ORLANDO, Fla. - Chimeric antigen receptor T (CAR T) cells have proved to be a major advance in treating patients with refractory B-cell malignancies so far. But, often, in approaching those issues "we solve one and we create another," Stephen Schuster, a doctor at the Abramson Cancer Center at the University of Pennsylvania in Philadelphia, told reporters at the 61st American Society of Hematology (ASH) annual meeting Saturday. Two new CAR T agents targeting CD19 have been approved in the last two years. A third of patients' lymphomas respond to at least one of the two. "However, the two-thirds of patients who don't respond to CAR T-cell therapy are now our new unmet need," he said.
Pursuing one potential solution to the issue, Schuster and colleagues tested Genentech Inc.'s mosunetuzumab, an investigational off-the-shelf candidate that targets two proteins, one on the surface of tumor cells (CD20) and the other on the surface of the recipient’s T cells (CD3). Results of their phase I/Ib study found that patients with B-cell non-Hodgkin lymphoma (NHL) that had returned after or failed to respond to a median of three prior therapies showed not just complete responses but also durable remissions after being treated with the candidate. Even among 30 patients whose lymphoma progressed after treatment with CAR T-cell therapy, 22% had complete remissions after receiving mosunetuzumab.
"Unlike CAR T-cell therapy, mosunetuzumab is an off-the-shelf immunotherapy product that can be given to patients without having to genetically modify their T cells,” said Schuster.
"One of the problems with the CAR T-cell approach is it can take three weeks to make the cells, it can take two weeks to get insurance approval before you can do apheresis, a week to schedule that ... A month or two months doesn't sound long, but it's an eternity when you have a patient with a very fast-paced disease," he said.
Top-line results from the dose-escalation study showed an objective response rate of 62.7% in slow-growing NHL and 37.1% in aggressive NHL. Additionally, the results showed a complete response rate of 43.3% in slow-growing NHL and 19.4% in aggressive NHL.
Nancy Valente, Genentech's head of oncology product development, told BioWorld that "the data are showing really promising efficacy and safety in phase I, and durability." Results showed 82.8% of patients with slow-growing NHL remained in remission up to 26 months off initial treatment and 70.8% of patients with aggressive NHL remained in remission up to 16 months off initial treatment.
Out of 270 patients evaluable for safety, about 29% experienced cytokine release syndrome, with the majority of those events being grade 1 or 2, while about 44% experienced neurological events, such as headache, insomnia or dizziness.
With positive data in hand, Genentech, part of Basel, Switzerland-based Roche Holding AG, is looking to accelerate mosunetuzumab's development, Valente said.
Genentech is also presenting data at ASH on its evaluation of a second CD20-CD3 bispecific, CD20-TCB, which has been tested in combination with Gazyva (obinutuzumab) and Tecentriq (atezolizumab). Results of a phase I/Ib dose-escalation study of the Gazyva combination in people with relapsed or refractory B-cell NHL showed an objective response rate (ORR) of 54% and a complete response (CR) rate of 46%. That included an ORR and CR of 66.7% in people with follicular lymphoma and an ORR of 50% and a CR of 40.9% in aggressive NHL.
"Our ultimate goal," Valente said, “is to develop these bispecific therapies that are both bispecific safe and that can be combined with immunotherapies, targeted therapies, and chemotherapy that can be moved into earlier lines so it can be used for earlier phases of treatment."