Neoadjuvant immunoradiotherapy for HPV mediated oropharynx cancer

项目摘要 HPV介导的口咽癌（HPVOPC）预计在美国的发病率将高于2008年。 未来20年目前，降低HPVPC非手术治疗的尝试尚未成功 治疗方案导致显著的长期发病率。最近，PD-1抑制剂获得批准作为一线药物， 复发性/转移性头颈部鳞状细胞癌（r/mHNSCC）的治疗，达到约15-20% 总体响应率。然而，PD-1抑制在先前患有前列腺癌的患者中没有表现出益处。 未经治疗的局部晚期HPVOPC/HNSCC和新出现的新辅助治疗机会窗试验 检测PD-1抑制仅记录了适度的反应。靶向立体定向体部放射 （SBRT）的肿瘤，同时保留肿瘤引流血管，可能会增加对PD-1抑制的反应 作为一种新的理性治疗策略的一部分。为了支持这一假设，我们已经证明切除肿瘤- 引流淋巴管阻断对PD-1抑制的反应，选择性淋巴结照射减弱抗肿瘤作用 免疫和T细胞浸润。此外，我们发现，早期， 但不延迟，淋巴消融阻断了对SBRT和PD-1联合抑制的反应，表明 免疫活性的引流淋巴结床对于在术后产生有效的抗肿瘤免疫是至关重要的。 PD-1抑制。我们在最近的可切除的HNSCC患者的I期临床试验中探索了这一前提， 接受纳武利尤单抗联合SBRT至总肿瘤体积（GTV），然后进行确定性手术 切除术（NCT 03247712）。令人惊讶的是，HPV+患者的病理完全缓解率为90%， 没有病人需要辅助放疗或放化疗。此外，CD 47抑制剂和抗CD 47抗体的组合， 与单独的PD-1抑制相比，在两种临床前试验中，（依沃太平洋）与PD-1抑制相比显示增强的应答。 模型和r/mHNSCC中。我们的总体假设是，保留免疫淋巴轴， 新辅助免疫放射治疗（NIRT）可促进抗肿瘤免疫，增强检查点， 阻断治疗和恢复有效的癌症免疫监视。因此，我们提出了IIb期，单一 新辅助8 Gy x 3 SBRT治疗GTV，随后联合evorpacept和pembrolizumab的一项臂临床试验 既往未经治疗的局部晚期、可切除的HPVOPC患者，随后接受风险适应性佐剂 疗法我们特别假设，新辅助SBRT和依沃帕塞+帕博利珠单抗联合治疗将 1)在可切除的HPVOPC患者中提供>80%的完全/主要病理学缓解，2）安全， 导致功能和生活质量指标类似于或更好于用标准治疗的患者 治疗，和3）通过驱动肿瘤的引发和扩增来增强细胞毒性CD 8 T细胞抗肿瘤免疫。 反应性T细胞沿着肿瘤免疫淋巴轴。高病理反应率和有利的 拟议试验中的毒性特征将支持随后的范式转变，随机II期 一项比较SBRT与GTV非手术治疗后免疫治疗与标准治疗的试验 同时进行细胞毒化疗。

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.