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.

Synergistic effects of anti-PDL-1 with ablative radiation comparing to other regimens with same biological effect dose based on different immunogenic response

“…[9,10]. It has also been noted that radiation doses and fractionation schemes distinctly impact both the host immune system and the tumor cell's immunogenicity [11,12]. Many studies are ongoing to characterize their inhibitory and stimulatory effects [13], and to improve their effects by combinations of RT and immunotherapy [14,15].…”

Development and Radiation Response Assessment in A Novel Syngeneic Mouse Model of Tongue Cancer: 2D Culture, 3D Organoids and Orthotopic Allografts

“…Our in vivo orthotopic model could also serve as a valuable tool to examine the activity of novel immunotherapeutic strategies against this disease. While immune checkpoint inhibitors have recently received approval for clinical use in head and neck cancer patients [41], the optimal dose, schedule and sequence of combining checkpoint inhibitors with standard of care chemoradiation regimens is still unclear [42,43]. As such, several ongoing trials are investigating the combination of these immune-oncology agents with chemotherapy, radiation and targeted therapies [43].…”

Hyperthermia and immunotherapy: clinical opportunities

“…Published literature supports widespread clinical experience indicating that radiation and various regulatory approved immunotherapeutic agents can be safely combined [22]. The questions of sequencing and timing of radiation and immunotherapy to elicit optimal response have been more complex [23,24]. This question has been made more challenging by the limitations on the use of ionizing radiation.…”