Victoria Gershuny Abstracts
Victoria Gershuny
Ph.D. Candidate
Applied Mathematics GIDP
American Conference on Pharmacometrics
San Diego, California
October 8-10, 2018
Objectives: FOLFOX (5-fluouracil, leuvcovorin, and oxaliplatin) is in wide clinical use for colorectal adenocarcinoma. In addition to direct cytotoxic effects, this chemotherapy is now known to have immune effects, including stimulation of natural killer (NK) cells by oxaliplatin and elimination of myeloid derived suppressor cells (MDSCs) by 5-fluorouracil. This study aims to quantify the relative magnitudes of direct cytotoxicity and these two immune effects. Increased understanding of the immune system’s role may lead to improved therapeutic design.
Methods: A mathematical model is developed, consisting of 17 nonlinear coupled ordinary differential equations, accounting for the tumor as well as CD4+ and CD8+ T cells, Tregs, NK cells, dendritic cells, MDSCs, and both immunostimulatory (IL-2, IFN-gamma) and immunosuppressive (IL-10, TGF-beta) molecules. Tumor cell kill results from direct cytotoxicity as well as NK-cell- and effector T-cell-induced lysis. All parameters are estimated from experimental data, and predicted cell counts and plasma levels are checked against values in human patients.
Results: Whereas direct FOLFOX cytotoxicity and elimination of MDSCs by 5-FU both contribute significantly to tumor growth delay, oxaliplatin enhancement of NK cells has a negligible effect. The model is consistent with experimental studies showing that NK cells have less effect on tumor control than CD8+ T-cells, primarily because of low recruitment to the tumor site. In the case without surgery where 12 cycles of FOLFOX extend survival by 191 days, immune effects account for 23 days. In the case with surgery where FOLFOX extends survival by 128 days as compared to surgery alone, the immune effects account for 7 days.
Conclusions: The immunologic effects of FOLFOX are a significant component of its success in delaying tumor growth, suggesting additional immunotherapy might be beneficial. Targeting immunosuppressive effects appears to be a more promising strategy than attempting to enhance immune tumor cell lysis.
Abstract for Lay Audience
FOLFOX is a chemotherapeutic cocktail of three drugs that is widely used to treat colorectal cancer. In addition to directly killing tumor cells, this chemotherapy is now known to have effects on the immune system: stimulation of natural killer (NK) cells, which are responsible for killing any foreign cells, and elimination of myeloid derived suppressor cells (MDSCs), that play a role in preventing immune response. But how important are its different mechanisms for the chemotherapy’s success?
There isn’t a clear way for experimentalists to answer this question, thus a mathematical model is developed that accounts for the tumor and the different immune cells and molecules that interact with it. Tumor cells are killed both directly by the chemotherapy as well as by NK cells and other tumor-specific immune cells. All parameters are estimated from experimental data, and predicted cell counts and molecule concentrations are checked against values in human patients.
It is found that killing tumor cells directly by chemotherapy and eliminating MDSCs are vital in the success of this treatment. However, the role of NK cells is negligible. The model is consistent with experimental studies showing that NK cells have less effect on tumor control than tumor-specific immune cells, primarily because of trouble infiltrating the tumor site. In the case without surgery where FOLFOX extends survival by 191 days, immune effects account for 23 days. In the case with surgery where FOLFOX extends survival by 128 days as compared to surgery alone, the immune effects account for 7 extra days.
Thus, the immune effects of FOLFOX are a significant component of its success in delaying tumor growth, suggesting additional utilization of the immune system might be beneficial. Targeting immunosuppressive effects appears to be a more promising strategy than attempting to enhance tumor kill by immune cells. There is no way to make these conclusions experimentally, and mathematical modeling is instrumental in being able to quantify the different aspects of chemotherapy. With math as a tool, it is possible to continue to drive development of new successful chemotherapy and utilize existing chemotherapy more effectively.