Mathematical Modeling and Computational Predictions in Oncoimmunology

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Impact of TRT dose on (A) tumor volume and (B) Survival metrics. Impact of CAR-T cell therapy dose on (C) tumor volume and (D) Survival metrics. A threshold of approximately 6.3 kBq for TRT and 0.7 million CAR-T cells is required to observe an increase in PFS. Impact of timing of second dose of TRT on tumor burden (E) and survival (F). Impact of timing of second dose of CAR-T cell therapy on tumor burden (G) and Survival (H). When splitting the doses, the TRT dose was 3.7 kBq while CAR-T cell dose was 0.5 million cells for each administration. At these doses, the second dose needs to be given before day 12 for either TRT or CAR-T therapy to note any advantage in PFS. The model predicts that 7.4 kBq single dose or 1 million CAR-T cell dose that are split into two doses have a minimal effect on survival (D,E blue arrow).
Original Research
18 April 2024

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.

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