Developing CAR T-Cell Therapies for Pediatric Solid Tumors.

Abstract

Chimeric antigen receptor (CAR) T cells have revolutionized the treatment of hematological malignancies, inducing notable and durable clinical responses.

However, for solid tumors, including but not limited to pediatric tumors, several peculiar biological features posed substantial challenges for achieving comparable results.

Despite sound pre-clinical evidence of the ability of CAR T cells to eradicate solid malignancies, their activity remains suboptimal when facing the in vivo complexity of solid tumors, characterized by antigen heterogeneity, scarce T-cell infiltration, and an immunosuppressive microenvironment.

Neuroblastoma was amongst the first tumors to be evaluated as a potential candidate for GD2-targeting CAR T cells, which recently documented promising results in high-risk, heavily pre-treated patients.

Moreover, innovative engineering strategies for generating more potent and persistent CAR T cells suggest the possibility to reproduce, and potentially improve, these promising results on a larger scale.

In the next years, harnessing the full therapeutic potential of CAR T cells and other immunotherapeutic strategies may open new possibilities for effectively treating the most aggressive forms of pediatric tumors.

COI Statement

Declarations. Funding: The work was supported by grants from the 5×1000 Project of the Ministry of Health to Del Bufalo and Ricerca Finalizzata of the Ministry of Health to Del Bufalo (GR-2021-12372614). Conflicts of Interest/Competing Interests: Gabriele Canciani, Francesco Fabozzi, Claudia Pinacchio, Manuela Ceccarelli, and Francesca del Bufalo have no conflicts of interest that are directly relevant to the content of this article. Ethics Approval: Not applicable. Consent to Participate: Not applicable. Consent for Publication: Not applicable. Availability of Data and Material: Not applicable. Code Availability: Not applicable. Authors’ Contributions: GC and FdB conceptualized and drafted the manuscript. FF, CP, and MC critically revised and contributed to the organization of the submitted version.

References:

Gross G, Waks T, Eshhar Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci U S A. 1989;86:10024–8.
Eshhar Z, Waks T, Gross G, Schindler DG. Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proc Natl Acad Sci U S A. 1993;90:720–4. https://doi.org/10.1073/pnas.90.2.720 .
June CH, Sadelain M. Chimeric antigen receptor therapy. N Engl J Med. 2018;379:64–73. https://doi.org/10.1056/NEJMra1706169 .
Brocker T, Karjalainen K. Signals through T cell receptor-zeta chain alone are insufficient to prime resting T lymphocytes. J Exp Med. 1995;181:1653–9. https://doi.org/10.1084/jem.181.5.1653 .
Newick K, O’Brien S, Moon E, Albelda SM. CAR T cell therapy for solid tumors. Annu Rev Med. 2017;68:139–52. https://doi.org/10.1146/annurev-med-062315-120245 .

Article info

Journal issue:

Volume: 27
Issue: 1

Doi:

10.1007/s40272-024-00653-7

More resources:

MedlinePlus Health Information

Medical

Free resource

Springer

Full Text Sources