Radiation therapy and immunotherapy: what is the optimal timing or sequencing?

Abstract

Radiotherapy is a component of the standard of care for many patients with locally advanced nonmetastatic tumors and increasingly those with oligometastatic tumors. Despite encouraging advances in local control and progression-free and overall survival outcomes, continued manifestation of tumor progression or recurrence leaves room for improvement in therapeutic efficacy. Novel combinations of radiation with immunotherapy have shown promise in improving outcomes and reducing recurrences by overcoming tumor immune tolerance and evasion mechanisms via boosting the immune system's ability to recognize and eradicate tumor cells. In this review, we discuss preclinical and early clinical evidence that radiotherapy and immunotherapy can improve treatment outcomes for locally advanced and metastatic tumors, elucidate underlying molecular mechanisms and address strategies to optimize timing and sequencing of combination therapy for maximal synergy.

Keywords: CTLA4; PD1/PDL1; adoptive cell therapy; cancer immunotherapy; cancer vaccines; combination therapy; cytokines; immune checkpoint inhibitors; radiation; sequence; timing.

Figure 1.. Combinations of immunotherapy and radiotherapy with respect to timing and sequencing.

Figure 2.. Radiation effects on the tumor microenvironment and potential strategies for combining radiation with immunotherapy.

After radiation therapy, cancer cell antigens are released and recognized by dendritic cells, which upon activation cross present these antigens to T cells, which are then primed and activated. This cascade of events can be potentiated by using agents that enhance DC activation and T-cell priming and activation. Upon activation, circulating T cells infiltrate the tumor and engage cancer cell antigens to trigger immune-mediated cell death. Trafficking of activated T cells to both primary tumor and metastatic sites could be enhanced by stromal-disrupting agents.