Bispecific Antibodies and Immunotherapy for Aggressive Lymphomas

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals exploring the latest innovative research and clinical advances in the field of oncology.

Thank you for joining us for another episode of Cancer Advances. I'm your host Dr. Dale Shepard, a Medical Oncologist, Director of International Programs for the Cancer Institute at Cleveland Clinic and Co-Director of the Cleveland Clinic Sarcoma Program.

Today I'm happy to be joined by Dr. Paolo Caimi, Associate BMT Director for Cellular Therapy at Cleveland Clinic. He was previously a guest on this podcast to discuss new developments in cell therapy and that episode is still available for you to listen to. He's here today to discuss bispecific antibody combinations, the latest advances in immunotherapy for aggressive lymphomas. So welcome back.

Paolo Caimi, MD: Thank you for having me.

Dale Shepard, MD, PhD: Remind us again what you do here at Cleveland Clinic.

Paolo Caimi, MD: So, I'm a lymphoma specialist. I treat patients with lymphoma, but I'm also part of the bone marrow transplant team and I focus primarily on the cell therapy research aspect of our group.

Dale Shepard, MD, PhD: Excellent. So we're going to talk about a study related to refractory and relapsed diffuse large cell lymphoma. Give us a little bit of an idea, a lot of people listening in, different backgrounds. What's kind of the standard therapy? What's the fundamental question that drove to a need for this study?

Paolo Caimi, MD: So, the patients that have initial diagnoses of diffuse large B cell lymphoma tend to have relatively good prognosis and to be very chemo sensitive. And the vast majority of people, about 70% of people tend to have a remission and many of them have durable remissions. The problem disease is that third of people who don't have disease that responds to initial treatment who relapse and who are now eligible to receive and the vast majority of people to receive CAR T-cell therapy, but many of them cannot receive it. We have some significant amount of data showing that many patients who should be prescribed a CAR T-cell don't have access to them, not just in the US but outside of the US in terms of because of the cost, because of the logistics.

So for those patients, we've traditionally prescribe salvage chemoimmunotherapy and eventually those few patients that respond to the salvage chemoimmunotherapy, which is usually less than 30% or around 30%, those patients will proceed to a stem cell transplant, to an autologous stem cell transplant, so high doses of chemotherapy and then your own stem cells. And that's more or less the reality of what we're dealing with is if ideally we can try to offer CAR T-cells to these patients for whom the outcomes can be curative and about 40 to 50% of people will hopefully stay in remission within a year, but a vast majority of patients are not getting access to this treatment. So we actually need to improve the performance of our second-line therapy to be able to control disease in novel ways.

Dale Shepard, MD, PhD: So, couple of questions, just again to clarify for background, if people don't have access to CAR T, are they more likely, less likely, how does that normally track with their access to transplants?

Paolo Caimi, MD: So similar to what your access to transplant, it's a little bit more complicated to get CAR T-cells because you actually need to, there's other barriers to get it. Getting a transplant is usually a matter of getting in remission and then being able to transport to get your transplant and staying within that region. And those are normal barriers that you see for CAR T-cells. The additional barrier for CAR T-cell is that you need to get your cells taken out under some manufacture period. So there's a disease biology barrier where if you have a rapidly progressing disease, you just can't get to CAR T because your disease is going to progress in those three weeks, you're going to need bridging. Usually, it's not super effective. So that's yet another barrier for patients. So we think that there's a built-in inherent selection process, a selection bias to CAR T where patients who actually have good biology, who have the resources to travel are getting CAR T-cells and they're doing well because of that.

Whereas the people who have probably bad disease biology and they don't have the resources, then they cannot access the main center and then they're not getting the treatment that would potentially control it. We have done studies with CAR Ts that are manufactured very quickly. We are not having access to CAR Ts that are manufactured by a period of days versus weeks. And we see that people who are very refractory can have good responses to CAR Ts, but the challenge is that most of those CAR Ts are academics, so they're not commercial and the manufacturing centers like ours, but not every center has it and it's a limited number of people. So we need to work more on validating how can we facilitate the access to CAR Ts, but also we need to work on can we get better therapies as well for people who can access it or alternatives to these agents too.

