MB-106 Elicits Durable Responses and Demonstrates Tolerable Safety Profile in DLBCL, MCL, Follicular Lymphoma

Mazyar Shadman, MD, MPH

MB-106, a CD20-targeting chimeric antigen receptor (CAR) T-cell product, induces impressive rates of response in patients with relapsed diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and follicular lymphoma (FL), according to Mazyar Shadman, MD, MPH. He added that the agent was also associated with a remarkable safety profile.

For patients with relapsed DLBCL, MCL, or FL, standard treatment includes autologous CD19-targeting CAR T-cell agents. However, their long-term efficacy for DLBCL is about 40% and is unknown for other histologies, and physicians struggle to manage treatment-related toxicities.

As such, CD20-targeted CAR T-cell therapies represent a promising adoptive immunotherapy option that could be used to treat these patient populations. Shadman is the principal investigator in an ongoing phase 1/2 clinical trial (NCT03277729) investigating the safety and efficacy of MB-106, a fully human 3rd-generation CD20-targeted CAR T-cell product.

“Importantly, the remissions [with MB-106] are ongoing,” he said. “We have robust T-cell expansion and persistence. For that reason, now we have remissions in the follicular lymphoma cohort of more than 2 years. We have also seen a number of convergences from partial response to complete response and this is consistent with a strong CAR T persistence that we're seeing in these patients.”

In an interview with OncLive^®, Shadman, physician, Seattle Cancer Care Alliance; associate professor, Division of Medical Oncology, University of Washington School of Medicine; and associate professor, Clinical Research Division, Fred Hutchinson Cancer Research Center, discussed the utility of MB-106 for the treatment of patients with relapsed/refractory B-cell non-Hodgkin lymphoma (B-NHL) and chronic lymphocytic leukemia (CLL) based on data presented at the 2021 ASH Annual Meeting & Exposition in December.

OncLive^®: Could you explain the rationale for this research?

Shadman: We know that autologous CAR T products that target CD19 are now standard-of-care for several B-cell lymphomas. The idea here was to use a different target, CD20, and try to either improve the efficacy and safety of CAR T therapy in patients with lymphoma and with a plan to either replace the current products or to have another reliable product that we can use after CD19-targeted CAR T therapy. The idea was to come up with another therapeutic option. [The investigated agent, MB-106], is a third-generation CAR-T product, with both 4-1BB and CD28 costimulatory molecules.

Could you walk through the methods and design of this study?

All patients with CD20-positive B-cell lymphoma were eligible for this study, and that includes a number of histologies. For each surgery, we had specific eligibility criteria that was different for [patients with] high-grade vs low-grade lymphomas and [those with] CLL. As long as patients had the target, which was CD20, they were eligible.

We required a biopsy before and a research biopsy after, but the rest of the treatment approach and treatment schema was similar to what's being done with the current CD19 targeted CAR T-products. [Notably], this is an outpatient CAR [product], so except for the first patient of each dose cohort who needed to be observed overnight at the research unit, everybody else received the treatment in the outpatient setting.

What were the findings from this study?

This study is currently ongoing, so [the current data is] on 20 patients who reached the assessment cutoff for this CAR treatment, meaning that they reached the day 28 assessment. Out of 20 patients, 15 had follicular lymphoma. That's the majority of our patients. We also had 2 patients with MCL, 1 patient with CLL, 1 patient with DLBCL and 1 patient with Waldenström macroglobulinemia.

The take home point from this study is [primarily the] efficacy. In the 15 out of 20 patients who had follicular lymphoma, we observed a 92% overall response rate [ORR] and a 73% complete response [CR] rate. That's a high efficacy rate. Among all 20 participants, the overall response rate was 95% with a CR rate of 65%.

The patient with CLL had high-risk disease defined by complex karyotype BTK inhibitor failure and significant venetoclax [Venclexta] intolerance and the patient with large B-cell lymphoma was also high risk and CD19-negative. She received treatment with CD20 CAR [based on] our institutional guidelines. Same thing with a patient with Waldenström macroglobulinemia who was BTK inhibitor refractory.

Most of our responses are ongoing, and we're excited about that. More importantly, while we're excited about the great efficacy, we are pleasantly surprised about the favorable safety profile that this product is showing so far. Of the 20 patients that we've treated, we have not seen any grade 3 or 4 neurotoxicity or any grade 3 or 4 cytokine release syndrome.

Neurotoxicity is an adverse event that we've seen in 2 patients, 1 with grade 1 and 1 with grade 2. None of our patients with follicular lymphoma [have experienced] neurotoxicity at any grade.

The safety profile is always important, but it's specifically important when we look at low-grade lymphomas where risk and benefit ratio is even more important and there's a lower threshold of concern about the safety profile. Especially with the current competitive landscape in follicular lymphoma and CLL, the safety profile would be a differentiating factor.

Have you planned any next steps for MB-106?

This is a single-institution study at Fred Hutchinson Cancer Research Center and Seattle Cancer Care Alliance [SCCA] and this study continues to enroll. We are focusing now more on post-CD19 failures, and we now have patients who were not part of this presentation, but are currently being treated or have been treated. We're excited to follow those patients and look at the efficacy and safety. We're also focusing more on histologies [such as] CLL and Waldenström macroglobulinemia in the currently ongoing study.

More importantly, based on these results, the overall program is now moving to the next level. There will be a national, multicenter study that will be conducted starting in 2022 with Fred Hutch and SCCA leading the study. We're excited to have that study going with different cohorts, focusing on CLL, low-grade lymphomas, and high-grade lymphomas.

Reference

1. Shadman M, Yeung C, Redman M, et al. Safety and efficacy of third generation CD20 targeted CAR T (MB-106) for treatment of relapsed/refractory B-NHL and CLL. Blood. 2021;138(suppl 1):3872. doi:10.1182/blood-2021-14981