Deeper Understanding of immune System Could Advance Treatment Options in Lymphoma

Stephen M. Ansell, MD, PhD

Further understanding of the biology of the immune system and its deficiencies in patients with lymphoma could help expand the development and use of immune therapies for the treatment of this patient population, according to Stephen M. Ansell, MD, PhD.

“The immune system is a lot more complex than we think. It's nice when we're doing presentations or giving talks to simplify it down to just one cell working in one direction. However, there is complexity in the [immune] environment, including other cells and soluble proteins. Understanding that is important,” said Ansell, who presented on harnessing the immune system in lymphoma during the 2023 SOHO Annual Meeting.

In an interview with OncLive®, Ansell discussed the successes and challenges of utilizing immune therapy across the landscape of hematologic malignancies, the importance of increasing the understanding of how the immune system functions in patients with lymphoma, and ongoing research of immune therapy for this patient population.

Ansell is a professor of medicine, interim chair of the Department of Oncology, chair and consultant of the Division of Hematology, Department of Internal Medicine, and chair of Faculty Development and Recruitment at Mayo Clinic in Rochester, Minnesota.

OncLive: Could you provide a brief overview of the goal of your presentation on harnessing the immune system in patients with lymphoma?

Ansell: It's been a very exciting time in the world of hematology, particularly lymphoma, seeing how immune therapies have come front and center. As we are doing that and getting good results, [we’re getting] a better understanding of exactly how the immune system functions, and how to optimize [that understanding] is critical for the next steps [of investigating immune therapy]. The presentation [focused on] where the immunological deficiencies are in lymphoma and how immunotherapies might combat that.

What are some of the challenges and successes of integrating immune therapy into the treatment paradigm for lymphoma and other hematologic malignancies?

In the world of immune checkpoint blockade, PD-1 blockade has been a success in Hodgkin lymphoma, and not so much in [other hematologic malignancies]. However, when we talk more about CAR T-cell therapies and bispecific antibodies, lymphomas and other hematological malignancies are much more front and center.

Why are immune checkpoint blocking antibodies [less effective]—or so it seems—in lymphomas? It comes to the biology of what's going on. The key question is: Are the T cells ready to fight and being held back, or are they immunologically compromised? Even if you remove the negative PD-1 signal, the T cells are not fully unleashed. I believe the second scenario is the problem: T cells need to be activated in lymphomas to have a better result.

Are there any potential avenues where immune therapy could make inroads in lymphoma and hematologic malignancies?

There are multiple categories that [have shown] a huge promise. CAR T-cells are obviously one, particularly in lymphoma, targeting CD19. We are starting to see a lot of other areas where we're starting to broaden out and target other molecules. In multiple myeloma, [we have seen] high efficacy targeting BCMA.

Regarding bispecific antibodies, many of which are now targeting CD20 and CD3, but some are going broader than that, targeting multiple immune checkpoints and different immune cells. All of those [agents] are in development.

Finally, not only on the adaptive immune system and T-cell side of things, but also in the macrophage and innate immune system, they're working on CD47-targeted therapies. Those are still being explored. Results are still a little questionable in that space, but understanding how to engage the immune system is going to be central.

As additional therapies with novel targets are developed, how could this affect treatment decisions for patients with lymphoma?

There is a little bit of individualization that always needs to happen. I would also argue that [these treatment decisions] will not just be about sequencing; they could also be about combinations. The reason for that is: you only have to cure cancer once. If you could work out what's the best way to get the immune system engaged, that's what we're strategizing for.

Ideally, if we do need to sequence things, [there are factors] we need to work out for each patient. What is their greatest need right now? Is it to assist a T cell that is already activated, or is it a way to activate the immune system? Those may be different, and that may actually change how you sequence things.

Regarding ongoing trials, are there any in particular that you're intrigued by?

The thing that is exciting to me is looking at rational combinations. I use the word “rational” very carefully, because what we don't necessarily want to do is put [different agents] together because just we have them. In the immune space, that can result in a lot of complexity and sometimes toxicity.

However, if you have a way to make a CAR T-cell work better, if you have a way to repurpose a CAR-T cell that is losing its way, or if you have a way to, for example, combine a bispecific with a product that would prevent the activated cells from being exhausted, those are rational combinations that could make a difference for patients.

Reference

Ansell SM. Harnessing the immune system in patients with lymphoma. Presented at: 2023 SOHO Annual Meeting; September 6-9, 2023; Houston, TX.