Designing combination therapies for cancer treatment: application of a mathematical framework combining CAR T-cell immunotherapy and targeted radionuclide therapy.

Autor:	Adhikarla V; Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States., Awuah D; Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States., Caserta E; Department of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States., Minnix M; Department of Molecular Imaging and Therapy, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States., Kuznetsov M; Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States., Krishnan A; Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States., Wong JYC; Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA, United States., Shively JE; Department of Molecular Imaging and Therapy, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States., Wang X; Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States., Pichiorri F; Department of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States., Rockne RC; Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2024 Apr 18; Vol. 15, pp. 1358478. Date of Electronic Publication: 2024 Apr 18 (Print Publication: 2024).
DOI:	10.3389/fimmu.2024.1358478
Abstrakt:	Introduction: Cancer combination treatments involving immunotherapies with targeted radiation therapy are at the forefront of treating cancers. However, dosing and scheduling of these therapies pose a challenge. Mathematical models provide a unique way of optimizing these therapies. Methods: Using a preclinical model of multiple myeloma as an example, we demonstrate the capability of a mathematical model to combine these therapies to achieve maximum response, defined as delay in tumor growth. Data from mice studies with targeted radionuclide therapy (TRT) and chimeric antigen receptor (CAR)-T cell monotherapies and combinations with different intervals between them was used to calibrate mathematical model parameters. The dependence of progression-free survival (PFS), overall survival (OS), and the time to minimum tumor burden on dosing and scheduling was evaluated. Different dosing and scheduling schemes were evaluated to maximize the PFS and optimize timings of TRT and CAR-T cell therapies. Results: Therapy intervals that were too close or too far apart are shown to be detrimental to the therapeutic efficacy, as TRT too close to CAR-T cell therapy results in radiation related CAR-T cell killing while the therapies being too far apart result in tumor regrowth, negatively impacting tumor control and survival. We show that splitting a dose of TRT or CAR-T cells when administered in combination is advantageous only if the first therapy delivered can produce a significant benefit as a monotherapy. Discussion: Mathematical models are crucial tools for optimizing the delivery of cancer combination therapy regimens with application along the lines of achieving cure, maximizing survival or minimizing toxicity. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. (Copyright © 2024 Adhikarla, Awuah, Caserta, Minnix, Kuznetsov, Krishnan, Wong, Shively, Wang, Pichiorri and Rockne.)
Databáze:	MEDLINE
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