Regional Allogeneic Mesothelin-Targeted CAR (RamCAR) T-Cell Therapy for Esophageal Cancer: Clinical Trial Preparation and Phase 1 Clinical Trial
Abstract
Gross or microscopic peritoneal seeding is present in up to 20% of patients scheduled to undergo curative resection of gastroesophageal junction/gastric tumors and, in at least one series, was associated with a median overall survival of less than 6 months. Systemic intravenous chemotherapy has modest benefits, and efforts to intensify treatment by administering chemotherapy directly into the peritoneum have also failed to show clear benefit. Immune checkpoint inhibitors have limited activity in these tumors. There is therefore, an urgent need for novel therapies. We have developed and administered human T lymphocytes, a type of immune cell that is genetically engineered to target cell-surface antigens expressed on cancer cells by use of a chimeric antigen receptor (CAR). Our CAR T cells target mesothelin (MSLN), a cancer cell–surface antigen that is overexpressed in 40% of esophagogastric cancers (EGCs) and is associated with aggressiveness. To date, using MSLN-targeted CAR T cells, we have conducted two phase 1 clinical trials, treating 56 patients, with evidence of safety (no adverse events grade >/= 2 and no on-target, off-tumor toxicity) and antitumor efficacy. Efficacy was greater when combined with immune checkpoint inhibitor agents, which can rescue exhausted T cells and prolong the functional persistence of CAR T cells. Most importantly, we have demonstrated that CAR T cells have enhanced antitumor efficacy when administered regionally (in the vicinity of tumor), compared with systemically, which we have confirmed in our phase 1 study in patients with cancer in the chest cavity. On the basis of our promising preclinical and clinical data, we propose to use allogeneic, donor-derived T cells in the proposed trial of intraperitoneal delivery of MSLN-targeted CAR T cells. This approach is more practical, as it uses donor T cells, thereby reducing costs by avoiding the long, inevitable delay when using autologous T cells from patients. We have submitted an investigational new drug (IND) application for autologous M28z1XXPD1DNR CAR T cells that target MSLN-expressing cancer cells that have been potentiated by CD28 costimulation and 1XX CD3z mutations to prolong persistence, and that include a CAR T-cell-intrinsic PD-1 dominant-negative receptor to counteract T-cell exhaustion. These T cells will be administered intrapleurally in patients with pleural mesothelioma. On the basis of our own strong preclinical and clinical data (NCT02414269 and NCT02792114), in the proposed trial, patients with peritoneal EGC with MSLN-expressing tumors will be administered a single dose of regional allogeneic CAR T cells to investigate the clinical hypothesis that intraperitoneal administration of MSLN-targeted allogeneic CAR T cells is feasible and safe; we will also investigate the translational hypothesis that CAR T cell-induced targeted tumor lysis sustained by a cell-intrinsic checkpoint blockade strategy can release neoantigens and promote neoantigen and antibody responses. The primary end points of the study are safety and feasibility; the secondary end points are outcomes. Exploratory objectives, to characterize neoantigen T-cell and antibody responses, will lay the foundation for a phase 2 trial. Our laboratory’s use of a Department of Defense (DOD) Technology Development Award (2011-2014) to execute three IND studies and initiate three CAR T-cell trials, one of which is currently in phase 2, attests to the team’s translational expertise and our potential for success. Our collaborative strategy is practical and cost-effective for conducting an innovative, highly impactful phase 2 clinical trial within the award period by using multiple resources with mutual benefit to all stakeholders. The DOD will support a trial for a rare yet deadly peritoneal EGC with limited funds; pharma will progress the trial to phase 2 if it is beneficial; and the institution will maintain academic excellence by conducting a novel trial t
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110761
Entities
People
- Prasad S Adusumilli
Organizations
- Sloan-Kettering Institute
- United States Army