Heiko Enderling, PhD
The combination of radiation and immunotherapy is currently enjoying unprecedented attention as a treatment strategy for patients with metastatic cancer. Clinical case studies and proof-of-principle clinical trials report on systemic, abscopal responses to the combination of focal irradiation and immunotherapy in patients who were progressing on immunotherapy alone.1 However, individualized treatment plans to optimally exploit the synergy between immunotherapy and radiotherapy remain elusive due to high intra- and inter-patient heterogeneity and a myriad of possible radiation fractionation protocols, immunotherapy agents, and scheduling options.
Integrated mathematical oncology provides tools that could dissect this complexity and contribute to the transition of synergistic radiation and immunotherapy and radiation-induced abscopal effects into the personalized medicine era. To this end, we need to develop tractable, quantitative models based on carefully selected cancer biology and immunology principles. Predictions of such models, calibrated with patient-specific clinical data, need to be validated in prospective clinical trials.
As a first step toward developing quantitative models, we recently developed a mathematical framework to simulate the systemic dissemination of T cells activated in response to focal therapy.2
Model simulations suggest that metastatic sites within individual patients do not participate equally in immune surveillance and thus are likely to exhibit different systemic responses after local irradiation. We hypothesized that such a model could help identify patient-specific radiation treatment targets that have a high likelihood of inducing abscopal effects. Such targeted treatment strategies would be then worthy of validation in a prospective clinical trial. In a subsequent commentary, this model was critically discussed, with a focus on complex biology that was not incorporated in the model.3
Here we discuss the raised concerns in light of the purpose and applicability of the mathematical model. We echo the need for clinical validation.
Clinical immunotherapy trials, especially if combined with adjuvant focal cytotoxic therapies, have generated encouraging results, including evidence of clinical remissions.4,5
Radiation therapy can synergize with immunotherapies, such as anti-CTLA4 antibodies or FMS-like tyrasine kinase 3 ligands to generate systemic responses outside the radiation field, as observed in a series of seminal studies by Demaria and Formenti.6-8
Immune activation after radiation-induced immunogenic cell death provides an explanation for the previously believed anecdotal abscopal effect. Clinical case reports of radiation-induced abscopal effects date back to the 1950s9
and are reported after other immune-activating local therapies such as thermotherapies, including hyperthermia, radiofrequency ablation, and cryotherapy.10-12
The FDA approval of multiple immunotherapeutic agents generates both a clinical need and a prime opportunity to explore and exploit radiation and immunotherapy synergy, particularly for patients with metastatic cancer. In a recent proof-of-principle clinical trial combining local radiotherapy and granulocyte-macrophage colony-stimulating factor, 11 of 41 patients exhibited an objective systemic (abscopal) response.1
However, which metastatic sites were irradiated remained a heuristic decision.
Identifying patient-specific treatment targets adds an additional layer of personalization based upon limited clinical and biological data available for decision making (Figure). Unraveling the complex, adaptive tumor–immune system interactions that determine a response to therapy—both locally in the primary tumor and systemically in metastatic disease—requires nonlinear understanding and analysis of the multifactorial dynamics that govern them. As identified by Demaria and Formenti, more basic and translational research is needed to decrease treatment outcome uncertainty associated with the biological complexity of these interactions.3
Such research should include: 1) best radiation technique and fractionation protocol to induce antitumor immunity, 2) sequencing of immune modulators, 3) radiation and immunotherapy sensitivity of different tumor types in primary or metastatic tissue environments, 4) possible lack of common expression of antigen(s) or neoantigens between the irradiated and unirradiated metastases, and 5) component of the local immune environment, such as the availability and infiltration of dendritic cells.