番茄社区

Lemzoparlimab, a novel CD47 antibody, in combination with rituximab was safe and well tolerated in heavily treated patients with relapsed or refractory non-Hodgkin lymphoma (NHL), according to interim data from presented at the recent American Society of Hematology (ASH) virtual meeting.

番茄社区 brought together three expert leaders in the field -- moderator , , and -- for a virtual roundtable discussion. This second of four exclusive episodes focuses on the lemzoparlimab data.

Following is a transcript of their remarks:

Flinn: Hello, I'm Ian Flinn from the Sarah Cannon Research Institute in Nashville, Tennessee. I'm joined today by Loretta Nastoupil from the MD Anderson Cancer Center [in Houston] and Amit Mehta from University of Alabama at Birmingham. We're going to talk about some of the exciting news that's come out at ASH 2021. It was a big year for lymphoma studies this year, and I think we have a great discussion.

So Amit, this year there were data at ASH about lemzoparlimab, a new CD47 construct with perhaps a better safety profile. We know magrolimab's been around for a few years and there was a lot of initial excitement about that CD47-blocking agent, originally a New England Journal [of Medicine] publication. And now there are several new agents that are being developed. There's SIRPα-Fc or CD47 blockade itself, but that access seems to be very important. Can you take us through this trial? I mean, it was early on in this study, but maybe you could help us understand this trial.

Mehta: Sure. Lemzoparlimab is one of the other CD47 antibodies. CD47 is a "don't eat me" signal, naturally also utilized by older red blood cells for elimination. So lemzoparlimab is a little bit different than magrolimab; it binds it to a different epitope, which does not cross-react with the red blood cell. So if you remember magrolimab initially, there was a prime dose for magrolimab to avoid that drastic drop in hemoglobin, which is not required for lemzoparlimab. So that's a major difference.

So during this study, a phase I study which was published, two different dosages were explored -- 20 mg/kg and 30 mg/kg. But because of that different epitope, there was no need of priming dose. And this was in combination with rituximab. So there were no DLT [dose-limiting toxicity]. Actually one patient had a disease progression and was counted related to lemzoparlimab. So that was considered as a DLT, but that did not affect the dose escalation. So ultimately, 30 mg/kg was the safe dose. And actually, if you look at eight or nine patients treated on that study, all of them had benefit in terms of response. Few of them, they were rituximab refractory. So overall, a new class of, so to speak, next-generation checkpoint inhibitor, not only [in] lymphoma, they have potentials to other solid tumors. One of the arms of the study is also exploring in combination with the PD-1 inhibitor in solid tumors. So very promising agent, like magrolimab.

Flinn: Okay, so I'm going to have a follow-up question here, because I watched your presentation and [I'm] still trying to understand the whole issue with red blood cells. So if I understand correctly from magrolimab that the CD47 is expressed on old age red blood cells. And here you're saying that it's a different epitope, but isn't CD47 still there? I guess I watched and I still don't understand why you don't get the decrement in red blood cells.

Mehta: So I think the epitope, in a way, is different so that the older red blood cells, even if the drug binds, doesn't get eliminated. So what happened with magrolimab [is] that there was an initial drop in the hemoglobin because of the same reason that macrophage still identifies the red blood cells and eliminates them. But that process does not happen with lemzoparlimab. So in magrolimab, the priming dose kind of helped initially to identify how much hemoglobin drop would happen with a tiny dose like 1 mg, compared to lemzoparlimab, which does not have that side effect. Even though if you look at the data, there was a dip in hemoglobin and compensated rise in the reticular sites, but it was not as bad as we saw with magrolimab.

Flinn: Okay, great. So Loretta, what do you think about this drug, and maybe in the class as a whole? I mean, it's pretty exciting this checkpoint inhibitor for the innate immune system. Hopefully we'll get one of these drugs approved have been this disease soon.

Nastoupil: I think we've been trying so hard to figure out how to utilize targeting of the microenvironment to eradicate, particularly follicular lymphoma, which again in my mind, that's where this really does look to be exciting. And I do think that these agents provide another approach. Now because the toxicity profile lends itself to combination strategies, I think that's really where it's going to get exciting and interesting ... how do you partner these drugs or do you need to sequence them to really harness the microenvironment?

Flinn: Checkpoint inhibitors are useful in certain B-cell malignancies, but for many they didn't pay off as much as we had thought they would. Do you think that's going to be a good combination or would you look to other combinations?

Nastoupil: Well again, this is harnessing macrophages. And so I think potentially cell mods for instance, would be an interesting combination where you could further enhance T cell and in NK cells. And the other area that I think we don't really understand is how do we sequence these treatments? And should you come in with a T-cell engager and then a macrophage engager if you don't eradicate the cell entirely? These are questions that I don't know the answer to, but I think having more options in different mechanisms of action is really just good news.

Flinn: Great. Thank you for that.

Watch Episode 1: Will Bispecific Antibodies Challenge CAR T-Cell Therapy in Follicular Lymphoma?

Comment