Neoadjuvant immunoradiotherapy for HPV mediated oropharynx cancer

新辅助免疫放疗治疗 HPV 介导的口咽癌

• 批准号: 10682257
• 负责人: Joseph A Califano
• 金额: $ 64.48万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-18 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10682257
• 关键词: Ablation; Adjuvant; Adjuvant Therapy; Anti-CD47; Architecture; Attenuated; Automobile Driving; B-Lymphocytes; Beds; Biological Models; CD4 Positive T Lymphocytes; CD47 gene; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Patient; Cell Adhesion; Cells; Clinical; Clinical Trials; Clone Cells; Common Terminology Criteria for Adverse Events; Cytotoxic Chemotherapy; Data; Dependence; Disease-Free Survival; Dose; Enteral Feeding; Excision; Frequencies; HPV oropharyngeal cancer; Head and Neck Squamous Cell Carcinoma; Heterogeneity; Human Papilloma Virus-Related Malignant Neoplasm; Human Papillomavirus; Immune; Immunocompetent; Immunologic Surveillance; Immunotherapy; In complete remission; Incidence; Infiltration; Lymphatic; Malignant Neoplasms; Measures; Metastatic/Recurrent; Morbidity - disease rate; Neck Dissection; Neoadjuvant Therapy; Nivolumab; Nodal; Operative Surgical Procedures; Outcome; PD-1 inhibitors; Pathologic; Patients; Phase; Phase I Clinical Trials; Pre-Clinical Model; Primary Neoplasm; Quality of life; Radiation; Radiation therapy; Radioimmunotherapy; Randomized; Research; Resectable; Risk; Safety; Sentinel Lymph Node; Structure of germinal center of lymph node; T cell clonality; T cell infiltration; T-Lymphocyte; Therapeutic; Throat Cancer; Toxic effect; Treatment Protocols; Tumor Antigens; Tumor Expansion; Tumor Immunity; Tumor Volume; United States; Up-Regulation; anti-PD-1; anti-PD1 therapy; anti-cancer; antigen-specific T cells; arm; cancer immunotherapy; cancer infiltrating T cells; chemokine; chemoradiation; chemotherapy; cytotoxic CD8 T cells; design; draining lymph node; head and neck cancer patient; immune activation; immune checkpoint blockade; immune function; improved; inhibitor; irradiation; lymph nodes; novel; pembrolizumab; phase I trial; phase II trial; pre-clinical; preservation; programmed cell death protein 1; response; standard of care; trial comparing; tumor; tumor ablation

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.

项目摘要 HPV介导的口咽癌(HPVOPC)在美国的发病率预计将在 接下来的20年。目前，降低HPVOPC非手术治疗的尝试并不成功 治疗方案会导致显著的长期发病率。最近，PD-1抑制剂被批准为一线药物 治疗复发/转移的头颈部鳞状细胞癌(r/mHNSCC)，达到~15%-20% 总体回复率。然而，抑制PD-1对既往 未经治疗的局部晚期HPVOPC/HNSCC和新兴的新佐剂机会窗试验 检测PD-1抑制只记录了温和的反应。靶向立体定向全身放射治疗 (SBRT)在保留肿瘤引流淋巴管的同时，可能增加对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，我们已经证明了消融肿瘤- 引流淋巴管阻断对PD-1抑制的反应和选择性结节照射减弱抗肿瘤作用 多个实验性HNSCC模型系统的免疫和T细胞浸润。另外，我们发现在早期， 但没有延迟，淋巴消融阻止了对SBRT和PD-1联合抑制的反应，表明 一个免疫活性的引流淋巴结床是建立有效的抗肿瘤免疫的关键 PD-1抑制作用。我们在最近对可切除的HNSCC患者进行的第一阶段临床试验中探索了这一前提 接受nivolumab联合SBRT测量大体肿瘤体积(GTV)，然后进行明确的手术 手术切除(NCT03247712)。令人惊讶的是，HPV阳性患者的病理完全应答率为90%， 没有患者需要辅助放疗或化疗。此外，CD47抑制剂的组合 (Evorpacept)与PD-1抑制相比，在两种临床前均显示出比单独抑制PD-1更强的反应 模型和r/mHNSCC中。我们的总体假设是在治疗过程中保护免疫淋巴轴 HPVOPC的新辅助免疫放射治疗(NIRT)将促进抗肿瘤免疫，增强检查点 阻断治疗，恢复有效的癌症免疫监测。因此，我们提议IIb阶段，单一 新佐剂8Gy3次SBRT治疗GTV后联合evorpacept和pembrolizumab的ARM临床试验 在以前未治疗的局部晚期、可切除的HPVOPC患者中，随后接受风险适应辅助治疗 心理治疗。我们特别假设联合新佐剂SBRT和evorpacept+pembrolizumab将 1)在可切除的HPVOPC患者中提供80%的完全/主要病理反应，2)是安全的 使功能和生活质量指标与接受标准治疗的患者相似或更好 治疗，以及3)通过推动肿瘤的启动和扩张来增强细胞毒性CD8 T细胞的抗肿瘤免疫- 沿肿瘤免疫淋巴轴的反应性T细胞。病理应答率高，疗效好 拟议试验中的毒性情况将支持随后的范式转换、随机第二阶段 非手术治疗SBRT与GTV后免疫治疗与标准治疗的比较研究 护理放射治疗与细胞毒化疗同步进行。