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D'Souza et al. J Cancer Metastasis Treat 2022;8:28 https://dx.doi.org/10.20517/2394-4722.2022.51 Page 11 of 15

CONCLUSION
CAR-T cell therapy for MM presents unique biological and clinical challenges similar to other advanced
solid malignancies. One of these challenges is tumor-antigen heterogeneity, which allows antigen-negative
tumor cells to escape CAR-T cell lysis and continue to grow. Theoretically, universal antigen expression on
tumors should not be required for CAR-T cells to eliminate the tumor, as CAR-T cell function can induce
an immunologic bystander effect, resulting in the non-antigen-specific antitumor immune response. The
latter is aided either by innate immune cell populations with tumor lytic abilities or, most significantly, by
cross-presentation of a diverse antigen repertoire to CD4+ and CD8+ T cells by antigen-presenting cells
(APCs) in the lymph nodes, resulting in activation of the T cell cytotoxic functions.

In the few studies conducted so far, it is clear that CAR-T cells are unable to induce strong bystander effects
in solid tumor models, yet some promising strategies exist that can potentiate a broad endogenous
antitumor response. Combination of CAR-T cells with immunomodulatory agents, and the design of novel,
sophisticated CAR constructs with secretory abilities might be ways to manage TME’s immunosuppression,
allowing CAR-T cells and the endogenous T cell repertoire to function more efficiently. While the
development of more advanced CAR-T cell therapies is underway, the presence or lack of bystander effects
following CAR-T cell therapy needs to be thoroughly investigated in more preclinical studies and, more
importantly, clinical trials that will ultimately determine whether these therapies can exhibit their full
therapeutic potential in solid tumors like MM.

DECLARATIONS
Authors’ contributions
Equally contributed to the design, writing, critically reviewing and final approval of the manuscript: D'Souza
RR, Dimou P, Bughda R, Hawkins E, Laboreiro Babe C, Klampatsa A

Availability of data and materials
Not applicable.

Financial support and sponsorship
Klampatsa A is supported by the Cris Cancer Foundation.

Conflict of interest
All authors declare that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.

Consent for publication
Not applicable.

Copyright
© The Author(s) 2022.

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