Assessment of Endogenous and CAR T-Cell Immunity Following Anti-PD-1 Agent as a Transition Step to Phase 2 Combination Immunotherapy
Abstract
Malignant pleural mesothelioma (MPM) remains a rare cancer with poor prognosis in need of novel therapies. Approximately 3000 new cases are diagnosed each year in the U.S. Even with combined chemoradiotherapy and surgical resection, survival is prolonged to only 9–17 months. There are no FDA approved therapies for MPM since 2003. In the largest series reported to date (n=945), from our group, one-third of patients were unresectable due to locally advanced tumors. Only 8% of patients had distant metastases. The localized nature of disease, accessibility of the pleural cavity, and relative lack of distant metastasis make MPM an excellent candidate for regional delivery of targeted therapies. To address the oncologic need for novel targeted therapies, we have leveraged the accessibility of the pleural cavity to regionally administer cancer antigen-targeted adoptive T-cell therapy. Our extensive work in clinically relevant mouse models has resulted in translation to MPM patients in a phase I clinical trial. We have demonstrated that patients with MPM who have a higher ratio of anti-cancer immune cells (T cells) to pro-cancer immune cells, which suppress immune functions, have prolonged survival. To precisely target cancer cells, we have utilized a genetic engineering technology to synthesize artificial receptors in T cells called chimeric antigen receptors (CARs). CAR-transduced T cells traffic to, target, and kill cancer cells without help from other immune cells. The efficacy of CAR T-cell therapy has been established in the treatment of therapyresistant blood cancers where patients with expected lifespans of a few months are able to prolong life for three to six years with no evidence of cancer relapse. These dramatic effects have resulted in FDA approval for CAR T-cell therapy for leukemia and lymphoma within the past few months. With the support of the DOD Technology Development Award (2011–2014), we have developed and translated cancer antigen Mesothelin (MSLN)–targeted CAR T-cell therapy to phase I clinical trials (NCT02414269 and NCT02792114). Mesothelin is associated with aggressiveness in MPM and other solid tumors such as colorectal, stomach, liver, lung and pancreatic cancers, all of which are at a higher prevalence in veterans and military personnel. To date, we have treated 26 patients with no adverse events and evidence of efficacy. The novelty of the NCT02414269 trial (n=18) includes its regional (intrapleural) delivery of CAR T cells; 16 of these patients have MPM. Our published data show that a single low dose of CAR T cells administered (as in this phase I trial) is exhausted by PD-1 upregulation in the presence of the overwhelming tumor antigen burden with upregulated PD-L1. To rescue exhausted CAR T cells, following establishment of safety, we administered anti-PD-1 agent (10 of 18 patients) and noticed dramatic responses: 5 of the 10 patients showed response with no additional therapies to date (1–15 months after CAR T-cell administration, 4 patients more than a year). More importantly, a patient with biphasic MPM (60% of tumor cells are MSLN negative) treated with anti-PD-1 agent following a single low dose of MSLN-targeted CAR T cells showed complete metabolic response (no PET-avid tumor at 15 months), raising the intriguing possibility of enhanced CAR Tcell as well as endogenous antitumor immune responses following anti-PD-1 checkpoint blockade (CPB). We have serially collected pleural effusions, pleural and lymph node biopsy specimens, and peripheral blood samples from MPM patients before and after both therapies, along with interval radiological imaging (CT and PET scans) and serum and pleural effusion tumor markers (serum soluble mesothelin related peptide). While the trial is ongoing with escalating doses, we herein propose to analyze the collected specimens (250 to date and more to be collected from future patients) using the DOD Translational Team Science Award.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910384
Entities
People
- Prasad S Adusumilli
Organizations
- Sloan-Kettering Institute
- United States Army