A Mathematical Modeling Approach for Targeted Radionuclide and Chimeric Antigen Receptor-T Cell Combination Therapy
| Autor: | John E. Shively, Megan Minnix, Alexander B Brummer, Amrita Krishnan, Xiuli Wang, Russell C. Rockne, Jeffrey Y.C. Wong, Flavia Pichiorri, Vikram Adhikarla, Enrico Caserta, Dennis Awuah |
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| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Combination therapy medicine.medical_treatment T cell Cell TRT actinium-225 Article combination therapy medicine Distribution (pharmacology) RC254-282 Multiple myeloma applied_mathematics business.industry Neoplasms. Tumors. Oncology. Including cancer and carcinogens Daratumumab Immunotherapy daratumumab medicine.disease targeted radionuclide therapy Chimeric antigen receptor CAR-T multiple myeloma medicine.anatomical_structure Oncology Cancer research immunotherapy CS1 alpha particle therapy business mathematical model |
| Zdroj: | Cancers Cancers, Vol 13, Iss 5171, p 5171 (2021) Volume 13 Issue 20 |
| Popis: | Simple Summary Targeted radionuclide therapy (TRT) and immunotherapy, an example being chimeric antigen receptor T cells (CAR-Ts), represent two potent means of eradicating systemic cancers. Although each one as a monotherapy might have a limited effect, the potency can be increased with a combination of the two therapies. The complications involved in the dosing and scheduling of these therapies make the mathematical modeling of these therapies a suitable solution for designing combination treatment approaches. Here, we investigate a mathematical model for TRT and CAR-T cell combination therapies. Through an analysis of the mathematical model, we find that the tumor proliferation rate is the most important factor affecting the scheduling of TRT and CAR-T cell treatments with faster proliferating tumors requiring a shorter interval between the two therapies. Abstract Targeted radionuclide therapy (TRT) has recently seen a surge in popularity with the use of radionuclides conjugated to small molecules and antibodies. Similarly, immunotherapy also has shown promising results, an example being chimeric antigen receptor T cell (CAR-T) therapy in hematologic malignancies. Moreover, TRT and CAR-T therapies possess unique features that require special consideration when determining how to dose as well as the timing and sequence of combination treatments including the distribution of the TRT dose in the body, the decay rate of the radionuclide, and the proliferation and persistence of the CAR-T cells. These characteristics complicate the additive or synergistic effects of combination therapies and warrant a mathematical treatment that includes these dynamics in relation to the proliferation and clearance rates of the target tumor cells. Here, we combine two previously published mathematical models to explore the effects of dose, timing, and sequencing of TRT and CAR-T cell-based therapies in a multiple myeloma setting. We find that, for a fixed TRT and CAR-T cell dose, the tumor proliferation rate is the most important parameter in determining the best timing of TRT and CAR-T therapies. |
| Databáze: | OpenAIRE |
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