Williams Cancer Institute

Triple Immunotherapy Targeting 41BB, LAG3 and CXCR1/CXCR2 Shows Excellent Response In Pancreatic Cancer

One of the areas that will result in a high percentage of future cures is combination immunotherapy.  It is clear that one drug is not enough; cancer will get around it.  It is also clear that combination immunotherapy given intravenously to the whole body will increase toxicity.  These combinations will need to mainly be injected into a tumor to teach the local immune cells to attack it.  Surprisingly, this is not just a local response but a global anti-cancer immune response potentially attacking cancer throughout the body.  The one question is, what are the most effective combinations?  We have done work with many, and a new study published by Gulhati et al. has shed even more light on a triple-drug combo for pancreatic cancer.  Pancreatic cancer is resistant and is an excellent proving ground for cancer treatment.  If you can treat pancreatic cancer, other cancer should respond, as it is one of the more resistant cancers.

Most standard immunotherapy is focused on PD-1 inhibitors, such as Opdivo or Keytruda, or CTLA-4 inhibitors, such as Yervoy.  This current article shows, as already known, that these drugs have little activity in pancreatic cancer.  Most research in a key immunotherapy for pancreatic cancer has been around an agent CD40.  The study by Gulhati from MD Anderson was published in Nature Cancer, titled “Targeting T cell checkpoints 41BB and LAG3 and myeloid cell CXCR1/CXCR2 results in antitumoral immunity and durable response in pancreatic cancer.”  This study shows an exciting combination and makes a fundamental discovery.

Many of us had already been studying and using 41BB and LAG3.  In pancreatic cancer, we had also seen success with CD40 agonists.  The results were good, but there is always room for improvement.  One area lacking is targeting myeloid-derived suppressor cells (MDSC).  Though we have some drugs and off-label medications that help, we need something better.  In this study, the experimental drug SX-682 plus 41BB agonist and LAG3 antagonist seemed to do the trick in the animal model with a 90% cure rate.  To avoid getting too complex with the explanation, if you have read my book, you know that MDSCs are immune cells that protect against cancer.  They can shut off the immune response.  When you use standard immunotherapy drugs to turn on the immune response against cancer, these are a group of immune cells that can shut it down.  Most immunotherapy, especially standard FDA-approved medications of today, focuses more on the T cells and does not address MDSC. It is a gaping hole in current cancer immunotherapy.  Though you may get an initial immune response going, in most cases, it will get shut down, and MDSC can play a significant role in that.

For this reason, you need combinations to affect the immune response at many angles.  The drug SX-682 inhibits CXCR1/2, which are chemokine receptors that recruit MDSC.  There are still many ways cancer can shut off the immune response; in reality, it may take even more extensive combinations to obtain a cure in a high percentage of patients.  There are so many immunotherapy agents in studies now that we have the weapons; we need to deploy them appropriately.

Reference: Gulhati, P. a.-J. (2023). Targeting T cell checkpoints 41BB and LAG3 and myeloid cell CXCR1/CXCR2 results in antitumor immunity and durable response in pancreatic cancer. Nature Cancer, 61-80.

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