Research Projects

What was achieved with ECEF funding support in the year 2024?

Memorial Sloan Kettering Cancer center is pleased to report the following accomplishments from 2024 with support from ECEF:

1. We have successfully completed preclinical studies to translate chimeric antigen receptor (CAR) T-cell therapy to patients with esophageal cancer. CAR T-cell therapy involves genetically engineering patients’ own immune cells­—T cells—to recognize and kill cancer cells when given back to the patient. These studies were conducted in clinically relevant models established with the support of ECEF. A manuscript summarizing these results is in peer review; we anticipate publication in 2025.
   
2. Our phase I clinical trial has been approved by the Memorial Sloan Kettering Cancer Center Institutional Review Board, the U.S. Food and Drug Administration, and the U.S. Department of Defense Human Research Protection Organization. The clinical trial (NCT06623396) is included in the ClinicalTrials.gov clinical research study database: https://clinicaltrials.gov/study/NCT06623396. We were able to initiate the clinical trial on the timeline established in our previous progress report.
   
3. To date, 41 patients have been screened, and 4 patients have been enrolled in the trial. These patients’ own immune cells have been successfully genetically engineered, and the patients are ready for treatment. One patient has already been treated with genetically engineered CAR T cells.

What are the goals for the project we are supporting for this coming 2025?

In 2025, we will continue to accrue patients to the clinical trial, and we expect to report preliminary results from the initial cohort of patients with esophageal cancer treated with CAR T cells. In addition, serial peripheral blood, ascites fluid, and tissue samples obtained from these patients before and after treatment will be analyzed; these data will form the foundation to advance CAR T-cell therapy to patients.

In parallel, tumor immunology studies designed to elucidate the esophageal cancer immune microenvironment are ongoing in our laboratory. These parallel investigations will uncover key factors in immunomodulation to benefit patients with esophageal cancer.

What would you say are the long-term goals for the projects ECEF is supporting?

The long-term goal is to investigate immunotherapies and incorporate them in the treatment of patients with esophageal cancer. We aim to complete initial-phase trials as a near-term goal, with a further objective to conduct a definitive trial if preliminary results are promising.

Can you tell us the role that ECEF has played in these projects?

Funding from ECEF supported the completion of two trials, the results of which have been peer-reviewed and published in high-impact journals. Furthermore, these results will allow the progression to future immunotherapy trials. With the funding support from ECEF during the last 10 years, we have (a) developed an esophageal cancer clinicopathological database to advance investigations, (b) developed biomarkers for esophageal cancer prognostication and treatment and published these studies with the acknowledgment of ECEF support, (c) conducted a prospective clinical trial (n=200 patients) to validate the biomarkers developed, (d) completed and published immune-marker studies from a prospective trial, (e) completed and published a clinical trial in which we measured intraoperative oxygen saturation of the gastric conduit in patients with esophageal cancer using a device we developed in the laboratory, (f) methodically constructed tissue microarrays from esophageal cancer and peritumoral normal esophagus, (g) conducted immune studies as a correlative to clinical trials that have now been published, (h) conducted CAR T-cell therapy preclinical investigations required to obtain Department of Defense support to initiate a clinical trial for patients with esophageal cancer, and (i) successfully initiated a CAR T-cell therapy trial for patients with esophageal cancer and peritoneal carcinomatosis.

The actual explanation of the projects we are supporting with our grants is as follows:

Project 1: CAR T-cell immunotherapy for patients with esophageal cancer and peritoneal carcinomatosis

Description: With the support of ECEF, we identified mesothelin as a cancer cell-surface antigen to redirect the body’s own immune cells—T cells—to target esophageal cancer. Our laboratory developed mesothelin-targeted CAR T cells and translated them in phase I and II clinical trials to patients with mesothelioma, lung cancer, and breast cancer. After we reported that mesothelin is an effective target to treat patients with esophageal cancer (research supported by ECEF), we obtained funding from the Department of Defense to conduct a phase I clinical trial for patients with esophageal cancer. The ECEF award has sustained studies in which we (a) established esophageal cancer cells with and without mesothelin expression, (b) developed clinically relevant mouse models, including essential models of aggressive peritoneal carcinomatosis, and (c) optimized the imaging modalities and protocols used to monitor tumor burden in these mice. With the support from ECEF, we completed testing of CAR T cells against esophageal cancer cells both in vitro and in vivo; the results were promising and will allow us to proceed to a clinical trial. In the upcoming years, our goal is to complete a clinical trial to evaluate the feasibility, safety, and efficacy of targeted CAR T-cell therapy and to analyze clinical samples to obtain further knowledge to advance this treatment.

Project 2: Immune microenvironment in esophageal cancer

Description: Our laboratory’s principal research focus is tumor immunology and immunotherapy. The tumor immune microenvironment in esophageal cancer is not well studied. To advance immunotherapy, it is essential to understand the basic immune microenvironment of esophageal cancer. For this purpose, we developed a well-annotated clinicopathological database consisting of well-characterized tissue from a cohort of patients with esophageal cancer participating in an immunotherapy clinical trial led by Dr. Geoffrey Y. Ku (gastrointestinal medical oncologist and cellular therapist at Memorial Sloan Kettering). To date, we have completed analysis of tumor biopsies obtained in two trials; in one of the trials, we compared the tumoral and stromal immune microenvironment in esophageal tumors from patients who received immunotherapy with or without chemoradiation therapy. With the support from ECEF, we have now completed a tissue microarray using posttreatment specimens of esophageal cancer and peritumoral normal esophagus. We will continue to analyze the tumor immune microenvironment in this tissue microarray.