MSGID: 1:317/3 62735303   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    New target for CAR T cells in solid tumors    
    Chimeric antigen receptor T cells that target OR2H1 inhibit lung and   
   ovarian tumor growth in mice    
      
     Date:   
         May 4, 2022   
     Source:   
         H. Lee Moffitt Cancer Center & Research Institute   
     Summary:   
         Researchers share the identification of a new potential target   
         for CAR T cells called OR2H1 that they have demonstrated inhibits   
         growth in lung and ovarian tumors.   
      
      
      
   FULL STORY   
   ==========================================================================   
   Chimeric antigen receptor T-cell therapy, or CAR T, has made a big   
   impact on the treatment of certain blood cancers, allowing patients   
   with relapsed/ refractory disease to live longer, healthier lives. But   
   in clinical study, the cellular therapy has not been as successful for   
   patients with solid tumors, due in part to the lack of tumor targets   
   not expressed in vital tissues. In a new study published in Molecular   
   Cancer Therapeutics, a journal of the American Association for Cancer   
   Research, Moffitt Cancer Center researchers share the identification   
   of a new potential target for CAR T cells called OR2H1 that they have   
   demonstrated inhibits growth in lung and ovarian tumors.   
      
      
   ==========================================================================   
   The key to CAR T-cell therapy is the genetic modification made to the   
   patient's T cells. Their cells are collected through a process called   
   apheresis, and then shipped to a laboratory where the cells are modified   
   to contain a gene for the T cell receptor that recognizes a specific   
   marker on cancer cells. Those modified T cells, now CAR T cells, are   
   stimulated to grow and multiply before being sent back to the hospital   
   to be infused back into the patients. The receptor on the CAR T cells   
   acts as a GPS, seeking out their specific marker on the surface of the   
   cancer cells. Currently there are CAR T therapies approved to treat   
   patients with lymphoma, leukemia and multiple myeloma, but there are no   
   approved CAR T therapies for solid tumors.   
      
   Moffitt researchers are working to identify tumor markers that can make   
   CAR T an effective therapy for patient with solid tumors. The goal is to   
   find a marker that is expressed on tumor cells but not on normal cells,   
   to reduce the potential for unwanted toxicities. The team, led by Dr. Jose   
   Conejo-Garcia, focused the search on a family of proteins called olfactory   
   receptors that are expressed in the nose and contribute to the perception   
   of smell. During lab experiments, they discovered that the protein OR2H1   
   is expressed in a variety of solid tumors, ranging from 4% of colon cancer   
   samples to 69% of cancers of the gall bladder. Importantly, of all normal   
   tissues examined, OR2H1 was found only in the testis, suggesting that   
   therapies that target OR2H1 would have minimal effects on normal cells.   
      
   The researchers then created CAR T cells that were specific to the OR2H1   
   protein. The OR2H1 CAR T cells were able to kill lung and ovarian cancer   
   cells that expressed OR2H1 but had no effect on healthy cells. The OR2H1   
   CAR T cells also had anti-tumor effects in vivo in immunodeficient mice   
   challenged with human tumors. Tumor inhibition was observed in lung   
   and ovarian cancer mice models with varying levels of OR2H1, including   
   ovarian cancer cells that were resistant to chemotherapy.   
      
   These combined data suggest that OR2H1 may be an effective target for CAR   
   T therapies in solid tumors. The researchers hope these initial studies   
   will lead to the development of OR2H1 CAR T cells for a wide variety of   
   patients with solid tumors.   
      
   "Our work demonstrates the applicability of this therapy to a wide   
   variety of patients, given the expression of OR2H1 in a subset of solid   
   tumors across multiple histologies, including high-grade serous ovarian   
   cancers, lung carcinoma, cholangiocarcinoma, prostate cancer and ovarian   
   cancers of multiple other histologies. Targeting a molecule that is not   
   expressed in vital tissues would allow us to further engineer T cells to   
   overcome immunosuppression at tumor beds, if needed," said Conejo-Garcia,   
   chair of Moffitt's Department of Immunology.   
      
   This work was supported by the National Cancer Institute (P30CA076292,   
   R01CA157664, R01CA124515, R01CA178687, R01CA211913, U01CA232758,   
   T32CA009140, K99CA266947), the Moffitt Foundation, Moffitt's Junior   
   Scientist Research Partnership Award and the American Cancer Society   
   Postdoctoral Fellowship.   
      
      
   ==========================================================================   
   Story Source: Materials provided by   
   H._Lee_Moffitt_Cancer_Center_&_Research_Institute. Note: Content may be   
   edited for style and length.   
      
      
   ==========================================================================   
   Journal Reference:   
      1. Alexandra L. Martin, Carmen M. Anadon, Subir Biswas, Jessica   
      A. Mine,   
         Katelyn F. Handley, Kyle K. Payne, Gunjan Mandal, Ricardo   
         A. Chaurio, John J. Powers, Kimberly B. Sprenger, Kristen   
         E. Rigolizzo, Patrick Innamarato, Carly M. Harro, Sumit Mehta,   
         Bradford A. Perez, Robert M.   
      
         Wenham, Jose R. Conejo-Garcia. Olfactory Receptor OR2H1 is   
         an effective target for CAR T cells in human epithelial   
         tumors. Molecular Cancer Therapeutics, 2022; DOI:   
         10.1158/1535-7163.MCT-21-0872   
   ==========================================================================   
      
   Link to news story:   
   https://www.sciencedaily.com/releases/2022/05/220504110424.htm   
      
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