Melanoma Vaccine Trial Yields Promising Results
Developments in deep sequencing genomic technologies and bioinformatics have made it possible to identify mutations in melanoma and to predict targetable neoantigens.
In a small but promising clinical trial, researchers used cancer neoantigens to create personalized vaccines targeting melanoma tumors — with remarkably effective results.
“What we want is something that is going to hit the tumor but not create collateral damage,” said Dr Catherine J. Wu, MD, a member of the Broad Institute of the Massachusetts Institute of Technology and Harvard's Cancer Program and associate professor of medicine at Harvard Medical School in Cambridge, Massachusetts.
The authors noted consistent responses in this study: “of six vaccinated patients, four had no recurrence at 25 months after vaccination, while two with recurrent disease were subsequently treated with anti-PD-1…therapy and experienced complete tumour regression, with expansion of the repertoire of neoantigen-specific T cells.”1
T cells targeting cancer neoantigens have long been associated with anti-tumor immunity.
“The neoantigen immunotherapeutic concept,” as a 2014 paper explained, involved triggering those natural defenses against mutated antigens.2 “High avidity cytotoxic T cells can be selectively amplified and stimulated to attack and kill cells that present mutated peptides. Since neoantigen peptides are only [sic] found in tumor cells, the CTLs [cytotoxic T lymphocytes] should show exquisite specificity, reducing the opportunity for autoimmune disease.”
For the clinical trial, the authors wrote, “[we] hypothesized that vaccination with neoantigens can both expand pre-existing neoantigen-specific T cell populations and induce a broader repertoire of new T cell specificities in cancer patients, tipping the intra-tumoural balance in favour of enhanced tumour control.”
Not only did the vaccine stimulate production of polyfunctional CD4+ and CD8+ T cells that targeted “up to 20 predicted personal tumor antigens,” the study stated, but the T cells “discriminated mutated from wild-type antigens, and in some cases directly recognized autologous tumour.”
“In each of the 6 the responses were detectable in both CD4+ and CD8+,” Dr Wu explained. “There were strong responses that came up after vaccination, not before. For the CD8+ T cells, they were consistently able to target the mutant peptide, not the wild type. For the CD4+ T cells, this was the case 70% to 80% of the time.”
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The trial, the authors stated, “provides proof-of-principle that a personal vaccine can be produced and administered to a patient to generate highly specific immune responses against that individual's tumour.”
Recognizing the role of T cells in fighting cancer was, however, only part of the puzzle.