New Grant Funding Aims to Quell Pancreatic Cancer with Immunotherapy
Article Summary
- A new $660,000 grant will help Sylvester researchers test a new treatment approach for a subset of patients with pancreatic cancer.
- The approach seeks to make such cancers more susceptible to immunotherapy.
- The project shows how clinical observations can lead to laboratory research, with the aim of moving these discoveries back to the clinic.
The advent of immunotherapy has made a big difference in the lives of many patients with blood cancers and some solid tumor types, like melanoma and lung cancer.
But one particularly lethal type of cancer is poorly responsive to immunotherapy, as well as a host of other treatments — pancreatic cancer. Only about 13% of people diagnosed with pancreatic cancer in the U.S. survive to five years.
One research challenge is to find ways to therapeutically increase the susceptibility of pancreatic tumors to immunotherapy drugs. A new $660,000 grant awarded to researchers at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine, aims to tackle this challenge.
Sylvester physician-scientists Peter Hosein, M.D., and Jashodeep Datta, M.D., are co-principal Investigators of the grant, awarded in June by the V Foundation.
The grant builds on key findings from an earlier clinical study at Sylvester of 12 pancreatic cancer patients with mutations in BRCA1, BRCA2 or related genes. The data suggest that immunotherapy may be effective in a sizable proportion of these patients, particularly those with resistance to the standard, platinum-containing chemotherapy agents, such as oxaliplatin or cisplatin. The grant will enable the researchers to explore why.
Data suggests that the tumors of responsive patients may be enriched for immune-invigorating pathways, such as type 1 interferon signaling and high levels of an innate immune regulator called STING.
The project’s findings may inform the design of a future clinical trial at Sylvester, said Drs. Hosein and Datta.
“We want to understand the molecular foundations of why these patients are uniquely sensitive to immunotherapy, and then generalize that,” said Dr. Hosein, who led the earlier clinical study. “The overall goal is to make many more patients responsive to these drugs.”
From the Bedside…
BRCA1, BRCA2 and related genes are best known for their links to breast and ovarian cancer. However, mutations in these genes also accumulate in 10% to 15% of pancreatic tumors during the course of the disease. In addition, up to 10% of patients have inherited mutations.
In Sylvester’s earlier clinical study, nearly two-thirds of patients with inherited mutations in such genes responded to the immune checkpoint inhibitors ipilimumab and nivolumab, administered together. Several patients had durable responses, “unheard of in pancreatic cancer,” said Dr. Datta, the DiMare Family Chair in Immunotherapy.
Five years later, one patient on the trial, 66-year-old Miami Beach resident Luis Rios, is still cancer-free.
“It’s extremely uncommon to see that in chemotherapy-refractory patients,” said Dr. Hosein. “We believe we are onto something.”
Like most of the immunotherapy-responsive subjects in the trial, Rios had become resistant to platinum-based therapy and was running out of options.
…to the Bench
To delve further into the clinical findings, the researchers went back to the bench.
Working in Dr. Datta’s lab, they developed preclinical models of platinum-resistant and -sensitive BRCA2-deficient pancreatic cancer. In sync with their clinical observations, they found that only tumors resistant to platinum-containing chemotherapy ultimately responded to the immunotherapy.
Deep molecular analyses suggested that an immune-related molecular pathway involving type 1 interferons was activated in these platinum-resistant tumors. As a result, T cells were activated and infiltrated the tumors, which may make the tumors more susceptible to immunotherapy.
The molecular pathway driving this activity is thought to be mediated by STING, a molecule being studied as a potential drug target in multiple clinical trials.
…and Back to the Bedside
The researchers plan to explore their findings further in biopsies from patients with BRCA-deficient pancreatic cancer as well as in their preclinical models using methods to uncover the workings of the immune response. These include single-cell sequencing and spatial profiling.
Questions include whether platinum resistance increases STING activity and if STING is required to confer susceptibility to immunotherapy. The researchers may also ask if STING-activating compounds sensitize cancer cells with BRCA mutations to immune checkpoint inhibitors.
Though the studies are still in the formative stages, positive findings could potentially set the stage for a clinical trial. One possibility is to test experimental STING-agonistic drugs, in combination with immunotherapy, in pancreatic cancer patients with such mutations.
The research could also provide insight into how to treat an even broader swath of pancreatic cancer patients with immunotherapy and could help researchers understand other types of BRCA1/2-driven tumors, said Dr. Hosein.
A Tight-knit Research Community
The project aligns with Sylvester’s goals of performing patient-oriented research with an emphasis on serving the Sylvester community, said Dr. Datta. The Miami area has a high percentage of patients with inherited BRCA1 and BRCA2 mutations, he noted.
Dr. Datta credits Sylvester Director Stephen Nimer, M.D., with fostering a tight-knit, collegial environment where physicians and scientists interact to generate ideas for investigator-driven clinical trials. These include an ongoing study testing a separate approach sensitizing pancreatic tumors to immunotherapy.
Collaborators on the current project include Sylvester scientist Glen Barber, Ph.D., professor and chairman of cell biology at the Miller School, whose research led to the discovery of STING.
“We always try to take our outstanding, homegrown science and move it to clinical trials,” said Dr. Datta. “That’s what it takes to be a patient-focused, NCI-designated cancer center with a meaningful impact on our community.”
Tags: 2024 V Foundation, Dr. Jashodeep Datta, Dr. Peter Hosein, immunotherapy, pancreatic cancer, Sylvester Comprehensive Cancer Center, V Foundation