MSGID: 1:317/3 64a6436c   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    Vaccine delivers a boost to T cell therapy    
    The new strategy may enable engineered T cells to eradicate solid tumors   
   such as glioblastoma    
      
     Date:   
         July 5, 2023   
     Source:   
         Massachusetts Institute of Technology   
     Summary:   
         A new vaccine boosts the response of engineered CAR-T cells and   
         helps the immune system generate T cells that target other tumor   
         antigens. The researchers found this approach made it more likely   
         that a tumor can be eradicated in mice.   
      
      
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   Engineering T cells to destroy cancer cells has shown success in treating   
   some types of cancer, such as leukemia and lymphoma. However, it hasn't   
   worked as well for solid tumors.   
      
   One reason for this lack of success is that the T cells target only one   
   antigen (a target protein found on the tumors); if some of the tumor   
   cells don't express that antigen, they can escape the T cell attack.   
      
   MIT researchers have now found a way to overcome that obstacle, using a   
   vaccine that boosts the response of engineered T cells, known as chimeric   
   antigen receptor (CAR) T cells, and also helps the immune system generate   
   new T cells that target other tumor antigens. In studies in mice, the   
   researchers found that this approach made it much more likely that tumors   
   could be eradicated.   
      
   "This vaccine boosting appears to drive a process called antigen   
   spreading, wherein your own immune system collaborates with engineered   
   CAR T cells to reject tumors in which not all of the cells express   
   the antigen targeted by the CAR T cells," says Darrell Irvine, the   
   Underwood-Prescott Professor with appointments in MIT's departments of   
   Biological Engineering and of Materials Science and Engineering, and a   
   member of MIT's Koch Institute for Integrative Cancer Research and the   
   Ragon Institute of MGH, MIT, and Harvard.   
      
   Irvine is the senior author of the study, which appears today in   
   Cell. The lead author of the paper is Leyuan Ma, a former postdoc at   
   the Koch Institute and currently an assistant professor of pathology and   
   laboratory medicine at the University of Pennsylvania School of Medicine.   
      
   Engineered T cells The U.S. Food and Drug Administration has approved   
   several types of T cell treatments for blood cancers. These treatments   
   are based on CAR-T cells, which are engineered to display receptors that   
   can recognize a specific antigen found on cancer cells.   
      
   To try to adapt this kind of treatment to glioblastoma, a type of brain   
   cancer, researchers have designed CAR-T cells that target a mutated   
   version of the EGFR receptor. However, not all glioblastoma cells express   
   this antigen, and when attacked by CAR-T cells, some glioblastoma cells   
   respond by halting production of the target antigen.   
      
   In a 2019 study, Irvine and his colleagues enhanced CAR-T cells'   
   effectiveness against glioblastoma by delivering a vaccine to mice   
   shortly after the engineered T cells were administered. This vaccine,   
   which carries the same antigen targeted by the CAR-T cells, is taken up by   
   immune cells in the lymph nodes, where the CAR-T cells are exposed to it.   
      
   In that study, the researchers found that this vaccine boost not only   
   helped the engineered CAR-T cells attack tumors, but it had another,   
   unexpected effect: It helped to generate host T cells that target other   
   tumor antigens.   
      
   This phenomenon, known as "antigen spreading," is desirable because   
   it creates populations of T cells that, working together, can fully   
   eradicate tumors and prevent tumor regrowth.   
      
   "That would be exactly the kind of thing that could help you deal with   
   the antigen heterogeneity of solid tumors, because if you primed host   
   T-cells to attack other antigens, they may be able to come in and kill   
   the tumor cells that your CAR-T cells cannot," Irvine says.   
      
   An immune boost In their new study, the researchers wanted to explore   
   how that additional T- cell response becomes activated. They used the   
   same type of CAR-T cells from their 2019 study, which are engineered   
   to target mutant EGFR, and the same vaccine. The mice in the study were   
   given two doses of the vaccine, one week apart.   
      
   The researchers found that in these boosted mice, metabolic changes   
   occurred in the CAR-T cells that increased their production of interferon   
   gamma, a cytokine that helps stimulate a strong immune response. This   
   helps the T cells to overcome the immunosuppressive environment of the   
   tumor, which normally shuts down any T cells in the vicinity.   
      
   As the CAR-T cells killed tumor cells expressing the target antigen,   
   host T cells (not the engineered CAR-T cells) encountered other antigens   
   from those tumor cells, stimulating those host T cells to target those   
   antigens and help destroy tumor cells.   
      
   Without that host T cell response, the researchers found, tumors would   
   regrow even if the CAR-T cells destroyed most of the original tumor   
   cells. This happens because tumor cells treated with CAR-T cells often   
   stop producing the antigen targeted by the engineered cells, allowing   
   them to evade those cells.   
      
   Tumor eradication The researchers then tested their approach in mice with   
   tumors that had different levels of the target antigen. They found that   
   even in tumors where only 50 percent of the tumor cells expressed the   
   target antigen, about 25 percent of the tumors could still be eradicated,   
   by a combination of CAR- T cells and host T-cells.   
      
   The success rate was higher for tumors with greater levels of the target   
   antigen. When 80 percent of the tumor cells expressed the antigen targeted   
   by CAR-T cells, tumors were eliminated in about 80 percent of the mice.   
      
   The technology used in this study has been licensed to a company   
   called Elicio Therapeutics, which is working on developing it for   
   potential testing in patients. In this study, the researchers focused   
   on glioblastoma and melanoma, but they believe it could potentially be   
   used to combat other types of cancer as well.   
      
   "In principle, this should apply to any solid tumor where you have   
   generated a CAR T-cell that could target it," Irvine says.   
      
   The researchers are also working on ways to adapt CAR-T cell therapy so   
   that it can be used to attack tumors for which no targetable antigens   
   have been identified.   
      
   The research was funded by the National Institutes of Health, the Marble   
   Center for Cancer Nanomedicine at the Koch Institute, an ASPIRE Award   
   from The Mark Foundation for Cancer Research, an American Cancer Society   
   postdoctoral fellowship, the Cell and Gene Therapy Collaborative at the   
   Children's Hospital of Philadelphia, the W.W. Smith Charitable Trust, and   
   a Koch Institute Support (core) Grant from the National Cancer Institute.   
      
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   Journal Reference:   
      1. Leyuan Ma, Alexander Hostetler, Duncan M. Morgan, Laura Maiorino,   
      Ina   
         Sulkaj, Charles A. Whittaker, Alexandra Neeser, Ivan Susin Pires,   
         Parisa Yousefpour, Justin Gregory, Kashif Qureshi, Jonathan Dye,   
         Wuhbet Abraham, Heikyung Suh, Na Li, J. Christopher Love, Darrell   
         J. Irvine. Vaccine- boosted CAR T crosstalk with host immunity   
         to reject tumors with antigen heterogeneity. Cell, 2023; DOI:   
         10.1016/j.cell.2023.06.002   
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   Link to news story:   
   https://www.sciencedaily.com/releases/2023/07/230705115136.htm   
      
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