In an interview with Targeted Oncology, Mazyar Shadman, MD, MPH, discussed his research of MB-106 as treatment for patients with relapsed or refractory B-non-Hodgkin lymphoma and chronic lymphocytic leukemia.
MB-106, a novel CD20 chimeric antigen receptor (CAR) T-cell therapy, is currently being evaluated in a phase 1/2 clinical trial (NCT03277729) to determine its safety and efficacy in patients with positive B-cell malignancies, including relapsed/refractory B-cell non-Hodgkin lymphoma (B-NHL) and chronic lymphocytic leukemia (CLL).
Data from the study were presented during the 2022 Transplantation & Cellular Therapy Meetings. Findings revealed that across all patients enrolled in the trial, the overall response rate (ORR) was 96%, including a 72% complete response (CR) rate.
Further, within the follicular lymphoma cohort that included 18 patients, the ORR demonstrated was 94%. Of the 18 evaluable patients, 14 (78%) had a CR as their best response. Additionally, high efficacy was demonstrated within patients as well as ongoing remissions.
Of the patients with diffuse large B-cell lymphoma (DLBCL), 2 patients were treated, including 1 with a prior CD19 CAR treatment, and 1 who achieved a complete remission. Additionally, a patient with CLL achieved complete remission, and 2 patients with Waldenstrom macroglobulinemia both responded with 1 having a complete remission, and 1 in a very good partial remission.
Further, a favorable safety profile was demonstrated with no grade 3/4 cytokine release syndrome (CNS) and no grade 3/4 neurotoxicity shown in the overall patient population.
In an interview with Targeted OncologyTM, Mazyar Shadman, MD, MPH, physician, Seattle Cancer Care Alliance, associate professor, Division of Medical Oncology, University of Washington School of Medicine, associate professor, Clinical Research Division, Fred Hutchinson Cancer Research Center, discussed his research of MB-106 as treatment for patients with relapsed or refractory B-NHL and CLL.
Can you discuss the phase 1/2 clinical trial of CD20-directed CAR T for patients with CD20-positive B-cell malignancies?
We reported the updated results of our ongoing phase 1/2 clinical trial using a CD20 directed CAR T product. This is a third generation CAR with both a CD20 and 4-1BB costimulatory molecule. We have treated 25 patients so far, and that's what we presented at the TCT meeting. A majority of our patients have follicular lymphoma, 18 out of 25, but we have patients with CLL, patients with diffuse large B-cell lymphoma, and Waldenstrom. We reported the safety and efficacy of this treatment in patients that we've treated so far.
For this presentation, we were reporting on patients who had the prior treatment with CD19 CAR. As we think about the implications and indications of new CAR T products for the current treatment landscape, the post CD19 CAR space is clearly a clinical unmet need and area. We're excited to see responses about patients that we wish to be treated in that setting, and for the safety profile in lymphoma in general, low grade lymphomas, follicular lymphoma and CLL. It is extremely important that the product has a very acceptable safety and toxicity profile.
What were the characteristics for patients enrolled in this phase 1/2 study?
Patients with relapsed/refractory CD20-positive B-cell malignancies were eligible, including CLL. Each histology had a specific inclusion and exclusion criteria. For large cell lymphoma vs CLL vs for follicular lymphoma, we had a specific eligibility criteria, but basically they had to be in the relapsed/refractory setting and as part of the study, the CD20 expression needed to be confirmed.
What were the methods used to conduct your analysis?
The method was very similar to the 2 other FDA approved autonomous CAR T products. Patients would, after enrollment, undergo leukapheresis and in the meantime, while the cells were being manufactured, some patients needed bridging therapy. When cells were ready, they received them for chemotherapy using fludarabine and cyclophosphamide, and after 2 days of rest, they received their cell dose. We had a disease assessment of 28, including a PET scan and bone marrow biopsy if necessary.
When examining the objectives of the study, what were the findings?
We continue to see very high efficacy with this CAR T product. As I mentioned, 25 patients that have been treated so far and reached their disease assessment time point at the time of our presentation [at TCT]. Among follicular lymphoma patients, we are currently observing an overall response rate of 94% with complete response rate of 78% as the best response which of course, shows a very high efficacy profile for this product. Overall the study shows 96% overall response and 72% complete response.
Out of the diffuse large B-cell lymphoma patients, we have treated 2 patients, 1 with a prior CD19 CAR treatment and 1 patient achieved a complete remission. The other patient had a partial response and a repeat PET scan will happen soon. The CLL patient achieved a complete remission and the Waldenstrom patients both responded, 1 converted from a very good partial response to complete remission, and the other is currently in a very good partial remission. So very high efficacy, and these remissions are ongoing.
Can you further discuss the results of the patients with ongoing responses? What did the safety profile of MB-106 look like?
We have a patient with more than 2 years of follow up after CR and we have 5 patients who are in CR, more than 1 year. These remissions are ongoing, and that is consistent with the CAR T-cell persistence that we are observing these patients.
Another important feature that we have observed is the safety profile of this CAR T. This is an outpatient CAR T, so we don't have any planned admission for this study. Only the first patients of these cohorts spent 1 night in the hospital for observation. But otherwise, all treatments are given in the outpatient setting.
We have not observed any grade 3 or 4 cytokine release syndrome [CRS] in the entire cohort, and also no grade 3 or 4 ICANS or neurotoxicity. All of the CRS and ICANS were grade 1 or 2. We actually only had 2 patients with ICANS, 1 with grade 1 and 1 with grade 2. Among follicular lymphoma patients, we have not observed any neurotoxicity of any grades.
What unmet needs still exist in this space?
In my opinion, there are 3 areas that we could think about. Number 1, in areas where there is an FDA approved CD19 CAR, the question is what happens to patients who don't respond to those CARS? In large cell lymphoma, you have 60% of patients who unfortunately don't respond to relapse after a CD19 targeted CAR, so there is a lot of need for therapeutic interventions in that setting.
In indolent and low grade lymphomas in general, we do need CAR Ts with a much better safety profile than what we already have. To use a CAR T product in the second-line or third-line of follicular lymphoma with so many other alternative options, I think the safety profile of CAR T is extremely important.
There are other histologies where we don't have a CAR T approved. For example, it is expected that CLL may have a CAR T approved at some point, but again, we have to look at the safety profile. For a diagnosis like Waldenstrom macroglobulinemia, there is no CAR T product and though we have made a lot of progress, there are definitely areas to work on and there's potential for improvement.
What other research do you think will be next in this space? What excites you for the future?
We are very excited because based on the results of this study, we have expanded this current single institution study that is ongoing at Fred Hutch, and our protocol now includes patients with primary and secondary CNS lymphoma. That is an unmet need, and so we're hoping that with the safety profile that we're seeing with minimal neurotoxicity, hopefully we can help with patients with primary CNS and secondary CNS lymphoma among other histologies.
The second very exciting news is that, based on the promising results of this study, we are now moving to a multicenter trial that includes 5 other academic centers in addition to Fred Hutch. This study will be open soon, in the next month or so, for enrollment. The product is going to the next level and hopefully we can treat more patients and we'll see if we can find 1 of the unmet areas that I mentioned. Hopefully we can use this product in the future.