Dale Shepard, MD, PhD: And I guess one last question just sort of as a backdrop here, not having treated lymphomas for a very long time, but you mentioned about the biology of the disease and sort of timeframes and things, relapsed disease, so relapse refractory, so oftentimes, they both are in need for second line therapy, oftentimes I see where those are sort of lumped, but they're two different things. Is there a difference kind of fundamentally we think in the biology of someone who is refractory versus a relapsed?

Paolo Caimi, MD: So yes, actually there's never more, I guess nuanced distribution of patients and the approvals for drugs go on that. The people who have disease that is primary refractory, we know they have bad biology, have disease that it's going to be very sensitive to chemotherapy, but we also extended that kind of poor prognosis group to those who had disease that relapses within a year and then people who relapse beyond the year after completing their initial chemotherapy, so the late relapsers versus the early relapsers and the refractory people tend to have a better prognosis. This has been validated in retrospective analysis and the randomized studies that compared traditional salvage chemotherapy with the CAR Ts were done on that poor prognosis group. So people who relapsed early within a year and those who were primary refractory.

There are some data tissue studies from the Vancouver group. It's a very robust histology and molecular biology group that are indicating that there probably are different biologic pathways or signaling pathways in these two groups. So really, we're talking about two different diseases. We all know that diffuse large B is kind of a larger group of lymphoma that is kind of all bundled together based on one histologic look, but now we're starting to see that the clinical response and the clinical behavior after initial chemotherapy is based on a biologic difference.

Dale Shepard, MD, PhD: Got you. We're going to talk about . Tell us a little bit about what does that mean, what is a bispecific antibody and how are those being incorporated into treatment now?

Paolo Caimi, MD: I think most of us in the oncology field that are kind of very habituated to knowing about regular monoclonal antibodies that target a single antigen on the surface of cells. Bispecific antibodies, as it's indicated, target two different antigens and they don't necessarily target two antigens on the cancer cell. What they're actually are doing is they target the ones that are now approved target CD20, which is the same antigen on the cancer cell that Rituximab targets, but they also target CD3, which is a T-cell target. They also have the functional part of the antibody, the Fc gamma part, it's inactivated so they don't activate the immune system as antibodies. What they're primarily doing is redirecting the T-cell to the cancer cell. They bind to the T-cell, they bind to the bad B-cell and they're able to put them together and they can create this immune synapse where they're redirecting the cell and they're now approved in another the tumors as well. So they're able to bring the T-cell in proximity to the cancer cell and by binding CD3 you can actually activate those T cells. So it's another T-cell redirecting therapy.

Dale Shepard, MD, PhD: So tell us a little bit about, there's a study that you looked at an early phase study with Glofitamab and Rituximab and chemotherapy. Tell us a little bit about what you did.

Paolo Caimi, MD: There's several bispecific antibodies. Glofitamab and Epcoritamab are antibodies that are approved for diffuse large B cell lymphoma, then third line and beyond, and what we're seeing now is these are early studies of combinations of bispecifics with other agents. The study we participated in is a combination of Glofitamab with a traditional chemotherapy that we've used a salvage which is ICE. I think many of us are familiar with ICE. Prior to trying to take a patient to transplant, we used to do our ICE or R-ICE and this study was looking at can we do this combination safely with the new monoclonal antibody or new bispecific antibody Glofitamab plus ICE chemotherapy. And that was a Phase I study aimed specifically of where we normally use ICE, which is before a transplant or before a CAR T-cell. So trying to get that remission for a patient that is relapsed after initial therapy. And this included both early and late relapsers and is primarily looking at two to three cycles of this treatment prior to the consolidation with either transplant or CAR T-cell.

