Skip to main content

REVIEW article

Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1407992
This article is part of the Research Topic Emerging Strategies to Overcome Current Roadblocks in CAR T Cell Immunotherapy View all 4 articles

Fully Equipped CARs to Address Tumor Heterogeneity, Enhance Safety, and Improve the Functionality of Cellular Immunotherapies

Provisionally accepted
Antonio M. Alviano Antonio M. Alviano 1Marta Biondi Marta Biondi 1,2Erica Grassenis Erica Grassenis 1Andrea Biondi Andrea Biondi 1Marta Serafini Marta Serafini 1,3*Sarah Tettamanti Sarah Tettamanti 1
  • 1 Tettamanti Center and Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy, Monza, Italy
  • 2 Department of Medicine and Surgery, University of Milano Bicocca, Monza, Italy
  • 3 School of Medicine and Surgery, University of Milan-Bicocca, Milano, Italy, Milano, Italy

The final, formatted version of the article will be published soon.

    Although adoptive transfer of chimeric antigen receptor (CAR)-engineered T cells has achieved unprecedented response rates in patients with certain hematological malignancies, this therapeutic modality is still far from fulfilling its remarkable potential, especially in the context of solid cancers. Antigen escape variants, off-tumor destruction of healthy tissues expressing tumor-associated antigens (TAAs), poor CAR-T cell persistence, and the occurrence of functional exhaustion represent some of the most prominent hurdles that limit CAR-T cell ability to induce long-lasting remissions with a tolerable adverse effect profile. In this review, we summarize the main approaches that have been developed to face such bottlenecks, including the adapter CAR (AdCAR) system, Boolean-logic gating, epitope editing, the modulation of cell-intrinsic signaling pathways, and the incorporation of safety switches to precisely control CAR-T cell activation. We also discuss the most pressing issues pertaining to the selection of co-stimulatory domains, with a focus on strategies aimed at promoting CAR-T cell persistence and optimal antitumor functionality.

    Keywords: CAR-T cells, adapter CARs (AdCARs), Tandem CARs (tanCARs), Logic-gated CARs, safety switches, epitope editing, Antigen density

    Received: 27 Mar 2024; Accepted: 15 May 2024.

    Copyright: © 2024 Alviano, Biondi, Grassenis, Biondi, Serafini and Tettamanti. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Marta Serafini, Tettamanti Center and Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy, Monza, Italy

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.