Harnessing tumor immunity with chemotherapy: Mathematical modeling for decision-making in combinatorial regimen with immune-oncology drugs.

• DOI: 10.1200/jco.2020.38.15_suppl.e14095
• Publication Date: 2020-05-25T15:17:49Z
• Authors: Vesna Cuplov; Guillaume Sicard; Dominique Barbolosi; Joseph Ciccolini; Fabrice Barlesi
• Keywords: Pemetrexed

e14095 Background: Combining chemotherapy and immune checkpoint inhibitors (ICI) is challenging due to the near-infinite choice of dosing, scheduling sequencing between drugs. The aim this work develop a phenomenological model that describes synergistic effect cytotoxics check point in patients with cancer. Methods: Inspired from literature, we have developed an integrative mathematical includes tumor cells, cytotoxic T cells (CTLs) regulatory (TREGs) plus pharmacokinetics (PK) inputs. Loss mass combined direct chemotherapy-induced cytotoxicity CTLs response, which turn inhibited by mitigated TREGs micro-environment. as well impact lymphodepletion on tolerance, whereas ICIs protect against inhibition. Identification model’s parameters simulations various were performed using Mlxplore software Python standalone code. In vitro vivo experiments lung cancer models generate experimental data adjust parameters. Results: Complex interplays best described 10-parameters so ensure better identifiability. PK/PD relationships integrated compartmental modeling. silico show how changes dosing efficacy endpoints, observation line literature. Ongoing pemetrexed-cisplatin doublet anti-PD1 pembrolizumab help optimizing self-learning loop. Conclusions: This at frontier modeling therapeutics ICIs. could narrow down treatment choices define optimal combinations prior running clinical trials. Such will identify scheduling, achieve synergism efficacy.