Abstract 4542: A mathematical model for immuno-chemotherapy

Abstract

Abstract Chemotherapy and immunotherapy have sometimes been considered two mutually exclusive approaches. On the one hand, chemotherapy has long been considered as a modestly effective treatment (outside pediatric oncology), with a short-lived effect caused by drug resistance, a poor tolerance profile and a detrimental effect on the immune system. On the other hand, the oncologist continues using chemotherapies for many reasons: if the control of a large tumor mass has to be obtained urgently irrespective of the side effects on the immune system, if immunotherapy has failed or has not been validated as a first line of treatment, when no targeted therapy can apply, etc. However, the issue of modifying the long-validated chemotherapy protocols to make them a good fit for an adjuvant (or concomitant) immunotherapy has not been addressed yet. The practice of gluing together an old Maximum Tolerated Dose (MTD) protocol with a new immunotherapy protocol is often the standard practice, even though some re-design would be needed to mitigate the massive and prolonged immunosuppression caused by chemotherapy protocols. This lack of flexibility in the chemotherapy regimen could seriously jeopardize the effects of adjuvant or concomitant immunotherapy. Fortunately, chemotherapy and immunotherapy may not be incompatible per se: there are accumulating evidence that low-dose chemotherapies with little or no break-period (the so-called metronomic regimen) might have an immunological mode of action (in addition to the classical explanation of its anti-angiogenic effect and cytotoxicity). Furthermore, even with MTD protocols, experienced oncologists can improve the clinical outcome with the rationale use of pro-immunogenic drugs. Nevertheless, the best way to combine chemotherapy with immunotherapy is unknown and to find it in a trial and error manner is unrealistic (high number of possibilities). This is why we present a pharmacodynamic model of chemotherapy in combination with immune checkpoint blockers, in order to provide a practical tool for the design and the management of clinical trials. Based on simple equations, this model does not predict a priori the best protocol, but helps the analysis of clinical data and the subsequent identification of optimal combinations. The mathematical model is based on discrete-time equations of the tumor mass dynamics, under the retro-control of a specific immune response partly antagonized by chemotherapy, but also stimulated by the release of tumor antigens. An original dynamic model of lymphopenia is introduced to describe the immunosuppressive consequences of chemotherapy. The effects of immune checkpoint blockers are described in coherence with a previous publication in Cancer Research by the same authors. Acquired drug resistance and tumor angiogenesis are also modeled. Examples of practical applications are provided by showing how the model can describe various pre-clinical and clinical data. Citation Format: Raphael Serre, Dominique Barbolosi. A mathematical model for immuno-chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4542. doi:10.1158/1538-7445.AM2017-4542