Ian W. Flinn, MD, PhD: The big area that we haven’t talked about is immunotherapy. There’s a huge array of different tools, from checkpoint inhibitors to antibody—drug conjugates to bispecific antibodies to CAR T cells. We’re going to get everyone in on this discussion, but let’s start with Greg.
Grzegorz S. Nowakowski, MD: I’d probably start by saying that if you look at follicular lymphoma, this should be the prime target for immunotherapy. We know about the role of the microenvironment in this disease; it has been extensively studied with some T-cell exhaustion. So, if we can reactivate those T cells, they could probably have an anti-tumor effect. There’s also significant acquisition of somatic mutations, which, at least in solid tumors, have been shown to be a biomarker of response to checkpoint inhibitor therapy. With all this knowledge, it’s really a good target for immunotherapy approaches.
Having said so, response to checkpoint inhibitor therapy—for example, the single agent—has been quite disappointing. I think this is where the field is moving, out toward combinations. You can do that in many different ways. For example, you could combine checkpoint inhibitor therapy with antibody therapy, that makes sense, and activation of the immune compartment to increase the antitumor response.
We should also not shy away from combinations with chemotherapy, by the way, or chemoimmunotherapy. It always brings up the discussion that we had when rituximab was first introduced. Should we be combining this acute therapy or not? It’s immunotherapy, and then you’re suppressing the immune system by adding chemotherapy. Needless to say, chemoimmunotherapy became a standard. And here I think combination of checkpoint inhibitors with chemoimmunotherapy is also worth studying, because chemotherapy could be inducing additional genomic instability and producing new androgens that can then make checkpoint inhibitor therapy much more active.
Ian W. Flinn, MD, PhD: That always seemed to be a little bit concerning in the sense that all of our therapies for lymphoma are directed at killing lymphocytes, right? Is that a problem? If you give someone BR followed by a checkpoint inhibitor, what have we done?
Grzegorz S. Nowakowski, MD: That’s absolutely right. This is a concern because it does lower the lymphocyte count, or NK cell counts, and we know that NK cell counts of lymphocytes are actually prognostic in a lymphoma and in other tumors as well. So, having higher counts is better. On the other hand, there is the example of Rituxan (rituximab). You are suppressing the immune system with chemotherapy, yet the combination of chemotherapy with rituximab seems to be effective. I think we are possibly underappreciating the role of chemotherapy in inducing those new antigens and actually helping the immune system to recognize the tumor. If you introduce this genomic instability, if you’re causing cell death and apoptosis, a lot of those antigens are being exposed and then the immune system can be activated. So, it’s a balance. Yes, we do probably suppress some of the effector cells with chemotherapy, yet we’re uncovering those tumor cells through the immune system.
Ian W. Flinn, MD, PhD: Loretta, was the hypothesis behind your study with pembrolizumab and rituximab new antigens being exposed with rituximab? What’s the basis of that?
Loretta J. Nastoupil, MD: Yes, it has been mentioned. The microenvironment, or targeting of the microenvironment, has been something that has been highly sought after. Regarding how you do it, there are various means of accomplishing it. What we’ve seen in preclinical models is that the T cells that are infiltrating, particularly in follicular lymphoma, tumors often have PD-1 overexpression. And so, if you could reverse that T-cell exhaustion through a checkpoint inhibitor, maybe you could actually enhance the antitumor endogenous immunity. If you combine it with a CD20, which also has an impact on NK cells, that may actually result in some synergism. We know that a single agent’s checkpoints in relapsed follicular lymphoma have been modest at best, probably not adequate enough to move forward as a single agent. That was really the rationale of the combination. We have studied this in relapsed follicular lymphoma patients. What we see is that the response rates are quite high, but probably even more importantly, there’s a subset where those responses are very durable. Again, can we identify who those patients are and not treat the patients who have a suboptimal, or no, response?
You can potentially characterize the pretreatment immune cell subsets and identify patients who have a higher CD8 T-cell effector score, for instance, who are more likely to respond to this targeted approach. However, it’s very complex and probably more than just PD-1 inhibition that’s going to achieve a more durable response; that’s the next phase. Can we identify rational combinations with co-inhibitory approaches that can potentially also lead to more toxicity or combination approaches that have been mentioned with various mechanisms of action? There’s still a lot to be learned.
Ian W. Flinn, MD, PhD: So, there’s an antibody—drug conjugate, polatuzumab vedotin, which is an anti-CD79B antibody–drug conjugate. Anas, do you think that’s rational? It has single-agent activity. There are some problems with neuropathy, but do you think that might combine well with a checkpoint inhibitor?
Anas Younes, MD: It can be combined with many other agents. The signal coming now, which is really nice, is with bendamustine-based therapy. And polatuzumab is basically targeted chemotherapy; it’s like chemotherapy on a stick and is being selectively delivered to the tumor cells. The data look very interesting, very promising, that it may be adding value to what we do outside this precision and the mutations and so forth. It could be a simple targeted delivery of chemotherapies in a way that can make a difference.
But going back to the immune therapy checkpoint inhibitors, I agree with Greg and what he said. I think the same debate was had with rituximab: Should we combine it with steroids? Could we give it with R-CHOP with steroids? It may have attenuated the efficacy of single-agent Rituxan, but that didn’t nullify it completely. All randomized trials show that if you combine rituximab to chemotherapy, there was an advantage. But with immune checkpoint inhibitors, it doesn’t have to be with chemotherapy. There’s a tendency to combine with small-molecule immune modulators. We have to be mindful of the safety when we do that, because you may augment the immune response beyond just killing the tumor cells. You may induce excessive autoimmunity. But there are multiple other ways of combination that need to be tested.
Transcript Edited for Clarity