By Bhisham Chera, MD, University of North Carolina School of Medicine
The discovery of immunotherapy has resulted in a paradigm shift in oncology. There is a lot of excitement in combining immunotherapy with radiation therapy, with the hopes of capitalizing on a possible synergy. Radiation therapy can have both proimmunogenic and immunosuppressive effects,1 and thus the optimal combination of radiation therapy (technique, dose, volume, timing) with immunotherapy should harness the proimmunogenic effects. Many of the initial clinical trials have evaluated the traditional design of adding a new therapeutic concurrently with the standard of care radiation therapy or chemoradiotherapy regimens. Most of these trials, across various diseases sites, have neither shown an increase in toxicity nor improvements in cancer control. To date the PACIFIC trial has been the only positive, practice changing chemoimmunoradiotherapy trial.2 The PACIFIC trial showed that the addition of adjuvant durvalumab (PD-L1 inhibitor) to chemoradiotherapy improved progression free and overall survival in patients with unresectable stage III non-small cell lung cancer.2 A similar clinical trial, the JAVELIN trial, was conducted with patients with previously untreated locally advanced squamous cell carcinoma of the head and neck.3 Patients were randomized to avelumab (PD-L1 inhibitor) plus chemoradiotherapy followed by avelumab maintenance therapy versus placebo in combination with chemoradiotherapy followed by placebo maintenance. The trial was stopped at the time of preplanned interim analysis because of the lack of progression free survival improvement in the avelumab group.
Within the head and neck oncology community, there has been much discussion around whether the standard, large volumes used to treat head and neck cancer are overly immunosuppressive. Specifically, there is concern that the radiation of the draining regional nodal basins ablates cytotoxic T and other immuno-modulating cells that are necessary for antitumor immunity.
In the K. Kian Ang MD, PhD, FASTRO, Commemorative Plenary Session I, Robert Saddawi-Konefka, MD, PhD, presented the results of a preclinical study of neoadjuvant immunoradiotherapy in orthotopic murine oral squamous cell carcinoma models. The purpose of the study was to evaluate how ablation or preservation of the draining lymphatics affected the tumor immune microenvironment. They delivered different sequences of neoadjuvant immunoradiotherapy (PD-1 inhibition with stereotactic radiotherapy) along with procedures which ablate tumor-draining lymph nodes or lymphatic channels. The authors hypothesized that preserving the tumor-draining lymph nodes and lymphatic channels would potentiate PD-1 inhibition and promote antitumor immunity. When the lymphatic channels were ablated, they observed less prevalence of cytotoxic, tumor-antigen specific CD8 T cells within the tumor immune microenvironment. Within the tumor draining lymph nodes, they observed that dendritic cells were necessary for the neoadjuvant immunoradiotherapy response. In summary they demonstrated in a pre-clinical mode that targeting tumors with stereotactic radiation and PD-1 inhibition while sparing draining lymphatics enhances anticancer immunity.
These findings from Dr. Saddawi-Konefka and colleagues are very interesting and should be considered when designing future radioimmunotherapy trials for patients with head and neck cancer. Omission of radiation of regional nodal basins, especially elective nodal areas should be considered in future immunotherapy trials. However, occult metastases in regional lymphatics are a common occurrence in head and neck cancer and elective regional radiation therapy is standardly given in many clinical situations. Thus, careful, thoughtful trial design is needed. A possible opportunity may be in window of opportunity trials in the neoadjuvant setting prior to surgery.
Abstract 8 - Neoadjuvant Immunoradiotherapy in a Tobacco-Signature Preclinical Oral Squamous Cell Carcinoma Model was presented on February 24, 2022, during the K. Kian Ang, MD, PhD, FASTRO, Commemorative Plenary Session.
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