Dr. Eddie Garon from UCLA Medical Center reviews the general mechanism of action of immune checkpoint inhibitors and how they can be an effective therapy in lung cancer.
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Immunotherapy is fairly new, in a clinical way, to non-small cell lung cancer. In a research setting, people have looked at trying to harness the power of the immune system to fight lung cancer for many years, and the ideas behind this were really very exciting, and I sometimes joke that, for many years, the people who were interested in this tended to have presentations of, largely, posters at our meetings, where they would be in the back corner of the poster hall, because, although the ideas sounded very exciting, they weren’t very successful at actually controlling disease. And, the reason that they sounded so exciting was the hope that, if you were able to have a patient’s own immune system fight against the cancer, that the result would be a sort of long-lasting sort of effect, rather than what we see with chemotherapy, where you need to keep administering, for instance, something that’s job is really to poison the cell — instead, you would allow the patient’s own immune system to fight the cancer.
For the first time in lung cancer, we now do have data that this can actually happen, and that has really been with the immune checkpoint inhibitors, and more specifically, inhibition of the interaction between PD-1 and PD-L1. These are called immune checkpoints, and your immune system, of course, is designed to get rid of things that don’t belong there — largely, pathogens, viruses, bacteria, things like that. In PD-1 and PD-L1 inhibition, what happens is that PD-1 is on the surface of T-cells, largely, where as the expression of PD-L1 is more generalized, and PD-L1 can even be expressed on, for instance, tumor cells. So, PD-1 on the T-cell is called sort of a co-receptor, where, basically, its job is when PD-1 and PD-L1 bind, to prevent the T-cell from eliminating whatever cell it is interacting with — and that’s important, because, for instance, if you have a cell that is infected with a virus, you want your immune system to be able to eliminate it. On the other hand, you don’t want your T-cells, which can destroy normal cells, going around and destroying all sorts of cells that you want to have there. Of course, there are people who have autoimmune disease where the immune system does exactly that, and destroys cells that are normal cells. So, to prevent the immune system, which is so important at eliminating things that shouldn’t be there, from eliminating the things that should be there, there are a system of immune checkpoints, and, again, what we’re talking about largely is the PD-1/PD-L1 checkpoint.
When you block that interaction, it is basically blocking an inhibitory interaction for the immune system. So, you’re basically inhibiting an inhibitory effect, which means that you’re stimulating the immune system, and when clinical trials of this started, it may have seemed a little far fetched that just inhibiting this interaction would be able to induce the immune system, our patients’ own immune system, to destroy the tumor, while, in most cases, leaving intact all the things that should be there — not destroying normal cells. But, largely, that has occurred. Certainly, there are side effects that are induced by autoimmunity when you do, sort of, stimulate the immune system in this way. But, in general, compared to maybe what had been feared, the tolerability of these agents has been reasonably good. There are immune checkpoint inhibitors that are approved in melanoma, so, two PD-1 inhibitors, for instance, that are evaluated in lung cancer, Opdivo and Keytruda, are both approved in melanoma, which is cancer of the skin, and the drug Yervoy, which is an inhibitor of another checkpoint, CTLA-4, is also approved in melanoma. CTLA-4 is involved in a slightly different place in the pathway of immune stimulation, and when that was evaluated in melanoma, where it has been quite successful in leading to some patents who have now had 10 year durations of response from metastatic melanoma.
Compared to the CTLA-4 inhibitors, like Yervoy, the PD-1 and PD-L1 inhibitors, in general, have had a toxicity profile that is much more tolerable. Things like colitis, for instance, which is very frequently seen with drugs like Yervoy, have been less common with drugs like Opdivo or Keytruda.
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