promising approach is CAR engineering of immune effectors different from αβT lymphocytes. Herein we reviewed biological features, therapeutic potential, and safety of alternative effectors to conventional CAR T cells: γδT, natural killer (NK), NKT, or cytokine-induced killer (CIK) cells. The intrinsic CAR-independent antitumor activities, safety profile, and ex vivo expansibility of these alternative immune effectors may favorably contribute to the clinical development of CAR strategies. The proper biological features of innate immune response effectors may represent an added value in tumor settings with heterogeneous CAR target expression, limiting the risk of tumor clonal escape. All these properties bring out CAR engineering of alternative immune effectors as a promising integrative option to be explored in future clinical studies.
Highlights
T lymphocytes genetically redirected with antitumor chimeric antigen receptors (CARs) represent an innovative frontier of cancer adoptive immunotherapy
Target antigen repertoire would be effectively increased, recognized by T cell receptor (TCR) of CD4+ and CD8+ T cells promoting an endogenous antitumor response even in the absence of the given CAR target antigen [47]. In case of the latter, the reduced persistence of CAR γδT cells could be counteracted by possible multiple reinfusions given their ex vivo expansibility, and considering the future possibility of allogeneic donor sources based on their reduced alloreactivity across human leucocytes antigen (HLA)-barriers
Similar to γδT cells, NKT cells could be a safer option as an effector because they express an invariant TCR, which recognizes primarily glycolipid structures presented by CD1d which are not associated with the autoimmunity The risk of severe autoreactive toxicities observed in an autologous setting of CAR-modified T cells has not been observed in initial studies with autologous NKT cells [77,78] In a phase I clinical trial, the adoptive transfer of ex vivo-expanded autologous NKT cells in patients with advanced and recurrent non-small-cell lung cancer has not reported toxicity [79]
Summary
T lymphocytes genetically redirected with antitumor chimeric antigen receptors (CARs) represent an innovative frontier of cancer adoptive immunotherapy. Clinical responses and improved survivals were paralleled with important concerns about possible toxicities mostly due to on-target off-tumor effects or cytokine release syndrome (CRS) [13,14,15]. Research efforts are currently dedicated to improve the safety and efficacy of CAR-based adoptive immunotherapies, including their application to patients with solid tumors. Within this perspective, an intriguing approach is the alternative or integrative CAR engineering of immune effectors different from conventional αβ T lymphocytes. We discuss the main underlying rationale to explore different types of lymphocytes, their potential advantage and limitations, initial preclinical data, and a preview of pilot/ongoing clinical trials
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