Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

A Mathematical Modeling Approach for Targeted Radionuclide and Chimeric Antigen Receptor-T Cell Combination Therapy

Vikram Adhikarla
* ORCID logo ,
Dennis Awuah
ORCID logo ,
Alex Brummer
,
Enrico Caserta
,
Amrita Krishnan
,
Flavia Pichiorri
,
Megan Minnix
,
John E. Shively
,
Jeffrey Y.C. Wong
,
Xiuli Wang
,
Russell C. Rockne
* ORCID logo
Version 1 : Received: 15 September 2021 / Approved: 17 September 2021 / Online: 17 September 2021 (09:32:33 CEST)

A peer-reviewed article of this Preprint also exists.

Adhikarla, V.; Awuah, D.; Brummer, A.B.; Caserta, E.; Krishnan, A.; Pichiorri, F.; Minnix, M.; Shively, J.E.; Wong, J.Y.; Wang, X.; Rockne, R.C. A Mathematical Modeling Approach for Targeted Radionuclide and Chimeric Antigen Receptor T Cell Combination Therapy. Cancers 2021, 13, 5171. Adhikarla, V.; Awuah, D.; Brummer, A.B.; Caserta, E.; Krishnan, A.; Pichiorri, F.; Minnix, M.; Shively, J.E.; Wong, J.Y.; Wang, X.; Rockne, R.C. A Mathematical Modeling Approach for Targeted Radionuclide and Chimeric Antigen Receptor T Cell Combination Therapy. Cancers 2021, 13, 5171.

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 (CAR) T-cells therapy in hematologic malignancies. Moreover, TRT and CAR T therapies possess unique features that require special consideration when determining how to dose, time, and sequence combination treatments, including the distribution of TRT dose in the body, the decay rate of the radionuclide, and the proliferation and persistence of the CAR-T cells. These characteristics complicate additive or synergistic effects of combination therapies and warrant a mathematical treatment which includes these dynamics in relation to the proliferation and clearance rates of the target tumor cells. Here we combine two previously published mathematical models in a multiple myeloma setting to explore the effects of dose, timing, and sequencing of TRT and CAR-T cell based therapies. 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.

Keywords

CAR T; Targeted Radionuclide Therapy; TRT; Mathematical Model; Multiple Myeloma; Immunotherapy; Daratumumab; CS1; Combination Therapy

Subject

Computer Science and Mathematics, Applied Mathematics

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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