Dr Tycel Phillips on Progress in B-Cell Lymphoma Treatment

In this interview with The American Journal of Managed Care® (AJMC®), Tycel Phillips, MD, associate professor of medicine, Division of Lymphoma and Bone Marrow Transplantation, City of Hope, Duarte, California, discusses the advancements that are shaping the future of B-cell lymphoma treatment, as well as access barriers.

AJMC^®: What advancements in research and technology are shaping the future landscape of B-cell lymphoma treatment?

Phillips: I think the biggest advancement in the field of lymphoma treatment has really been T cell-directed therapies. We have CAR-T with the approval of 3 CAR-T products in diffuse large B-cell lymphoma and also approval of CAR-T products in mantle cell lymphoma and follicular lymphoma. Because of how these therapies work, obviously, with use of the patient's autologous T cells, meaning the patient's own T cells being collected, manufactured and then reinfused, it does allow for a 1-time treatment. And at least with large cell lymphoma, we have evidence of these patients, at least those who get a complete remission, are being cured with this type of treatment. With the other 2 lymphomas we mentioned, there are very good long durations of response, but as of yet, the data does not support that these lymphomas will be curable with CAR-T. But compared to what we have for other treatments in that space, the durability of remissions appears quite impressive. Sort of in the same vein, there are bispecific antibodies, which function very similar to CAR-T, more of an off-the-shelf antibody that, again, recruits T cells to fight off the cancer. There are several bispecific antibodies that have been studied. And there are 2 that recently got approved: mosunetuzumab AB in follicular lymphoma and epcoritamab in diffuse large B-cell lymphoma. There are several sort of modifications being made both to CAR-T and with device specific and in some situations, quite specific antibodies improve outcomes in these patients. But I would say as of right now, those are sort of the biggest treatments of in this patient space.

AJMC^®: What is the role of CAR-T cell therapy in the future treatment landscape of B-cell lymphoma?

Phillips: To sort of piggyback on what we talked about as far as the efficacy and the duration of response, I think the problem we've run into with CAR-T, at least in certain areas, is limited access. And that is partly related to CAR-T has to be given in specialized centers. In certain areas of the country, there are quite a few CAR-T centers. Here in LA, there are several centers that can perform CAR-T treatment. And if you go to the East Coast, New York, Boston, Philadelphia, Washington DC, it's a highly concentrated area of CAR-T centers. But as you move out of those sort of areas toward the Midwest, the Great Plains, and even the areas of the Southwest, there are very few centers that are equipped to do CAR-T, and so it does limit access to these treatments to the vast majority of patients. So, until we can further improve access of CAR-T and potentially reduce some of the cost burdens as well, it's going to make it very difficult for this to really become a mainstay in most patients. But for those who can get CAR-T it looks as if, especially in large cell lymphoma, it is a curative therapy that is firmly entrenched in second line for patients with refractory disease, with primary refractory disease and who relapse early, and likely will be explored in earlier lines of therapy in diffuse large B-cell lymphoma, potentially mantle cell lymphoma. And I'm sure it will be explored in some of the other B-cell lymphomas.

AJMC^®: What are the challenges and opportunities in developing more effective and less toxic therapies for B-cell lymphoma?

Phillips: Well, some of the biggest challenges, like CAR-T, is access. Some of the other ones, even with the bispecifics, as of right now, the side effect profile is something that a lot of the community physicians don't have experience dealing with. And so, to introduce these drugs into that setting without experience with dealing with the adverse events does make it quite difficult and probably create some hesitation for these physicians to use these treatments. Even as we advance and get treatments which overall may be less toxic than what we see with chemotherapy, the different toxicity profiles, that comfort level needs to be sort of reached before I would say everybody's OK with using any sort of treatments. Really as we move along, and we start sort of continuing to try to enrich and sort of utilize the patient's own immune system to try to fight off these cancers, these are some of the things that we're going to have to try to navigate. So that's one of the biggest challenges in sort of looking at opportunities. Obviously, again, I think a lot of the focus is using patients’ T cells, which is an immune cell, the natural killer cells, which are also immune cells, sort of figuring out ways to sort of overcome resistance mechanisms that some of these tumors have with some of these T cell-directed therapies by targeting not just 1 epitope, maybe 2 epitopes, trying to figure out other ways to try to knock down sort of other tumor-suppressive sort of avenues that tumors might utilize to sort of resist the effects of these sort of immune-directed therapies.

