Advancing Immunotherapy and Combination Treatments for T-Cell Lymphoma

Pharmacy Times interviewed Stefan Barta, MD, MS, MRCPCUK, director of T-Cell Lymphoma Program, executive officer of the AIDS Malignancy Consortium, and associate professor of clinical medicine (hematology-oncology) at Penn Medicine, on his presentation at the SOHO 2024 Annual Meeting on the promise of immunotherapies in T-cell lymphoma. Barta focused on the complexities and recent advancements in the treatment of T-cell lymphomas with monoclonal antibody therapies and CAR T-cell therapies, while also highlighting the potential of combinatorial regimens to improve treatment outcomes while managing toxicities.

Pharmacy Times: How do responses to immunotherapy vary among different T-cell lymphoma subtypes?

Stefan Barta, MD, MS, MRCPCUK: We have monoclonal antibody therapies and in, for example, cutaneous T-cell lymphomas, which target, for example, CCR4 and mogamulizumab [Poteligeo;Kyowa Kirin, Inc], and they have very specific toxicities that are mainly related to immune stimulation that can be a rash that actually is a prognostic good sign. So, patients who develop a rash, for example, to mogamulizumab therapy can expect a better response and a more durable response, which tells us that activating the immune system, and not only by suppressing suppressive immune cells, and not only by tagging the cells for destruction by immune cells is another mechanism of action of some of the drugs. Autoimmune phenomena can occur both with the anti-CCR4 targeting antibodies, but also with checkpoint inhibitors of any kind. Then some of the antibody drug conjugates, their toxicities are related to the payload, the toxin or the drug that they're conjugated with. And that can be, for example, for brentuximab [vedotin (Adcetris; Seattle Genetics Inc and Takeda Oncology)], particularly neuropathy, and for example, for the recombinant infusion protein denileukin diftitox (Lymphir; Citius Pharmaceuticals, Inc) could be cytokine leakage syndrome. So, they're very specific for each drug. So, it can be difficult to get a very generalized statement.

Of course, with any antibody, you can also have infusion reactions and allergic reactions. That is probably the most common thread throughout these. Then when we move on to CAR T-cell therapies, again, you have the typical CAR T-cell toxicity, such as cytokine release and neurological toxicities, in addition to infections, opportunistic infections, or viral reactivations that can be seen.

Pharmacy Times: How can biomarkers be utilized to predict response to immunotherapy in T-cell lymphoma?

Stefan Barta, MD, MS, MRCPCUK, discusses the potential role of biomarkers in predicting treatment outcomes, the emerging use of CAR T-cell therapy, and the benefits and challenges of combination therapies in managing T-cell lymphoma. Image Credit: © Dr_Microbe - stock.adobe.com

Barta: That's a great question, and once we have those biomarkers, that would really be cracking the issues that we have in oncology with predicting which patient is going to respond to which therapy. Certainly, a very tempting approach would be to look at expression of the antigen and see whether strength of expression of the antigen that is being targeted in antigen targeting therapies is associated with survival and or response to therapy. Unfortunately for the most commonly used target, CD30, there have been several studies that have shown that CD30 expression, for example, is not necessarily a good or reliable predictive marker for response to CD30 targeting agents.

But on the other hand, we have some other examples that, for example, loss of a protein such as CD52 or CCR4 then predicts a lack of response in later lines to therapies that have been previously used to target the same antigen as expression. Loss of target antigen is a mechanism of resistance, so certainly, strength of antigen expression is something we use, and may or may not be helpful.

We do not have very good molecular markers at this point in time to predict response to therapies. For specific diseases, there may be some prognostic biomarkers, but those are not necessarily predictive. It may be an exception again for [janus kinase (JAK)] inhibitors, where we have seen that either having a mutation in the JAK-STAT pathway may be predictive of response, either positively or negatively, and signs of activation of the pathway can be checked on immunohistochemistry [IHC], such as STAT3 IHC, can again be associated with an improved response, but this is all at this point investigation and not yet part of routine clinical care.

Pharmacy Times: What is the role of CAR T-cell therapy in treating T-cell lymphoma?

Barta: So at this point in time, it is still investigational, but the early data in both T-cell ALL and T-cell non-Hodgkin lymphoma shows that it is feasible that we can overcome the obstacles that have hampered our development of these drugs through various mechanisms, and we have seen consistent responses in patients that can be durable, with expected side effects, such as the side effects we see with other CAR T-cell therapies, and particularly infections or cytopenia, and we're learning a lot more how we can best target these antigens and reduce the toxicities at the same time. But certainly [this is an] area of very active research and hopefully will really bring in a new era in how we treat T-cell malignancies in the future.

Pharmacy Times: What is the role of combination therapies in the treatment of T-cell lymphoma?

Barta: T-cell lymphoma usually we can divide, like any other lymphoma, into aggressive T-cell malignancies and less more indolent T-cell malignancies. So in terms of the aggressive T-cell malignancies, as we have learned from other lymphomas, really targeting just one pathway is usually not enough, and cancer cells develop resistance very quickly, which lends support to combinatorial regimens. And for many years, we have dealt with single agents in the relapse/refractory setting treating aggressive T-cell lymphomas that have had response rates in around the 30% range and progression free and overall survival that's very short, and we've had several now early phase 2 uncontrolled clinical trials that have shown us that higher response rates in the 50% to 60% range are possible with rational combination of agents, but unfortunately, there have not been any randomized clinical trials that really can convincingly tell us which combinations are better than which single agents and how do we, for example, sequence certain therapies in less aggressive lymphoma, such as, for example, some forms of cutaneous T-cell lymphomas. We do know that we are dealing with an incurable disease, and it has been shown that more is not always more, and the higher response rate are often bought at the expense of significant toxicities with progression free and overall survival being equivalent. There we often use single agents in order to reduce the toxicity and increase quality of life. But again, we have now non-cytotoxic drugs that have a much more favorable side effect profile. So, I think also they we will be moving up for select patients more into certain combinatorial regimens, and combining particularly immunotherapies with molecularly targeted therapies holds a lot of promise for these rare diseases.