MSGID: 1:317/3 6273530c   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    Investigating cancer drug toxicity leads to a critical discovery    
    Researchers uncover a new strategy to avoid cancer immunotherapy side   
   effects    
      
     Date:   
         May 4, 2022   
     Source:   
         La Jolla Institute for Immunology   
     Summary:   
         When patients started showing adverse side effects during a cancer   
         immunotherapy trial, researchers went back through the data and   
         worked with patient samples to see what went wrong.   
      
      
      
   FULL STORY   
   ==========================================================================   
   It's not often that a failed clinical trial leads to a scientific   
   breakthrough.   
      
      
   ==========================================================================   
   When patients in the UK started showing adverse side effects during   
   a cancer immunotherapy trial, researchers at La Jolla Institute for   
   Immunology (LJI) Center for Cancer Immunotherapy and University of   
   Liverpool went back through the data and worked with patient samples to   
   see what went wrong.   
      
   Their findings, published recently in Nature, provide critical clues to   
   why many immunotherapies trigger dangerous side effects -- and point to   
   a better strategy for treating patients with solid tumors.   
      
   "This work shows the importance of learning from early stage clinical   
   trials," says La Jolla Institute for Immunology (LJI) Professor   
   Pandurangan Vijayanand, M.D., Ph.D., who co-led the new research with   
   Christian H. Ottensmeier, M.D., Ph.D., FRCP, a professor with the   
   University of Liverpool, The Clatterbridge Cancer Centre NHS Foundation   
   Trust, and adjunct professor at LJI.   
      
   Limited success with immunotherapies Both Vijayanand and Ottensmeier   
   are physician scientists, and Ottensmeier is an attending oncologist   
   who treats solid tumor patients. In just the last decade, he has seen   
   more and more patients thrive thanks to advances in immunotherapies,   
   which work with the immune system to kill cancers.   
      
      
      
   ==========================================================================   
   "In the oncology world, immunotherapy has revolutionized the way we   
   think about treatment," says Ottensmeier. "We can give immunotherapies to   
   patients even with metastatic and spreading disease, and then just three   
   years later wave goodbye and tell them their cancer is cured. This is an   
   astounding change."  Unfortunately, only around 20 to 30 percent of solid   
   cancer patients given immunotherapies go into long-term remission. Some   
   people see no change after immunotherapy, but others develop serious   
   problems in their lungs, bowel, and even skin during treatment. These   
   side effects can be debilitating, even fatal, and these patients are   
   forced to stop receiving the immunotherapy.   
      
   Important lessons from a clinical trial The researchers at LJI and the   
   University of Liverpool worked with samples from a recent clinical trial   
   in the UK for patients with head and neck cancers. The patients were   
   given an oral cancer immunotherapy called a PI3Kd inhibitor. At the time,   
   PI3Kd inhibitors had proven effective for B cell lymphomas but had not   
   yet been tested in solid tumors.   
      
   PI3Kd inhibitors are new to the cancer immunotherapy scene, but   
   they hold promise for their ability to inhibit "regulatory" T cells   
   (Tregs). Tregs normally try to stop other T cells, called effector   
   T cells, from targeting the body's own tissues. Oncologists inhibit   
   Tregs inside tumors so effector T cells can let loose and generate   
   cancer-killing CD8+ T cells.   
      
      
      
   ==========================================================================   
   "Having an oral tablet that can take off the brakes -- the Tregs --   
   can be a great asset for oncologists," says Vijayanand.   
      
   Unfortunately, 12 of the 21 patients in the trial had to discontinue   
   treatment early because they developed inflammation in the colon,   
   a condition called colitis. "We thought this drug wouldn't be toxic,   
   so why was this happening?"  says Vijayanand.   
      
   LJI Instructor Simon Eschweiler, Ph.D., spearheaded the effort to go back   
   and see exactly how PI3Kd inhibitor treatment affected immune cells in   
   these patients. Using single-cell genomic sequencing, he showed that in   
   the process of increasing tumor-fighting T cells in tumors, the PI3Kd   
   inhibitor, also blocked a specific Treg cell subset from protecting the   
   colon. Without Tregs on the job, pathogenic T cells, called Th17 and   
   Tc17 cells, moved in and caused inflammation and colitis.   
      
   It was clear that the cancer trial patients had been given a larger   
   PI3Kd inhibitor dose than they needed, and the immunotherapy had thrown   
   the delicate composition of immune cells in the gut out of balance.   
      
   The pathway that leads to the toxicity seen in the new study may   
   be broadly applicable to other organs harboring similar Treg cells,   
   and to other Treg cell-targeting immunotherapies like anti-CTLA-4,   
   Eschweiler says.   
      
   New dosing strategy may save lives The team found that intermittent dosing   
   could be a valid treatment strategy that combines sustained anti-tumor   
   immunity with reduced toxicity.   
      
   The researchers are now designing a human clinical trial to test the   
   intermittent dosing strategy in humans.   
      
   "This research illustrates how you can go from a clinical study to   
   a mouse study to see what's behind toxicity in these patients," says   
   LJI Professor and Chief Scientific Officer Mitchell Kronenberg, Ph.D.,   
   whose lab led much of the mouse model work for the new study.   
      
   How to explain lack of toxicity in trials for B cell lymphomas? Eschweiler   
   says lymphoma patients in previous studies had been given several prior   
   therapies leading to an overall immunocompromised state. This means the   
   lymphoma patients didn't have the same type -- or the same magnitude   
   -- of immune response upon PI3Kd inhibition. Meanwhile, the head and   
   neck cancer patients were treatment- naive. Their immune system wasn't   
   compromised, so the immune-related adverse events were both more rapid   
   and more pronounced.   
      
   Overall, the new study shows the importance of studying not just   
   personalized therapies but personalized therapy doses and schedules.   
      
   As Ottensmeier explains, doctors ten years ago only had one type of   
   immunotherapy to offer. It either helped a patient or it didn't. Doctors   
   today have a rapidly growing library of immunotherapies to choose from.   
      
   Vijayanand and Ottensmeier are among the first researchers to use   
   single-cell genomic sequencing tools to determine which therapeutic   
   combinations are most effective in individual patients -- and the best   
   timeline for giving these therapies. In a 2021 Nature Immunology study,   
   the pair showed the potential importance of giving immunotherapies in   
   a specific sequence.   
      
   "If you design your clinical trials well and apply sophisticated genomics,   
   you have a lot to learn," says Vijayanand. "You can figure out what's   
   happening and go back to the patients."   
      
   ==========================================================================   
   Story Source: Materials provided by   
   La_Jolla_Institute_for_Immunology. Original written by Madeline   
   McCurry-Schmidt. Note: Content may be edited for style and length.   
      
      
   ==========================================================================   
   Journal Reference:   
      1. Eschweiler, S., Rami'rez-Sua'stegui, C., Li, Y. et al. Intermittent   
      PI3Kd   
         inhibition sustains anti-tumour immunity and curbs irAEs. Nature,   
         2022 DOI: 10.1038/s41586-022-04685-2   
   ==========================================================================   
      
   Link to news story:   
   https://www.sciencedaily.com/releases/2022/05/220504110410.htm   
      
   --- up 9 weeks, 2 days, 10 hours, 51 minutes   
    * Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)   
   SEEN-BY: 15/0 106/201 114/705 123/120 129/330 331 153/7715 218/700   
   SEEN-BY: 229/110 111 317 400 426 428 470 664 700 292/854 298/25 305/3   
   SEEN-BY: 317/3 320/219 396/45   
   PATH: 317/3 229/426