Dale Shepard, MD, PhD: I have a naive question from a biology standpoint. So it included Rituximab which binds to CD20, but then also the Glofitamab which binds to CD20. So there's two antibodies to the same CD20. How's that expected to interact?

Paolo Caimi, MD: Actually, they also included Obinutuzumab, which is Obinutuzumab, which is another CD20 antibody. What happens is that what we've learned on the single agent studies for this bispecific is that they're associated with the same type of side effects that you see with CAR T-cell, which is primarily cytokine release syndrome and a little bit of neurologic toxicity. So you actually need to deplete the circulating B cells before you give these agents and that's how the strategy has been for Glofitamab. A week before they get the initial dose of Glofitamab, they get a dose of Obinutuzumab which decreases the circulating B cells and then they get ICE, the chemotherapy, and really having some degree of decrease of the antigen actually improves the tolerability of the drugs.

The additional strategies that people have actually a ramp-up period on the first cycle they get, I usually call it an espresso cup, a medium cup, and then a big cup of the drug. So they're kind increasing doses, I call it on the Starbucks type of doses, but I don't want to make commercials here. But the idea is that over the first three weeks, people are ramping up on the dose of drug and that decreases the risk of having cytokine release syndrome. Still on a small percentage of people have it. So we haven't seen that it's using an antibody that targets the same epitope or same antigen is deleterious, probably improves the tolerability. All these drugs have several weeks of half-life, so you will see them mixed.

Dale Shepard, MD, PhD: So did this early phase study, what did you find from a response rate standpoint?

Paolo Caimi, MD: So just to put it in context, the response rate for ICE is around on a good day, 30 to 40% for most people who are relapsing, ICE alone or Rituximab and ICE. This is from all studies like the CORAL study from the early 2000s.

Dale Shepard, MD, PhD: As a sarcoma guy, I'm going to interject that I'm jealous.

Paolo Caimi, MD: Correct. Yes. So when you're seeing curves that are becoming straight lines, that's something that are... But the moment you have better responses, you start getting greedy, right? I think more is our favorite word. We always have better response in our target, but 30 to 40% response rate is something that you're jealous. The combination of these two drugs, overall response is 82% and the complete response rate of Glofitamab plus ICE was 68% and that is a trend that we're seeing with most bispecific combinations with chemotherapy.

You would also argue that if you're decreasing the immune system, you're impacting the T-cells with chemotherapy, may be combining with a bispecific would actually be deleterious to the effect, which seems that the combinations of cytotoxic chemotherapy with bispecific antibodies, whether it's this one or others that targets CD20, they seem to be being additive or synergistic. So on the same session where Glofitamab, R-ICE was presented, Glofitamab combination with antibody drug, immunoconjugate that target B-cells also having response rates over 70%, we're seeing... And also the GEMOX, which is another chemotherapy combination with Glofitamab has survival advantage versus GEMOX alone or on Rituximab. So certainly, these are drugs that are enhancing the activity of cytotoxic chemotherapy.

Dale Shepard, MD, PhD: So certainly, efficacy is improved. What was the finding from a safety standpoint?

Paolo Caimi, MD: So that's the additional positive side effect is that they didn't really increase what we know, the toxicity that we know of ICE. You always have to take a Phase I with a relative grain of salt. You know it well. The safety, the patients that we select for this group are usually relatively robust, particularly in the second line for a Phase I. But importantly, we saw that by using chemotherapy and using the strategy of using Obinutuzumab prior to the treatment with Glofitamab, we really saw single digits cytokine release events, no grade three cytokine release in any patient, even though we use steroids and Tocilizumab, which are measures to treat some of these side effects too. Because we're treating very early side effects, we're not waiting for grade three. We really didn't see severe cytokine release syndrome. We saw hematologic toxicity as you would expect with chemotherapy in a significant percentage of patients, but it wasn't really a larger number than you would expect with ICE alone even though these drugs are something that you have a little bit of a range of hematologic toxicity.

