A team led by Ludwig and Memorial Sloan Kettering (MSK) researchers has published a landmark study on the genetic basis of response to a powerful cancer therapy known as immune checkpoint blockade. Their paper describes the precise genetic signatures in melanoma tumours that determine whether a patient will respond to one 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.<\/p>\n
\u201cThe genetic signature we have found will be invaluable to understanding the biological mechanisms that drive therapeutic responses to immunotherapy for metastatic melanoma,\u201d says Jedd Wolchok, MD, PhD, director of the Ludwig Collaborative Laboratory and associate director of the Ludwig Center for Cancer Immunotherapy at MSK, who co-led the study with Timothy Chan, MD, PhD, of MSK\u2019s Human Oncology and Pathogenesis Program. \u201cFurther, our strategy can now be applied to determine the genetic signatures associated with the efficacy of a number of other immunotherapies and cancers.\u201d<\/p>\n
Few approaches to treating cancer have generated as much excitement as immunotherapy, in which the immune system is engaged to destroy malignancies. One class of such treatments targets CTLA-4, a molecule expressed on the surface of killer T cells that ordinarily blocks their proliferation. Antibody drugs that block CTLA-4 thus stimulate killer T cell responses\u2014which can target cancer cells\u2014and significantly extend survival for many melanoma patients. Yet not all patients respond equally to this treatment: some, remarkably, survive many years; others fail to respond at all.<\/p>\n
\u201cThere 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,\u201d says Wolchok. \u201cBut we did not know how to identify them, and that\u2019s what really drove this investigation.\u201d<\/p>\n
Cancer cells are swift but sloppy proliferators, generating countless mutations across their genome as they multiply. Those mutations are often expressed as changes in the chains of amino acids that make protein molecules. Like all cells, cancer cells chop up and hold out short fragments of such proteins\u2014each about 9 amino acids in length\u2014for the immune system to assess. These \u201cpeptides\u201d are held up and presented to immune cells by a protein complex known as MHC Class I, which varies significantly between people.<\/p>\n
\u201cPrevious studies by Jedd and others had shown that the particular MHC type of a patient doesn\u2019t appear to influence the efficacy of CTLA-4 blockade,\u201d says Chan. \u201cSo we decided to see if the tumour 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.\u201d<\/p>\n
Chan, Wolchok and their colleagues initially hypothesized that tumours that harboured highly mutated cells would be most responsive to CTLA-4 blockade. To test that hypothesis, they sequenced and compared all of the genes expressed as proteins (collectively known as the \u201cexome\u201d) in tumours taken from 25 patients treated with anti-CTLA-4 antibodies and found that this was, to some degree, true. \u201cBut looking at the data a little more deeply,\u201d says Wolchok, \u201cwe saw that there were outliers\u2014patients who had over one thousand mutations who didn\u2019t respond, and some with just a few dozen who did. This was a strong indication that the quality of the mutations matters.\u201d<\/p>\n
A sophisticated computational analysis of the cancer genomes revealed that a set of core peptide sequences\u2014each four amino acids long (tetrapeptides)\u2014within 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\u2014not just within mutant \u201cdriver\u201d genes that are already known to contribute to cancer.<\/p>\n
\u201cThe more mutated the tumor\u2019s genome is,\u201d says Chan, \u201cthe more likely it is that immunotherapy will work. Since tumours induced by tobacco\u2014such as those of non-small cell lung cancer\u2014have more mutations than most other cancers except melanoma, this finding has enormous medical implications for these genetically diverse cancers.\u201d<\/p>\n
It also helps explain, says Wolchok, why the relatively more mutated cancers have been found in clinical trials to be the most responsive to checkpoint blockade.\nLudwig Cancer Research<\/link>\n","protected":false},"excerpt":{"rendered":"
A team led by Ludwig and Memorial Sloan Kettering (MSK) researchers has published a landmark study on the genetic basis of response to a powerful cancer therapy known as immune checkpoint blockade. Their paper describes the precise genetic signatures in melanoma tumours that determine whether a patient will respond to one such therapy. It also […]<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_monsterinsights_skip_tracking":false,"_monsterinsights_sitenote_active":false,"_monsterinsights_sitenote_note":"","_monsterinsights_sitenote_category":0,"footnotes":""},"categories":[35],"tags":[],"_links":{"self":[{"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/posts\/1508"}],"collection":[{"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/comments?post=1508"}],"version-history":[{"count":0,"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/posts\/1508\/revisions"}],"wp:attachment":[{"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/media?parent=1508"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/categories?post=1508"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/tags?post=1508"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}