Analyzing Immunotherapy Options for the Treatment of Patients With Large-Cell Lymphoma

Andrew Zelenetz, MD, Memorial Sloan Kettering Cancer Center, New York, New York, shares insights into existing and future treatment developments in large-cell lymphoma research, specifically focusing on the importance of immunotherapy. 

Transcript:

Hi, I am Andrew Zelenetz, attending physician at Memorial Sloan Kettering Cancer Center in New York, and a member of the Lymphoma Service. 

Addressing the question of what am I excited about going forward in large-cell lymphoma, the major advances in large cell lymphoma in recent years revolve around immunotherapy. We have both [chimeric antigen receptor] (CAR-T) cells and bispecific antibodies. The CAR-T cells that have been approved for treatment of third line large-cell lymphoma are 3 agents: lisocabtagene maraleucel, tisagenlecleucel, and axicabtagene ciloleucel. And 2 of them, lisocabtagene and axicabtagene have been approved for second line treatment of large-cell lymphoma. Of course you move it from third line to second [line]. Can you move it to first line? I personally have a lot of difficulty with the concept of using a living drug with long-term consequences as first line therapy.

Given the excellent outcomes, we need to identify a truly terrible group of patients to justify it. Since we already can take patients who are demonstrating primary refractory disease and take them to CAR-T cell, I think it's very hard to identify a uniform group of patients for whom I can justify the potential long-term risk of CAR-T cell with its chronic B-cell suppression, and actually low T-cell counts, which serve a surprising side effect that we see after CAR-T cell therapy. 

The other interesting and emerging area are bispecific antibodies—2 are now approved: epcoritamab and glofitamab. These are anti-CD20, anti-CD3 antibodies. Obviously, you can make lots of different bispecifics, but those are the 2 that are approved and have shown excellent activity in [the] third line, [and] interestingly, really good activity even in CAR-T cell failures. So, what we know is that these are active drugs.

How do we incorporate these into frontline therapy? I think the long-term consequences are going to be different. This is not a living drug. These are antibodies. They're going to be metabolized and eliminated and eventually B-cells will recover. I think there really is the potential to use more effective CD20-targeting in combination with therapy. Now, I think we have to be a little bit smarter than the way some of the studies are being done. 

Some of the studies are just bispecific plus [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone] (R-CHOP] versus R-CHOP. That's sort of efficient to get regulatory approval, but is that really the best way you want to do it? I mean, cyclophosphamide kills T-cells. Do you really want to kill T cells when you're trying to use the T-cells? I think we need to start being a little bit creative about how we move these antibodies up.

We have a few interesting examples. We saw in the elderly untreated population at [the American Society of Hematology Annual Meeting] (ASH), a combination of mosunetuzumab, what we think is a weaker antibody in combination with polatuzumab. The results were quite good. And that was a 2-drug combination for elderly frail patients. I think if we're a little smarter about how we use our drugs, [and] really try to maximize the immune effects, we can probably do better than simply grafting the bispecific onto standard chemoimmunotherapy. But I think that's a real area of promise. And of course, drugs like this could potentially be incorporated into R-CHOP ICE; I would substitute the rituximab for a bispecific, but we would have to ask, do you really need to incorporate all these components, or can you safely drop some of the drugs because they're actually doing a little bit of harm to the overall outcome of the treatment.

Source:

Bantilan K, Smith A, Maurer J, et al. Matched control analysis suggests R-CHOP followed by (R)-ICE may improve outcome in non-GCB DLBCL compared to R-CHOP. Blood Adv. Published online January 25, 2024. doi: 10.1182/bloodadvances.2023011408