Neoadjuvant immunoradiotherapy for HPV mediated oropharynx cancer

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Project Summary HPV mediated oropharynx cancer (HPVOPC) is projected to increase in incidence in the United States over the next 20 years. Attempts to de-escalate nonsurgical treatment for HPVOPC have not been successful and current treatment regimens incur significant long-term morbidity. Recently, PD-1 inhibitors received approval as first line therapy for recurrent/metastatic head and neck squamous cell carcinoma (r/mHNSCC), achieving ~15-20% overall response rates. However, PD-1 inhibition has demonstrated no benefit in patients with previously untreated, locally advanced HPVOPC/HNSCC, and emerging neoadjuvant window of opportunity trials examining PD-1 inhibition have documented only modest response. Targeting stereotactic body radiation (SBRT) to the tumor while sparing the tumor draining lymphatics may increase the response to PD-1 inhibition as part of a novel rational therapeutic strategy. In support of this hypothesis, we have shown that ablating tumor- draining lymphatics blocks the response to PD-1 inhibition and that elective nodal irradiation attenuates antitumor immunity and T cell infiltration in multiple experimental HNSCC model systems. In addition, we found that early, but not delayed, lymphatic ablation blocks the response to combined SBRT and PD-1 inhibition, indicating that an immunologically competent draining lymph node bed is critical to mount effective antitumor immunity after PD-1 inhibition. We explored this premise in our recent Phase 1 clinical trial in resectable HNSCC patients who received nivolumab in combination with SBRT to gross tumor volume (GTV), followed by definitive surgical resection (NCT03247712). Astonishingly, the pathologic complete response rate in HPV+ patients was 90% and no patient required adjuvant radiation or chemoradiation. In addition, the combination of a CD47 inhibitor (evorpacept) with PD-1 inhibition shows enhanced response compared to PD-1 inhibition alone in both preclinical models and in r/mHNSCC. Our overall hypothesis is that preserving the immune-lymphatic axis during neoadjuvant immunoradiotherapy (NIRT) for HPVOPC will promote anti-tumor immunity, potentiate checkpoint blockade therapy and reinstate effective cancer immunosurveillance. Therefore, we propose a phase IIb, single arm clinical trial of neoadjuvant 8Gy x 3 SBRT to GTV followed by combination evorpacept and pembrolizumab in patients with previously untreated locally advanced, resectable HPVOPC, followed by risk adapted adjuvant therapy. We specifically hypothesize that combination neoadjuvant SBRT and evorpacept + pembrolizumab will 1) provide >80% complete/major pathologic response in patients with resectable HPVOPC, 2) is safe and will result in functional and quality of life metrics that are similar or better to those for patients treated with standard therapy, and 3) enhance cytotoxic CD8 T cell antitumor immunity by driving the priming and expansion of tumor- reactive T cells along the tumor-immune-lymphatic axis. A high pathologic response rate and favorable toxicity profile in the proposed trial will support a subsequent paradigm-shifting, randomized phase II trial comparing nonsurgical treatment with SBRT to GTV followed by immunotherapy versus standard of care radiation with concurrent cytotoxic chemotherapy.