Immune-Based Treatments and Rational Combinations for Relapsed/Refractory Mantle Cell Lymphoma
Immune-based approaches, including chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies, have shown promise in mantle cell lymphoma (MCL), with 1 CAR T-cell therapy already approved by the US Food and Drug Administration in the relapsed setting. As such, novel drug-drug combinations and their impacts on T-cell functionality are of interest.
How are immune-based treatments and rational combinations for MCL best used, and what does the future hold?
Chief of Hematologic Malignancies
Swedish Cancer Institute
“We want patients to have optimal T-cell functionality before receiving a cellular therapy or allogeneic stem cell transplantation, and this is where the novel drug-drug combinations may have a role.”
We are excited about the prospects of CAR T-cell therapy in patients with relapsed/refractory MCL for a number of reasons, perhaps the most important reason being that we now have an opportunity to provide a significant long-term survival advantage to very high-risk patients with MCL. In the ZUMA-2 trial of brexucabtagene autoleucel, for example, the overall response rates were greater than 80%, with approximately 60% of patients achieving complete remission. The time to initial response was approximately 1 month, and the time to complete remission was approximately 3 months.
Although we still have significant concerns regarding the cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome that we commonly associate with these agents, we are excited to have something effective to offer our high-risk patients. We want patients to have optimal T-cell functionality before receiving a cellular therapy or allogeneic stem cell transplantation, and this is where the novel drug-drug combinations may have a role. I think that the ibrutinib-venetoclax combination is appealing in this setting, as ibrutinib has been shown to normalize immune cell subsets and T-cell function in patients with relapsed/refractory MCL.
Professor of Medicine, Division of Oncology
“The CAR T-cell data look fantastic from an efficacy standpoint. There are some definite toxicity issues, including cytokine release syndrome and neurologic toxicities, but, by and large, it is a tolerable treatment.”
The bispecific and cellular therapies such as CAR T cells clearly fall in the category of immunotherapy. Lenalidomide may have some immunomodulatory properties; however, I do not consider the antibody-drug conjugates to be immunotherapies, as they are designed to deliver cytotoxic chemotherapy drugs that would otherwise be too toxic to administer as free drugs.
Data on the use of bispecific antibodies in patients with MCL are limited, but I think that those data will be expanding over the next year or 2, and I am looking forward to that. The CAR T-cell data look fantastic from an efficacy standpoint. There are some definite toxicity issues, including cytokine release syndrome and neurologic toxicities, but, by and large, it is a tolerable treatment.
Figuring out the best way to use these therapies is an exciting area. For example, should we consider developing CAR T-cell therapies for use in frontline settings, when appropriate? What is the best bridging therapy? There are data suggesting that ibrutinib has some beneficial effects on T-cell functions and thus may have a role in bridging prior to T-cell therapy. The question is: Do these data apply to other Bruton tyrosine kinase inhibitors that are more selective and have fewer off-target effects? So, we will need to investigate that. And then there are some potential bridging therapies that could be detrimental if given prior to T-cell therapy. For instance, bendamustine is very effective in patients with MCL, but it affects T-cell numbers and subsets rather profoundly, so that may be a bad choice as a bridging agent.
The Richard T. Silver Distinguished Professor of Hematology and Medical Oncology
“We do not have definitive data yet, but I would venture to say that there will be a fair amount of bispecific use in the future, perhaps as a precursor to CAR T cells or as an alternative to CAR T cells in some cases.”
With regard to CAR T cells, we have an approval for MCL with brexucabtagene autoleucel, and we have encouraging data for others. We have the most data for CAR T cells, but many patients with MCL are older and are not enthusiastic about this therapy. We also have promising data for bispecific antibodies and we have data for antibody-drug conjugates that are very early, so it is not clear where they will sit.
At the recent 62nd American Society of Hematology Annual Meeting and Exposition, data were presented from phase 1 and 2 trials of patients treated with 1 of 4 bispecific antibodies. Some of these studies included meaningful numbers of patients with MCL. I think that many of us view the bispecific antibodies as a kind of “CAR T cell light” in that they are probably less effective but more tolerable than CAR T cell therapy. Given the median age of patients with MCL and the fact that many individuals with MCL are treated in community settings, tolerability gains might be important. We do not have definitive data yet, but I would venture to say that there will be a fair amount of bispecific use in the future, perhaps as a precursor to CAR T cells or as an alternative to CAR T cells in some cases.
Davis JE, Handunnetti SM, Ludford-Menting M, et al. Immune recovery in patients with mantle cell lymphoma receiving long-term ibrutinib and venetoclax combination therapy. Blood Adv. 2020;4(19):4849-4859. doi:10.1182/bloodadvances.2020002810
Girard J, Reneau J, Devata S, et al. Evaluating acalabrutinib in the treatment of mantle cell lymphoma: design, development, and place in therapy. Onco Targets Ther. 2019;12:8003-8014. doi:10.2147/OTT.S155778
Jacobson CA, Maus MV. C(h)AR-ting a new course in incurable lymphomas: CAR T cells for mantle cell and follicular lymphomas. Blood Adv. 2020;4(22):5858-5862. doi:10.1182/bloodadvances.2020003391
Qin JS, Johnstone TG, Baturevych A, et al. Antitumor potency of an anti-CD19 chimeric antigen receptor T-cell therapy, lisocabtagene maraleucel in combination with ibrutinib or acalabrutinib. J Immunother. 2020;43(4):107-120. doi:10.1097/CJI.0000000000000307
Reagan PM, Friedberg JW. Axicabtagene ciloleucel and brexucabtagene autoleucel in relapsed and refractory diffuse large B-cell and mantle cell lymphomas. Future Oncol. 2021;17(11):1269-1283. doi:10.2217/fon-2020-0291
US Food and Drug Administration. FDA approves brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma. Accessed April 7, 2021. https://www.fda.gov/drugs/fda-approves-brexucabtagene-autoleucel-relapsed-or-refractory-mantle-cell-lymphoma
Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020;382(14):1331-1342. doi:10.1056/NEJMoa1914347
Wang M, Rossi JM, Munoz J, et al. Pharmacological profile and clinical outcomes of KTE-X19 by prior Bruton tyrosine kinase inhibitor (BTKi) exposure or mantle cell lymphoma (MCL) morphology in patients with relapsed/refractory (R/R) MCL in the ZUMA-2 trial [abstract 1126]. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020.