{"id":46558,"date":"2024-03-20T12:00:00","date_gmt":"2024-03-20T12:00:00","guid":{"rendered":"https:\/\/www.cancer.gov\/news-events\/cancer-currents-blog\/2024\/gene-alteration-boosts-t-cell-therapy"},"modified":"2024-11-03T15:11:52","modified_gmt":"2024-11-03T15:11:52","slug":"stealing-strategies-from-cancerous-t-cells-may-boost-immunotherapy","status":"publish","type":"post","link":"https:\/\/ogkologos.com\/en\/stealing-strategies-from-cancerous-t-cells-may-boost-immunotherapy\/","title":{"rendered":"Stealing Strategies from Cancerous T Cells May Boost Immunotherapy"},"content":{"rendered":"

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CAR T cells (yellow) may get a boost in cancer-killing abilities from the addition of mutations found in blood-cancer cells.<\/p>\n

Credit: iStock<\/p>\n<\/p><\/div>\n<\/figcaption><\/figure>\n<\/p><\/div>\n

For some people with blood cancers like leukemia and lymphoma, CAR T-cell therapies have proven to be a transformative treatment. But for solid tumors<\/a> like breast, colorectal, or pancreatic cancer, which make up about 90% of cancer cases, success with T-cell therapies has been harder to come by.<\/p>\n

One big reason for these failures is that T cells<\/a>, the immune system\u2019s<\/a> primary defense against infected and diseased cells, often become weakened and incapacitated in the toxic environment found within and around solid tumors. Researchers have been exploring many ways to help CAR T cells and other experimental<\/a> T-cell therapies survive within these hostile surroundings, known as the tumor microenvironment<\/a>.<\/p>\n

In a new study, an NCI-funded research team showed the promise of one such tactic: looking to the genetic changes that cancerous T cells themselves use to stay alive and grow. Incorporating those genetic changes into T-cell therapies, the team found, may make them better cancer killers<\/a>.<\/p>\n

When tested in mice, T cells engineered to have one specific genetic alteration the team discovered in cancerous T cells gave the engineered cells \u201csuperpowers,\u201d said Jaehyuk Choi, M.D., Ph.D., of Northwestern University, who co-led the study.<\/p>\n

Adding the genetic change, a fusion of parts of two genes, helped the engineered T cells divide faster, kill more tumor cells, and survive for more than a year in the treated mice. And, importantly, it didn\u2019t make the T cells behave like cancer cells, the researchers reported February 7 in Nature<\/em>.<\/p>\n

\u201cWhen we added [this] single mutation, we didn\u2019t see the sort of unrestrained [T-cell] growth [you see in cancer], but it gave [the engineered] T cells capabilities that they don\u2019t naturally have,\u201d explained the study\u2019s other leader, Kole Roybal, Ph.D., of the University of California San Francisco.<\/p>\n

The first two decades of T-cell therapy research focused on the basics, explained Rosa Nguyen, M.D., Ph.D., who studies cellular therapies in NCI\u2019s Center for Cancer Research<\/a> but was not involved in this study. That work included figuring out what molecules on cancer cells can be targeted by T cells and how to change T cells to better identify such targets, as is done in CAR T-cell therapies<\/a>.<\/p>\n

\u201cNow people are getting super creative in coming up with different things [to add] to these cells to make them work better,\u201d Dr. Nguyen said. \u201cThat\u2019s what the field is moving toward now.\u201d<\/p>\n

Harnessing nature\u2019s survival strategies<\/h2>\n

Any type of cell in the body has the potential to turn cancerous, even immune cells. As its name implies, the blood cancer called T-cell lymphoma starts in T cells.<\/p>\n

These cancerous T cells have something many normal T cells often lack: the ability to thrive in the hostile environment of a tumor. That environment can include other immune cells that actually work to slow down or disable T cells, as well as other cells and molecules that make it hard for T cells to function.<\/p>\n

Dr. Choi\u2019s lab has been studying the survival traits of T-cell lymphomas for over a decade. \u201cIt\u2019s \u2026 amazing how these T-cell cancers have developed ways to protect themselves,\u201d he explained.<\/p>\n

From the perspective of developing a T cell\u2013<\/span><\/span><\/span><\/span>based therapy, many of the mutations found in cancerous T cells provide an additional advantage, Dr. Choi explained: Any one of them, on its own, is not likely to direct a cell to become cancerous.<\/p>\n

Their years of research clearly showed that \u201cnature has already done this massive experiment to make [cancerous] T cells stronger,\u201d he explained. So \u201cwe thought maybe [nature] can show us the way\u201d to improve T-cell therapies.<\/p>\n

Better, faster-acting, and safe T cells<\/h2>\n

Joining forces with Dr. Roybal\u2019s lab, which specializes in T-cell engineering, the researchers first carefully analyzed a wide range of cancerous T cells from T-cell lymphomas, looking for genetic alterations that appeared to help them survive in that tumor microenvironment.<\/p>\n

They initially found 71 candidate alterations. In further laboratory experiments, they engineered CAR T cells to have some of the most promising candidate alterations, and this achieved what the researchers had hoped: They increased the CAR T cells\u2019 ability to kill cancer cells and keep creating more CAR T cells.<\/p>\n

