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WSJ: A Piece of the Immunotherapy Puzzle Solved

August 19, 2016
Just two weeks ago, the New York Times published a series of articles deeming immunotherapy as the future for cancer advances and new life-saving treatments - even though it’s not entirely clear why only some patients have success with the treatments. This week, the Wall Street Journal joined the immunotherapy conversation by highlighting two researchers who may have unlocked part of the mystery as to why only some patients benefit from immunotherapy.

When Dr. Michael Rosenblum’s stepmother was given six months to live, he cold-called a cancer specialist at his UCSF’s dermatology department - Dr. Adil Daud. While they never would have met outside of these circumstances, together they went on to collaborate on research to solve the puzzle as to why this new class of drugs called checkpoint inhibitors (immunotherapies) don’t work for most. As the article explains:
The prevailing theory of how checkpoint inhibitors work is based on evidence that immune-system fighters called CD8 cells, which are normally primed to kill enemy cells, initially see and infiltrate tumors but can end up in a state of chronic activation, too exhausted to mount an effective attack.

Dr. Daud initially treated Dr. Rosenblum’s stepmother with a checkpoint inhibitor that targets an “immune-system brake” called CTLA-4. As Harvard University puts it, immune checkpoint proteins act as ‘brakes’ on T cell activation – they moderate the reaction of the immune system to minimize collateral damage. Unfortunately, there were some serious side effects and he instead enrolled her in a trial for a checkpoint inhibitor that targets another immune-system break called PD-1. They shifted their focus to PD-1 and set out in Dr. Rosenblum’s immunology lab to perform a comprehensive analysis. Some of their findings included:
A candidate CD8 cell that had infiltrated tumors marked by levels of not only PD-1 but also of a second immune-system brake called CTLA-4.

If at least 30% of those cells were marked by PD-1 and CTLA-4, the patient responded to treatment. When fewer than 20% of the infiltrated cells had those markers, not one patient responded.

Further analysis showed that the anti-PD1 drug reactivated the exhausted CD8 cells, and when they were in sufficient numbers, they were able to mount an effective attack on the tumor.

But the findings did show that the particular CD8 cells identified “are the guys that are doing all the work to kill the tumor,” Dr. Rosenblum noted. Researchers are already exploring whether it’s possible to retrieve such cells from the tumor, expand them into huge quantities outside the body and infuse them back into patients—possibly using a PD-1 inhibitor—to increase the number of patients who respond.

Read the full piece here.