CAR-Based Strategies beyond T Lymphocytes: Integrative Opportunities for Cancer Adoptive Immunotherapy

Ramona Rotolo, Valeria Leuci, Chiara Donini, Anna Cykowska, Loretta Gammaitoni, Giovanni Medico, Giorgio Valabrega, Massimo Aglietta, Dario Sangiolo

Research output: Contribution to journalReview articlepeer-review


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.

Original languageEnglish
JournalInternational Journal of Molecular Sciences
Issue number11
Publication statusPublished - Jun 11 2019


  • Adaptive Immunity/physiology
  • Humans
  • Immunotherapy, Adoptive/methods
  • Natural Killer T-Cells/immunology
  • Neoplasms/immunology
  • Receptors, Antigen, T-Cell/immunology


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