The Goldilocks Window of Personalized Chemotherapy: Getting the Immune Response Just Right

Abstract

The immune system is a robust and often untapped accomplice of many standard cancer therapies. A majority of tumors exist in a state of immune tolerance where the patient's immune system has become insensitive to the cancer cells. Because of its lymphodepleting effects, chemotherapy has the potential to break this tolerance. To investigate this, we created a mathematical modeling framework of tumor-immune dynamics. Our results suggest that optimal chemotherapy scheduling must balance two opposing objectives: maximizing tumor reduction while preserving patient immune function. Successful treatment requires therapy to operate in a "Goldilocks Window" where patient immune health is not overly compromised. By keeping therapy "just right," we show that the synergistic effects of immune activation and chemotherapy can maximize tumor reduction and control.

Tumor neoantigen heterogeneity thresholds provide a time window for combination immunotherapy

“…The role of neoantigens and their heterogenous distributions across a tumor seems to be key in the response to checkpoint inhibition therapy. Multidisciplinary studies gaining insight into the dynamics of epitope heterogeneity and the possible existence of cooperative effects between targetedand immuno-therapies might shed new light into increasing the effectiveness of immune surveillance across different tumor evolutionary histories and types [16,36].…”

Changing Oncology Treatment Paradigms in the COVID-19 Pandemic

“…Although such validated assessments may not exist currently, past studies may pave the way for such decision-making tools. 12 Such studies include biophysical and mathematical models of cancer cell behavior that identify patterns of tumor cell expansion, even occurring on the individual patient level. 13 At the convergence of mathematical oncology, cancer cell biology, and immunology, there may be a meeting point that will help solve modern and urgent problems in practical cancer treatment by informing better timing of cancer treatment.…”

Delicate balances in cancer chemotherapy: Modeling immune recruitment and emergence of systemic drug resistance

“…The ability of drugs to induce anti-tumor immune responses is not sufficient by itself to insure a successful therapeutic response, as the effect on various compartments of the immune system, and thus on overall tumor burden can vary dramatically depending on dose, schedule and tumor type. Scheduling and dosing of an ICD drug is of critical importance in instigating an immune response, which relates to the concept of "getting things just right" [13,57]. For instance, administration of cyclophosphamide on a 6-day repeating schedule (Q6D) at 140 mg/kg per dose, dramatically improves the therapeutic outcome for murine GL261 gliomas through immunomodulatory mechanisms [9,10,11].…”

“…Ledzewicz, Behrooz, and Schättler proposed a minimally parameterized mathematical model for low-dose metronomic chemotherapy that explicitly considers tumor vasculature [61], and in subsequent work [62] applied optimal control theory to this system, so as to devise a treatment schedule that can minimize tumor burden subject to appropriate constraints. To the best of our knowledge, only one study has looked at modeling the immune recruitment by ICD drugs [57]. In that work, however, there was no experimental validation of the model proposed.…”