Dale Shepard, MD, PhD: What do you anticipate the sort of landscape of treatment will start looking like as we get these combinations that are working so well? Patients if they have a relapse, CAR T therapy, combination therapies. What's things going to look like as we move forward?

Paolo Caimi, MD: I think for aggressive lymphoma, maybe even also for slow growth or indolent lymphoma, we're seeing a remarkable change in the landscape. CAR Ts are well established in the relapse setting now in the first relapse, so you relapse after your initial therapy, you should be considered for CAR T, many of us are doing so in academic centers and getting referrals as well. What we're seeing is that we had this new class of immunotherapy that is also a T-cell therapy that it's emerging, it's shown activity as a single agent and it's showing remarkable activity in combinations, which will probably do because it's a little bit logistically easier to give, still requires multiple visits that ramp up cytokine release syndrome. We know that everybody learns to give these drugs over time. What we'll probably do is that they will fit themselves prior to CAR T, maybe induce a remission prior to CAR T and consolidate without a transplant.

And certainly there's larger Phase III studies looking disposition in second line prior to CAR T and there's now Phase III studies looking at these agents in first line therapy. So they could probably help scotch over CAR Ts and be a new immunotherapy that we're going to be using in frontline therapy. If you can get, again, we can bring the 70% rate of patients who never need a second line of therapy or 60 plus percent who never do need a second line therapy to 80, 90%. We're talking Hodgkin range improvements, whether that's true we need to see in the Phase III studies, but certainly very promising.

Dale Shepard, MD, PhD: So maybe ability to have fewer people that need these therapies in the first place, but even if they do, a little easier to give, cheaper, faster, you don't have the delays, things like that.

Paolo Caimi, MD: I think we need to start thinking about what is the role of cytotoxic chemotherapy in combination with these immunotherapies? What are the ideal partners? We've always worked with a CHOP backbone on frontline and other chemotherapies, platin agents in second line, and we are seeing very good performance with platin agents combined with this. Will the same story repeat itself as CHOP plus a bispecific perform as well? There's no reason why to think it wouldn't, but I think it'll be important to see that they perform well because if it could really change the landscape as new agents the same way maybe Rituximab introduces itself on the frontline therapy 20 plus years ago.

Dale Shepard, MD, PhD: What kind of work is being done to figure out biomarkers, histology, characteristics, patient selection? Is there anything that might... You mentioned before that this is kind of a heterogeneous group of patients. Are there patients that might be more favorable to go to straight to CAR T versus these combination therapies?

Paolo Caimi, MD: That's a great question. I think that it's really in CP. In very early studies, we are doing some correlative research trying to look at what happens with the T-cells of patients who get bispecifics. Are they good for making CAR Ts? Because we just don't know that, right? You always almost always given bispecifics after CAR Ts progress, but what happens if you do a bispecific and then you're left with CAR T? We need to understand the sequence because we're really using the same resource, right? So you're tapping into your T-cell activity. Can you do it twice or you just only have one shot?

At least it seems for now that some the data that you can manufacture CAR Ts and you can manufacture effective CAR Ts after bispecific, but the trend in diffuse large B has been looking at the molecular subtypes and primarily the intracellular signaling. And what we need to understand better is well, what are the other factors that affect our immune response towards a tumor, which I think in solid oncology is well advanced and I think it's starting to come up in lymphoma, which is what is the role of the microenvironment and what are the things that are preventing RT cells to act against the tumor? Because again, it seems that there are a big relevant factor for your response to immunotherapy and possibly also chemotherapy.

Dale Shepard, MD, PhD: Well, certainly interesting work and looks like lots of things we'll be hearing about here in the near future.

Paolo Caimi, MD: Lots of changes coming in lymphoma.

Dale Shepard, MD, PhD: Perfect. We'll look forward to hearing about it in the future.

Paolo Caimi, MD: Thank you very much.

Dale Shepard, MD, PhD: So, thanks for being here.

Paolo Caimi, MD: Thank you again.

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