Overview: The study revealed hundreds of previously unknown, “cryptic” peptides, specific to pancreatic tumor cells, representing a promising avenue for targeted vaccines and engineered T-cell approaches.
A collaborative study by MIT and the Dana-Farber Cancer Institute has identified a novel class of peptides, termed “cryptic peptides,” as a promising target for innovative therapies against pancreatic cancer. These peptides, derived from previously unrecognized regions of the genome, are uniquely expressed in pancreatic tumor cells and could be exploited to develop effective treatments.
Pancreatic cancer, known for its low survival rates, typically responds poorly to existing immunotherapies. However, the researchers discovered approximately 500 cryptic peptides exclusive to pancreatic tumors. This finding suggests a potential vulnerability in these cancer cells that could be targeted by therapies.
Researchers successfully engineered T cells to recognize and attack these tumor-specific cryptic peptides. These modified T cells demonstrated the ability to destroy pancreatic tumor organoids developed from patient cells and significantly slowed tumor growth in mouse models.
“This research unveils an unexpected vulnerability in pancreatic cancer cells, potentially opening doors to new therapeutic strategies,” stated Tyler Jacks, the David H. Koch Professor of Biology at MIT and a member of the Koch Institute for Integrative Cancer Research.
The study, published in Science, was led by Jacks and William Freed-Pastor, a physician-scientist at Dana-Farber and an assistant professor at Harvard Medical School. Zackery Ely and Zachary Kulstad were the lead authors.
Cryptic peptides, unlike typical antigens derived from known protein-coding genes, originate from previously uncharacterized genomic sequences. The researchers utilized immunopeptidomics to analyze tumor samples from over a dozen patients, creating pancreatic organoids to study. The analysis, conducted with the Broad Institute, revealed that the majority of novel antigens found in the tumor organoids were cryptic peptides, previously unseen in pancreatic tumors. Each tumor expressed an average of 250 unique cryptic peptides.
Further analysis of healthy tissues revealed that approximately 500 of these cryptic peptides were specific to pancreatic tumors, making them ideal targets for immunotherapy.
To validate their findings, the research team exposed immature T cells to these cancer-specific cryptic peptides. They successfully generated T cells that specifically targeted 12 of the antigens. These modified T cells effectively eliminated patient-derived pancreatic tumor organoids and significantly reduced tumor growth in mice.
“This represents the first evidence of utilizing T cells targeting cryptic peptides to destroy pancreatic tumor cells,” the researchers reported.
Freed-Pastor’s lab is exploring a vaccine approach using these cryptic antigens to stimulate the patient’s T cells to attack the tumors. This study also opens possibilities for designing other treatments, such as T cell engagers. However, researchers estimate that any potential vaccine or T cell therapy is several years away from human trials.
The research received funding from various organizations, including the Hale Family Center for Pancreatic Cancer Research, the Lustgarten Foundation, Stand Up To Cancer, the Pancreatic Cancer Action Network, the Burroughs Wellcome Fund, the National Institutes of Health, and the National Cancer Institute.
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