Research on a new way of deploying the immune system against pancreatic cancer, an exceptionally lethal cancer that has so far resisted new immunotherapies, will receive $1 million in initial funding from Stand Up to Cancer.
The project led by researchers from The University of Texas MD Anderson Cancer Center and Baylor College of Medicine will collect T cells – the immune system's targeted warriors — from tumors, expand their number by the billions and then customize them to resist being shut down by a common substance that's abundantly produced in tumor tissue.
Stand Up to Cancer, a program of the Entertainment Industry Foundation to encourage cancer research collaboration, and the American Association for Cancer Research on Tuesday announced funding of seven projects, the first under its Pancreatic Cancer Collective, a collaboration with the Lustgarten Foundation to accelerate research and improve patient outcomes for pancreatic cancer. Only about 8 percent of pancreatic cancer patients survive to five years, according to the National Cancer Institute.
"We're encouraged by Stand Up to Cancer's support for this potential approach to more efficiently target and overwhelm solid tumors with an immune response," said project leader Patrick Hwu, M.D., head of MD Anderson's Division of Cancer Medicine and chair of Melanoma Medical Oncology.
Immune checkpoint blockade drugs that unleash T cells to attack cancer have demonstrated some success in more than a dozen cancers, but have not worked against pancreatic cancer. Hwu is a pioneer in the field of adoptive cell therapy using tumor-infiltrating lymphocytes (TILs) – a process of capturing T cells that have attacked a patient's tumor, expanding them in the lab, and then re-infusing them in the patient by the billions.
Billions of T cells, genetically fortified
"We know pancreatic cancer is immunosuppressive and that very few T cells penetrate the tumor, so we hypothesize that checkpoint blockade doesn't work because there are too few T cells," said team co-leader Chantale Bernatchez, Ph.D., assistant professor of Melanoma Medical Oncology at MD Anderson.
The team's answer to this problem combines MD Anderson capabilities to massively expand the relatively few T cells found in pancreatic tumors with Baylor College of Medicine technology to insert a defective receptor for Transforming Growth Factor-Beta (TGF-Beta) on those T cells, allowing them to resist being deactivated by TGF-Beta secreted by the tumor and surrounding cells.
Co-leader Cliona M. Rooney, Ph.D., Baylor College of Medicine, professor of Hematology-Oncology and Cell and Gene Therapy, has developed the approach to insert a gene that expresses a truncated "decoy" receptor on the T cells that allows TGF-Beta to bind to the receptor, but not deactivate the T cell.
Rooney, Hwu and Bernatchez have collaborated for several years to optimize this gene modification on TILs used to treat melanoma. The anti-tumor efficacy of these genetically modified T cells is currently tested in a clinical trial to treat metastatic melanoma patients whose disease resists checkpoint blockade, a patient population with poor prognosis.
A durable response in a subset of these patients suggests that this strategy may work in tumor types not responsive to current immunotherapies, Bernatchez said.
The SU2C funding will support preclinical proof-of-concept studies testing this approach to treat human pancreatic cancer in mouse models. Stand Up to Cancer, 14 months from now, will select several of the original seven projects to fund clinical trials of the most promising approaches.
Bernatchez and her team demonstrated earlier this year that they could find enough T cells in human pancreatic tumors to cultivate them in a medium that includes interleukin-2 and two antibodies that stimulate T cell growth, creating the billions of T cells necessary to treat patients.
"We found we could grow enough T cells to infuse back into patients 90 percent of the time," Bernatchez said.
MD Anderson has joined with Iovance Biotherapeutics to open a clinical trial of these first-generation, unmodified TILs for patients with pancreatic cancer, ovarian cancer or osteosarcoma.
TILs have been used in a longstanding clinical trial for advanced melanoma, with MD Anderson reporting that 42 percent of 74 patients in the clinical trial had their tumors shrink, and 20 percent have durable responses. While checkpoint blockade drugs have superseded TILs in melanoma, researchers believe TILs might work in other tumor types, such as pancreatic cancer, that resist checkpoint blockade.
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