Ezra Cohen, MD, discusses anti–PD-1/PD-L1 combination regimens in HNSCC, the potential for CAR T-cell therapy, and remaining challenges with immunotherapy in the field.
Ezra Cohen, MD
The future of immunotherapy in head and neck squamous cell carcinoma (HNSCC) lies in combinations involving anti PD-1/PD-L1 agents, says Ezra Cohen, MD, adding that chimeric antigen receptor (CAR) T-cell therapy may have a role, as well.
In an interview with OncLive, Cohen, professor of medicine, division of Hematology/Oncology, University of California, San Diego, associate director for Translational Science, Moores Cancer Center, discussed anti—PD-1/PD-L1 combination regimens in HNSCC, the potential for CAR T-cell therapy, and remaining challenges with immunotherapy in the field.Cohen: When we talk about immunotherapy in head and neck cancer, we are really talking about squamous cell carcinoma where the exploration of anti—PD-1 and anti–PD-L1 has focused. Right now, we have 2 approved agents in patients with recurrent or metastatic disease—the first is pembrolizumab (Keytruda) and the second is nivolumab (Opdivo), in the order of their FDA approvals.
For now, we are using immunotherapy as standard-of-care in patients who have either recurred after curative intent therapy within 6 months of completing that therapy, or in patients who have had first-line platinum-containing therapy and have progressed. So, it’s really focused now on patients with recurrent or metastatic disease.For the future of immunotherapy in HNSCC, we are really thinking about combinatorial therapy. And what I mean by that, is now trying to integrate the agents we know have efficacy as single agents, so be it pembrolizumab, nivolumab, or even durvalumab (Imfinzi) and avelumab, (Bavencio).
Now, we are beginning to think—how will they fit with either immunotherapies and/or standard of care? First of all, there is a lot of excitement around combination immunotherapy, we are beginning to see data about doublets and the potential to really double response rates or even more for agents that are combined with anti—PD-1. We saw a very nice example at ASCO in June of 2017, where pembrolizumab and nivolumab were combined with IDO inhibitors, specially epacadostat. And what we saw was an almost 40% response rate in patients who were let’s say, relatively not heavily pretreated. That is an amazing response rate for a doublet immunotherapy.
Moreover, we are beginning to explore these agents in combination with standard chemotherapy, mostly platinum-containing regimens. And now, finally, in the locally advanced setting—in combination with radiation or with chemotherapy/radiation. Of course, those data sets will take some time to mature, we won’t get those data for another few years, but the tremendous promise has now led to extending these agents into earlier phases of disease. When we think about other types of immunotherapy that we could apply to head and neck cancer, we naturally have to think about adoptive cell therapy—and mostly we are thinking about T cells. We have to just step back for a second and realize that when we talk about adoptive cell transfer or adoptive cell therapy, it comes in many forms. It can come into the form of simple tumor-infiltrating lymphocytes (TILs), that is, taking TILs out of a person’s tumor, expanding them ex vivo, and then putting them back in. Or it can be much more sophisticated in the form of CAR T-cell therapy.
Now, the question of whether CARs can actually be applied to head and neck cancer is a good one, and one that is being intensively investigated. The real problem in head and neck cancer—as it is with many solid tumors—is finding the right target. What we’ve learned from other experience with CAR therapy is if you have the right target, you can see tremendous responses, acute lymphoblastic leukemia (ALL) is one such example with CD19. But, if you have the wrong target, patients can get into trouble—and there have even been fatalities, and unfortunately, there have been some notorious studies with that.
And so, the first challenge is finding the right target—and there are some, primarily stem cell antigens that are expressed exclusively or almost exclusively on cancer cells. ROR1 is one such target, and people are beginning to look at that in head and neck cancer. There may be some others that are a little bit earlier in development.
That’s the first challenge. The second challenge for CAR T-cell therapy in solid tumors in general is getting the cells to the tumor. As opposed to hematologic malignancies and even lymphoma, there are more barriers in solid tumors that will potentially prevent the T cells from getting there. Having said that, we are beginning to see some preclinical, and even clinical, data to suggest there are ways to overcome that, especially when we combine that with other T-cell regulating agents, such as anti—PD-1 or anti–PD-L1.
The third challenge in solid tumors is of course the density of the tumor. Even if the T cells get there, will they be able to eliminate the entire tumor burden? And that really is a question that we will only be able to answer in the clinic, and hopefully, we’ll have an answer to that in the near future.
CAR T cells can work, they should work in head and neck cancer, and my hope is in the next few years, we’ll be seeing some interesting data.The other thing that we are working on as a community in head and neck cancer, primarily as a result of what we’ve learned about cetuximab (Erbitux), is NK-directed therapy. Let me step back about a decade to the realization that part of the mechanism of action of cetuximab is the activation of antibody-directed cellular cytotoxicity (ADCC), and that depends—if not wholly—at least partially, on NKs. If we appreciate that, then the next step would be to try to activate NKs in a more profound way, or try to take advantage of their ability to kill tumor cells and bring those into the therapeutic arena. And that is exactly what many groups are doing through different mechanisms.
First, we now recognize that there are receptors on NK cells that lead to their activation, or the aggregation of negative impulses, and there are a few agents now that are moving into the clinic. Most notably, an anti-KIR antibody that has shown synergistic or perhaps additive, activity with nivolumab anti—PD-1.
And then right after that, are actually NK cell—directed therapies. Where, again, we can manipulate NKs ex vivo and then reinfuse them, or even create NKs from regular stem cells from the blood or skin, and infuse those back into the individual. Those, we believe, will work synergistically with other existing therapies, such as cetuximab, or other immunotherapies, and there is quite a lot of work being done in that area.For squamous cell carcinomas, and particularly those of the head and neck, the challenges with immunotherapy are really a few things. First of all, we have a disease that has both a viral etiology or a tobacco etiology, and for now, it may look like there may not be tremendous differences in response rate with the anti—PD-1s or the anti–PD-L1s for those 2 entities—perhaps the HPV-positive patients have a slightly higher response rate.
But as we move forward with other types of immunotherapies—with ones that are more targeted, with ones that may be more specific to a viral etiology—we’re going to have to figure out which agents are preferentially beneficial in HPV-related disease versus carcinogen- or tobacco-related disease. That’s one challenge.
The other challenge is one that is not necessarily unique to head and neck cancer, but is important to remember in many cancers and that is there is a group of patients with HNSCC that unfortunately have rapidly progressing disease. What we know about immunotherapy so far, is that it takes time to work. And if you think about it intuitively, that makes sense. You are not directly effecting the tumor cell, you are activating a system that is then going to kill the tumor cells. And there are patients who just don’t have the time to appreciate the benefit from immunotherapy and we have to overcome that by looking at ways to get the tumor under control for at least several weeks so that we can give immunotherapy time to work. And, of course, we are exploring that with different modalities like chemotherapy, radiation therapy, even oncolytic viruses that may really combine very well with existing and future immunotherapy.