Additional work revealed what appeared to be the most promising alteration: a fusion of parts of two genes, CARD11 and PIK3R3.<\/p>\n

\u201cThis single [fusion] activated many things that people have predicted would help [improve] T-cell therapies,\u201d Dr. Choi explained. In experiments in mice, treating them with CAR T cells engineered to express this fusion gene<\/a> increased the production of molecules that T cells need to survive and function.<\/p>\n

And these improvements only occurred when the specific protein<\/a> recognized by the T cells\u2019 specialized receptor, their chimeric antigen receptor<\/a>, was present. That is, these extra-engineered CAR T cells would only become supercharged where and when needed inside a tumor.<\/p>\n

Improved T cell survival and persistence in solid tumors<\/h2>\n

The team tested the CAR T cells engineered to express the gene fusion in mouse models of different cancers, including solid tumors like mesothelioma and melanoma. Across those experiments, they found that the treatment was much more effective at shrinking tumors\u2014and keeping them under control for longer\u2014than CAR T cells without the fusion.<\/p>\n

\u201cPersistence, the ability to stick around in the tumor microenvironment, is the biggest problem [these cells] solved,\u201d Dr. Choi said. While T cells without the fusion died within a few days, the ones with the fusion \u201cseem to stick around for as long as needed,\u201d he said.<\/p>\n

The treatment was very effective even though the mice didn\u2019t also get chemotherapy, Dr. Choi pointed out. That is important because currently, \u201calmost everyone who gets treated with [T-cell therapies] needs to have what\u2019s called conditioning chemotherapy beforehand,\u201d Dr. Choi explained. But this chemotherapy can cause side effects, often severe enough that patients have to wait longer to get the T-cell treatment or possibly preventing them from doing so at all.<\/p>\n

\u201cIf we ever want these sorts of therapies to be given in less specialized centers, or even in the outpatient setting, we need to get rid of these cumbersome techniques [like conditioning chemotherapy] that are toxic to patients,\u201d added Dr. Roybal.<\/p>\n

The researchers also engineered the fusion into a different type of T cell\u2013<\/span><\/span><\/span><\/span>based immunotherapy, called TCRs, and saw similar results.<\/p>\n

In a mouse model<\/a> of melanoma, for example, TCR T cells with the fusion gene flowed into tumors in much greater numbers and killed tumor cells much more effectively than TCR T cells without the fusion gene. The TCR T cells with the fusion even showed this advantage at starting doses 20 to 100 times lower than TCR T cells without the fusion.<\/p>\n

Being able to give a lower dose of a T-cell therapy would provide another safety advantage for patients, Dr. Roybal explained. Current CAR T-cell therapies, which are given in large doses, have the potential to cause a dangerous\u2014or even fatal\u2014immune system overreaction called cytokine release syndrome<\/a>. That risk would likely be lower with a smaller dose that ramps up its activity over time, he added.<\/p>\n

The researchers also tracked the T cells in the mice for more than 400 days after treatment. Though they initially multiplied rapidly to kill the tumors, their numbers then shrank back down and showed no signs of becoming cancerous themselves.<\/p>\n

Testing supercharged T cells in people<\/h2>\n

The researchers have launched a biotechnology startup to move their CAR T-cell therapy with this gene fusion into human trials, although they are likely 2 to 3 years away from launching these studies, Dr. Roybal explained.<\/p>\n

Eventually, researchers may want to try mixing and matching different ways to soup up T cells, Dr. Nguyen said. But these approaches first need to be tested one at a time to better understand how each one works. \u201cWe have to use a stepwise approach,\u201d she said.<\/p>\n

Drs. Roybal and Choi also want to keep exploring the dozens of other promising mutations their screen initially uncovered.<\/p>\n

\u201cWe found a lot of different mutations \u2026 that could [potentially] be used\u201d in T-cell therapies to treat \u201ca variety of different types of cancer,\u201d said Dr. Roybal.<\/p>\n

\u201cMaybe the [CARD11\u2013PIK3R3] fusion protein will be good for [fighting] some subset of solid cancers. And one of the other [mutations] we found will be important for another subset,\u201d he said. \u201cThis is the beginning [of this research], not the end.\u201d<\/p>\n

Source<\/a><\/p>\n","protected":false},"excerpt":{"rendered":"

March 20, 2024, by Sharon Reynolds CAR T cells (yellow) may get a boost in cancer-killing abilities from the addition of mutations found in blood-cancer cells. Credit: iStock For some people with blood cancers like leukemia and lymphoma, CAR T-cell therapies have proven to be a transformative treatment. But for solid tumors like breast, colorectal, […]<\/p>\n","protected":false},"author":2,"featured_media":46559,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_monsterinsights_skip_tracking":false,"footnotes":""},"categories":[5137],"tags":[],"class_list":["post-46558","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-world-news"],"_links":{"self":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts\/46558","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/comments?post=46558"}],"version-history":[{"count":1,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts\/46558\/revisions"}],"predecessor-version":[{"id":47089,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts\/46558\/revisions\/47089"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/media\/46559"}],"wp:attachment":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/media?parent=46558"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/categories?post=46558"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/tags?post=46558"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}