The Potential for Combining Checkpoint Inhibitors

Transcript:Ian W. Flinn, MD: It seems like that perhaps combinations are in the future rather than single agent. Is that your take on it, Krishna?

Krishna V. Komanduri, MD: Yes. We talked about this potential synergy between the post-transplant milieu and checkpoint-inhibition therapies. And, similarly, other novel agents, like targeted inhibitors, might also synergize with checkpoint inhibitors. There’s actually a lot of excitement at this meeting about preclinical data that were presented in the colorectal cancer setting. Roche is planning a trial on a combination of cobimetinib, which is a MEK inhibitor, with the RAS pathway being active in a lot of colorectal cancers and also active in a subset of AMLs and CLL, and atezolizumab, which is a recently approved checkpoint inhibitor against PD-L1, one of the ligands, as opposed to PD-1.

The only other thing I would add about that is we’ve had some interesting studies done in my laboratory, leading to a couple of recent papers, where we demonstrated that the RAS pathway is also important in IL-2 production in T cells. And we actually showed that MEK inhibition inhibits naïve and early membrane T cells, but spares the antigen-specific cells that I would predict would be important for malignancy control and are important for the control of chronic viruses. So, we have to be careful. Some of these targeted inhibitors, while they may actually lead to the death of cancer cells and lead to the exposure of antigens that may be good in terms of inducing an immune response, they may actually affect the effector T cells themselves. I think, obviously, we should have good preclinical models leading to clinical trials. And then, we have to look at both safety and efficacy, and that needs to happen.

Andre Goy, MD, MS: We have seen combination data, at the ASCO update, for melanoma where it’s very, very impressive: ipilimumab/nivolumab. The results are really outstanding compared to either as single agents. And, to the point that when we started talking about the mechanism of the checkpoint inhibition to regulate the immune response, it is a very complex mechanism with multiple checkpoint gate controls, gatekeepers. And so, there are at least 10 different antibodies, potentially, in the receptors that we could target. So, it makes sense that inhibiting one antibody, one receptor, is not enough. By extension, from the data in melanoma that are also now true in lung cancer, I think this will make a lot of sense for us to move in the hematologic malignancies, as well in combination, early on.

Ian W. Flinn, MD: How about the T cell-redirecting therapies, like the bispecific antibodies? Certainly, there are trials on the books looking at trying to combine those molecules with checkpoint inhibitors. Any thoughts there?

Krishna V. Komanduri, MD: I think that makes sense, as well, because, similarly, you have a cellular mechanism of action. And then I think that if you have the T cells, that may get engaged, may be in a maturation state, or may be inhibited. And so, you may need not only to get the T cell there with the bispecific agent that, for example, like blinatumomab, brings CD3 to the point of the tumor. But you may actually need to change the functional state of the tumor with a checkpoint inhibitor.

I think in that context, it’s just worth mentioning that there are some of the other checkpoint inhibitors therapies that we haven’t yet seen translated. LAG-3 (lymphocyte-activation gene 3) or CD22 is also another inhibitory receptor on the surface of T cells. It’s also present on regulatory T cells. It turns out that the adenosine pathway can actually have a negative effect on T cells. And there’s a company, Corvus, that’s developing therapeutics against this novel approach of doing checkpoint inhibition. I think we’re going to see not only all these interesting things, like where’s the timing? How does this synergize with either transplant or combination therapies? But we’ll also see novel agents that may have different patterns of activation of the immune response. So, it will be an exciting time.

Andre Goy, MD, MS: I think you mentioned the blinatumomab or the BiTE (bispecific T-cell engager) antibodies. There are many others. The BiTE antibody, for our audience, is actually a small molecule that is a combination of a recognition of a CD3 and CD19, for example, for blinatumomab. So, as you mentioned, Krishna, bringing them together and forcing the engagement of the T cells, that’s a way to release the T cells and engage them. And the responses have been amazing in lymphoma, including a refractory large-cell lymphoma. It has some issues, because it’s a continuous infusion program. So, it may be tedious, but there are amazing responses. It has a similar toxicity, as we see in CAR-T cells, with the CNS toxicity, because T-cell activation goes to the brain. But, at the same time, we see responses in ALL. In ALL, we actually get patients going into MRD-negativity, and that’s where it’s approved, in refractory ALL. This is really something that is going to be in a situation where you don’t have a CAR-T cell possibility that could be a great backbone to try to build up, maybe on BiTE antibody plus a checkpoint inhibitor. I think that would be very promising.

Transcript Edited for Clarity