Safety an ‘important differentiating factor‘ for novel CAR-T in B-cell malignancies
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A chimeric antigen receptor T-cell therapy induced high response rates across a range of B-cell malignancies, according to phase 1 study results presented at ASH Annual Meeting and Exposition.
An interim analysis showed a 93% overall response rate among 15 patients with relapsed or refractory follicular lymphoma who received the investigational therapy.
No patients had experienced grade 3 or greater cytokine release syndrome or neurotoxicity.
The favorable safety profile is potentially an “important differentiating factor” for this therapy, according to Mazyar Shadman, MD, MPH, associate professor in the clinical research division at Fred Hutchinson Cancer Research Center, attending physician for hematologic malignancies at Seattle Cancer Care Alliance and associate professor in division of medical oncology at University of Washington School of Medicine.
“We have seen impressive efficacy so far,” Shadman told Healio. “What will hopefully differentiate this product from others is its extremely favorable safety profile.”
Following overnight monitoring of the first patient at each dose level, researchers administered MB-106 (Mustang Bio) in the outpatient setting.
“We have two patients [aged older than 80 years] who received this product and neither one had to spend a single day in the hospital,” Shadman said. “The hope is that, at some point, a CAR-T like this will make it to smaller centers.”
MB-106 is a fully humanized, autologous, gene-edited CAR T-cell therapy that targets the CD20 protein on the surface of cancer cells. Researchers based the novel agent on work done at Fred Hutchinson Cancer Research Center, which is now collaborating with Mustang Bio to develop the cellular therapy.
MB-106 differs from approved commercial CAR T-cell therapies in that it contains both CD28 and 4-1BB costimulatory domains. Researchers altered its manufacturing process in 2019 to combine culture of CD4-positive and CD8-positive cells for the final infusion product.
“We aimed to achieve more efficacy by using two costimulatory molecules,” Shadman told Healio. “Clinically speaking, MB-106 is performing more like a 4-1BB CAR in terms of the onset of treatment-related toxicities.”
Shadman and colleagues conducted a single-center phase 1/phase 2 dose-escalation study to evaluate the safety and efficacy of MB-106 for patients with CD20-positive relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia.
The data presented at ASH included 20 patients (median age 59; range, 43-81; 55% male) who enrolled in the study after 2019 and received infusion products made using the modified manufacturing process. Disease types represented in the cohort included follicular lymphoma (n = 15), mantle cell lymphoma (n = 2), CLL (n = 1), diffuse large B-cell lymphoma (n = 1) and Waldenström macroglobulinemia (n = 1).
Patients with large B-cell lymphoma had two prior lines of therapy, whereas patients with follicular lymphoma or mantle cell lymphoma had at least one previous line of therapy.
Researchers enrolled patients with mantle cell lymphoma if they had disease progression after receiving a Bruton tyrosine kinase (BTK) inhibitor.
Patients will CLL had at least one previous line of therapy. They either experienced disease progression after receiving either a BTK inhibitor, or progressed after or were intolerant of venetoclax (Venclexta; AbbVie, Genentech).
All patients received lymphodepletion with cyclophosphamide and fludarabine prior to CAR-T infusion. Patients received one of five dose levels, ranging from 1 × 105 cells/kg to 1 × 107 cells/kg.
Nineteen of 20 patients (95%) achieved response to a single infusion of MB-106. Twelve patients (65%) achieved complete response.
Seventy percent of patients in the study had ongoing responses as of data cutoff date.
Researchers reported a 93% ORR and 73% complete response rate among patients with follicular lymphoma. An additional three patients (20%) with follicular lymphoma achieved partial response.
Both patients with mantle cell lymphoma achieved partial response but eventually experienced disease progression.
One patient each with CLL and DLBCL achieved complete response, and one patient with Waldenström macroglobulinemia achieved partial response. All three of these patients remained in response as of data cutoff.
Investigators reported no-dose limiting toxicities.
The most common treatment-related adverse events included neutropenia (95%) and anemia (55%).
Forty percent of patients experienced CRS, but no grade 3 or grade 4 cases occurred.
Two patients (10%) had grade 2 immune effector cell-associated neurotoxicity syndrome. Neither of these patients had follicular lymphoma.
“We are seeing very robust expansion and persistence of T cells — in some cases, for more than 600 days,” Shadman told Healio.
Although these are early results from a small cohort, the positive efficacy and safety signals among patients with follicular lymphoma appear strong, Shadman said. This will allow investigators to focus future enrollment on patients with other histologies that have shown promise thus far, including CLL and Waldenström macroglobulinemia.
“I'm not aware of any commercial activity related to CD19-directed CAR T cells for patients with Waldenström macroglobulinemia, and we don't have anything yet approved for patients with CLL,” he told Healio.
The CD20-directed CAR-T in this study will be better tolerated and could serve as an alternative for patients whose disease does not express the CD19 antigen, Shadman added.
“Even if CD19 therapy remains the standard of care for some patients ... 60% of patients [with large B-cell lymphoma] will need therapy beyond CAR T cells, so this remains an area of unmet need,” he told Healio. “In this regard, our CD20-directed therapy could be practice changing.”
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Shadman M, et al. Abstract 3872. Presented at: ASH Annual Meeting and Exposition; Dec. 11-14, 2021; Atlanta.
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