Strategies for Cancer Immunotherapy Clinical Trials

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Recent accomplishments include the following: BINTRAFUSP ALFA, A BIFUNCTIONAL FUSION PROTEIN TARGETING TGF-BETA AND PD- L1, IN PATIENTS WITH HUMAN PAPILLOMAVIRUS-ASSOCIATED MALIGNANCIES. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of transforming growth factor (TGF)-betaRII (a TGF-beta "trap") fused to a human IgG1 mAb blocking programmed cell death ligand 1. This is the largest analysis of patients with advanced, pretreated human papillomavirus (HPV)-associated malignancies treated with bintrafusp alfa. In these phase 1 and phase 2 trials, patients with advanced, pretreated, checkpoint inhibitor- naive HPV- associated cancers received bintrafusp alfa intravenously every 2 weeks until progressive disease, unacceptable toxicity, or withdrawal. Primary endpoint was best overall response per Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1; other endpoints included safety. The confirmed objective response rate per RECIST V.1.1 in the checkpoint inhibitor-naive, full-analysis population was approximately 30% to 40% (including some complete responses); eight patients had stable disease (disease control rate, 44%). In addition, three patients experienced a delayed partial response after initial disease progression, for a total clinical response rate of approximately 35% (95% CI, 23.6% to 49.1%). Approximately 83%of patients experienced treatment-related adverse events, which were grade 3/4 in 16 patients. No treatment-related deaths occurred. Bintrafusp alfa showed clinical activity and manageable safety and is a promising treatment in HPV-associated cancers. These findings support further investigation of immunotherapy in patients with advanced HPV-associated cancers. In addition, staff in the translational compoent of the CIO were involved in the planning, review, and analyses of the followig completed clinical study publications: [] First-in-human phase Ib trial of M9241 (NHS-IL12) plus avelumab in patients with advanced solid tumors, including dose expansion in patients with advanced urothelial carcinoma. Strauss...Schlom, Donahue, Tsai...Gulley. J Immunother Cancer, 2023. [] Flutamide with or without PROSTVAC in non-metastatic castration resistant (MO) prostate cancer. Madan...Donahue...Karzai...Strauss...Schlom, Gulley. Oncologist, 2023. [] Phenotypic plasticity and reduced tissue retention of exhausted tumor-infiltrating T cells following neoadjuvant immunotherapy in head and neck cancer. Sievers...Redman, Soon-Shiong, Schlom, Gulley, Allen. Cancer Cell, 2023. [] Avelumab in men with metastatic castration-resistant prostate cancer, enriched for patients treated previously with a therapeutic cancer vaccine. Madan, Redman, Karzai...Schlom, Gulley. J Immunother, 2023. [] Immune correlates with response in patients with metastatic solid tumors treated with a tumor targeting immunocytokine NHS-IL12. Toney, Gatti-Mays, Tschernia, Strauss, Gulley, Schlom, Donahue. Int Immunopharm, 2023. [] A phase 1 single arm study of bi-weekly NHS-IL12 in patients with metastatic solid tumors. Gatti-Mays, Tschernia, Strauss, Madan, Karzai, Bilusic, Redman... Floudas, Toney, Donahue, Jochems...Schlom, Gulley. The Oncologist, 2023. [] Phase 1 trial of CV301 in combination with anti-PD-1 therapy in non-squamous non-small cell lung cancer. Rajan...Donahue, Schlom, Gulley. Int J Cancer, 2023. [] Immune correlates of clinical parameters in patients with HPV-associated malignancies treated with bintrafusp alfa. Tsai, Strauss, Toney, Jochems, Gulley, Donahue, Schlom. J Immunother Cancer, 2022. [] A randomized phase II trial of mFOLFOX6 and bevacizumab alone or with combination immunotherapy with AdCEA vaccine plus avelumab in patients with previously untreated metastatic colorectal cancer. Redman, Tsai...Donahue... Gatti-Mays...Jochems...Schlom, Gulley, Strauss. The Oncologist, 2022. Ongoing clinical studies include: [] A Pilot Study of Avelumab (MSB0010718C) in Thymoma and Thymic Carcinoma after Progression on Platinum-Based Chemotherapy n=24 (Rajan) [] Combination Immunotherapy trial in mCRPC. Phase II. (Madan) [] QuEST: A Phase I/II Study of Immunotherapy Combination BN-Brachyury Vaccine, M7824, ALT-803 and Epacadostat (Gulley) [] A Phase I Study of TGF-beta trap (M7824) and NHS-IL12 (M9241) Alone and in Combination with Stereotactic Body Radiation Therapy (SBRT) in Adults with Metastatic Non-Prostate Genitourinary Malignancies (Apolo, Niglio) [] Phase I/II of NHS-IL12 Monotherapy in Advanced Kaposi Sarcoma (Yarchoan /Ramaswami) [] A Phase II, Open-Label Trial of Bintrafusp Alfa (M7824) in Subjects with Thymoma and Thymic Carcinoma (Rajan) [] Chemoimmunotherapy of Prostate Cancer mCRPC and mCSPC (Madan) [] BEST: Phase I/II Trial of the Combination of Bintrafusp Alfa (M7824), Entinostat and NHS-IL12 (M9241) in Patients with Advanced Cancer (Strauss) [] PRGN-2012 in RRP (Norberg) [] PECAN: A Phase I/II study of PD-L1 t-haNK cells plus Immunotherapy in Subjects with Advanced Cancer (Redman) [] SBRT + NHS-IL12 in localized Prostate Cancer (Madan) [] Phase II Study Evaluating the Efficacy of M9241 in Combination with Hepatic Artery Infusion Pump Therapy (HAIP) for Subjects with Metastatic Colorectal Cancer and Intrahepatic Cholangiocarcinoma (Hernandez) [] ConQueST: To determine the Role of N-803 Alone or in Combination with Brachyury Vaccine or M7824 in Response Among Patients with CRPC. (Gulley) [] A Phase II, Open-Label Trial of PT-112 in Subjects with Thymoma and Thymic Carcinoma (Rajan) [] A Phase 1/2, First-in-Human, Open-Label, Dose Escalation and Expansion Study of STAR0602, a Selective TCR Activation-Fusion Protein, in Subjects with Unresectable Locally Adv or Met Cancers that are Tumor Antigen-Rich or Have Limited Response to Immune Checkpoint Inhibition (START-001) (Gulley) [] A Phase IIB Clinical Trial of the Multitargeted Recombinant Adenovirus 5 (CEA/MUC1/Brachyury) Vaccine (Tri-Ad5) and Il-15 Superagonist N-803 in Lynch Syndrome (Szabo).