Dr Ghassan Abou-Alfa Explains STRIDE Regimen's Priming Dose of Tremelimumab


In his explanation of the tremelimumab priming dose, Ghassan Abou-Alfa, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, also reviews and analogizes checkpoint inhibitors as a whole.

In his explanation of the tremelimumab priming dose in the STRIDE regimen (single tremelimumab regular interval durvalumab), Ghassan Abou-Alfa, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, also provides a simplified explanation of how checkpoint inhibitors work to treat cancers.


Could you elaborate on the rationale behind the priming dose approach and how it contributed to the observed survival benefit?

To kind of simplify a little bit the checkpoint inhibitors...admittedly, I like to say that because, to be fair, most of us including myself, we're not really trained immunologists. If anything, we know back from the 60s there was always an excitement about, "How can we make the immune system attack the cancer?"

The idea is that any of us, any human being, if they were to be infected with a virus, bacteria, you name it, your immune system [is] going to go and fight. In regard to cancer, [we're] almost like picking up the phone by the cancer saying, "We're not bugging you, don't bug us." And that's why we leave the immune system at ease and not attacking the cancer. The whole checkpoint inhibitors idea is an inhibition of a checkpoint; you're trying to really limit that blockade that occurs. At the cell membrane level, this is where the T cells from our immune cells—coming from the lymph node in all of us—will try to go and attack the cancer. The PD-1 or PD-L1, think about it almost like a chair. The T cell will come and sit on that chair, cannot touch the surface of the cancer cell, nothing happens, everybody's happy. "Don't bug us, we don't bug you."

Interestingly, all that you have to do is, for the anti PD-1 [and] anti PD-L1, say for example the durvalumab kicked that chair out so the T cell will fall onto the cancer cell. However, we discovered that, for this to occur, you need to have a phone call from the boss. Somebody is going to tell the chair to move, to be kicked out. And that boss is nowhere better than of course at the top of the chain of command, which is the lymph node itself. In the lymph node, we have CD28 that talks to CD80 and CD86, and these 2 will pass on the message to the cell membrane level. Think about it like they're drinking some very robust coffee and are very energetic after doing that. And then some other entity comes in called CTLA4 to convince CD80 and CD86 to really work together. I don't know what they drink, but they all fall asleep and nothing happens.

Proudly, by the way, the CTLA4 was actually described—before his advent or coming to [Memorial] Sloan Kettering—our previous CEO, Dr Craig Thompson. Then interestingly, anti CTLA4 will come to take away CTLA4, letting CD80 and CD86 do their job to pass on the message. And one more time, from the work that was done at Sloan Kettering, Jim Allison [PhD] got the Nobel Prize in 2019 because of the anti CTLA4. And proudly, here we are, we come to the point where we shall combine those 2 together as we did in the HIMALAYA study, and hopefully for the positive outcome which of course we discovered in the study.

This transcript has been lightly edited for clarity.

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