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Neoadjuvant immunoradiotherapy for HPV mediated oropharynx cancer

新辅助免疫放疗治疗 HPV 介导的口咽癌

基本信息

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
项目类别：
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

项目摘要

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.

项目总结