A team led by Ludwig and Memorial Sloan Kettering (MSK) researchers has published a landmark study on the genetic basis of response to immune checkpoint blockade. Their paper, published online on 19 November 2014 in the New England Journal of Medicine, describes the precise genetic signatures in melanoma tumours that determine whether a patient will respond to such therapy. It also explains in exquisite detail how those genetic profiles translate into subtle molecular changes that enable the immune system attack of cancer cells in response to immune checkpoint blockade.
"The genetic signature we have found will be invaluable to understanding the biological mechanisms that drive therapeutic responses to immunotherapy for metastatic melanoma," says Dr Jedd Wolchok, director of the Ludwig Collaborative Laboratory and associate director of the Ludwig Center for Cancer Immunotherapy at MSK, who co-led the study with Dr Timothy Chan of MSK's Human Oncology and Pathogenesis Program. "Further, our strategy can now be applied to determine the genetic signatures associated with the efficacy of a number of other immunotherapies and cancers."
Few approaches to treating cancer have generated as much excitement as immunotherapy. One class of such treatments targets CTLA-4. "There is a subset of melanoma patients who are living far longer than anyone would have expected in the past, largely because of this treatment and other recently developed targeted and immunologic treatments," says Wolchok. "But we did not know how to identify them, and that's what really drove this investigation."
"Previous studies by Jedd and others had shown that the particular MHC type of a patient doesn't appear to influence the efficacy of CTLA-4 blockade," says Chan. "So we decided to see if the tumor genome has anything to say about whether or not people respond to this therapy. The result was entirely unexpected, and the answer is exceedingly important."
Chan, Wolchok and their colleagues initially hypothesised that tumours that harbored highly mutated cells would be most responsive to CTLA-4 blockade. To test that hypothesis, they sequenced and compared exomes in tumours taken from 25 patients treated with anti-CTLA-4 antibodies and found that this was, to some degree, true. "But looking at the data a little more deeply," says Wolchok, "we saw that there were outliers--patients who had over one thousand mutations who didn't respond, and some with just a few dozen who did. This was a strong indication that the quality of the mutations matters."
A sophisticated computational analysis of the cancer genomes revealed that a set of core peptide sequences within MHC Class I-presented peptides were unequivocally associated with response to treatment. To test the prognostic power of this genetic signature, the researchers sequenced the exomes of tumours from another 39 melanoma patients treated with CTLA-4 blockade. They found that all those in this set who had responded to the therapy had at least one and typically several more of the tetrapeptides they had identified. Those who failed to respond did not. Their results show that the mutant DNA sequences, can occur anywhere in the genome, not just within mutant driver genes that are already known to contribute to cancer.
"The more mutated the tumor's genome is," says Chan, "the more likely it is that immunotherapy will work. Since tumors induced by tobacco--such as those of non-small cell lung cancer--have more mutations than most other cancers except melanoma, this finding has enormous medical implications for these genetically diverse cancers."
It also helps explain, Dr Wolchok said in accompanied press release, why the relatively more mutated cancers have been found in clinical trials to be the most responsive to checkpoint blockade.
The researchers further validated their findings by showing in lab experiments that killer T cells taken from responsive patients were potently activated by synthetic replicas of the mutated tetrapeptides, but not by their normal counterparts. T cells from healthy people failed to respond to mutant peptides, indicating that the T cell response in question was specific to melanoma.
The researchers will next perform similar analyses on other immunotherapies and types of cancer, most notably lung cancer.
The study was supported by Ludwig Cancer Research and grants from the Frederick Adler Fund, the USA National Institutes of Health, Swim Across America, the Ludwig Trust, Melanoma Research Alliance, Stand Up to Cancer-Cancer Research Institute Immunotherapy Dream Team, Hazen-Polsky Foundation and the STARR Cancer Consortium.
Snyder A, Makarov V, Merghoub T, et al. Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma. NEJM 2014; November 19. [Epub ahead of print] DOI: 10.1056/NEJMoa1406498