As I mentioned, with the bispecifics, we have trispecific antibodies looking in multiple epitopes. They also are being infused with costimulatory antibodies to help improve T-cell activity. The research looking at NK cells, which are natural killer cells. There are research looking at allogeneic T cells, meaning T cells from another patient. So all these different avenues to try to figure out better ways to try to get these products to patients, potentially try to remove some of the major side effects from these products, and also trying to improve access, if we can potentially get off-the-shelf products, products that don't induce a lot of cytokine release syndrome and neurological toxicity, things like that, which will get more of the drugs in the hands of doctors and eventually into the bodies of the patients that need these type of treatments.

AJMC^®: How might precision oncology initiatives impact clinical trial design and patient enrollment in B-cell lymphoma research?

Phillips: To be very transparent, I think we're a bit of a ways away from really utilizing precision medicine to try to improve outcomes and designed treatments in B-cell lymphomas. If we take diffuse large B-cell lymphoma, which is the most common lymphoma by far, we've not done such a great job with trying to stratify patients based on certain cytogenetic or molecular or even protein expression to treatments that may, or we assume will be better or not. I think we're still in an infancy stage of trying to identify specific precision markers or precision sort of medicine type focus to improve outcomes in patients with B-cell lymphomas. I think we are learning more and more about the tumors and maybe some differences that may exist in the tumors based on some of this information. But for the most part, it hasn't really translated into effective treatments or different treatments for the majority of patients. And even when we do these more in-depth sort of molecular testing like the sequencing testing, looking at the DNA of tumors, a lot of the mutations that we find we don't really know what to do with or we don't have drugs that actually target these sorts of mutations or alterations that we're finding. And even the one—if we flip to follicular lymphoma, which is the second most common, the EZH2 mutation, which we have a test for—we have a drug for it. Some of the data is suggesting that maybe it's not as important to have a targeted treatment for this, that the drug just works and doesn't necessarily work substantially better in those who we suspected would, outside of maybe a certain sort of specific patient characteristic. I think we have a long way to go. Reardless of how solid tumor, especially lung cancer, is being treated, we're nowhere near that point.

AJMC^®: What are you working on in the management of B-cell lymphomas that you're excited to share?

Phillips: At City of Hope, we have several CAR-T studies ongoing. We have several bispecific studies. We have some pretty cool novel antigen drug conjugates, looking at some novel targets that are quite different than what we've done before. And personally, for our research in mantle cell lymphoma, we are working on several what we considered innovative studies, specifically looking at different groups of patients. Those we know who have high-risk features such as p53 mutation, we're specifically working on a clinical trial for those patients. We're working on a chemotherapy-free study for just patients in general. And we're likely to start working on a study looking for elderly patients and those who may have a few more comorbidities and may not be fit for some of these other treatments. So, I'm very excited about that work we're doing at least in the frontline setting. And we are working on some new concepts in those who have relapsed refractory disease. But, overall, I think at this institution, we have several CAR-T products looking at novel targets, several bispecifics, trispecifics, bispecifics with costimulatory sort of antibodies infused at the same time. I think we, at least at this point, have quite a bit to offer patients, which I think is a very good thing because the more options we have for our patients, the better we can sort of induce outcomes, especially in these cancers which we can't cure. And even in these curable ones that have unfortunately not necessarily responded to standardly FDA-approved products, having these clinical trials, I think, is very important to improving their outcomes.