The allogeneic CAR-T cell therapy ALLO-501, paired with the monoclonal antibody ALLO-647, demonstrated clinical responses and manageable toxicity in patients with pretreated large B-cell and follicular lymphomas in the Phase I ALPHA trial.
ALLO-501, an allogeneic CAR T-cell therapy, paired with ALLO-647, a monoclonal antibody, yielded high response rates and a manageable safety profile in patients with relapsed/refractory diffuse large B-cell or follicular lymphoma, according to a first-in-human study presented at the 2020 ASCO Virtual Scientific Program.
The 2 treatments were used sequentially in the open-label, phase I ALPHA study that occurred at 6 U.S. sites, demonstrating an overall response rate (ORR) of 63%, including a 37% complete response rate in 19 evaluable, previously treated adults.
Researchers believe that allogeneic CAR T therapy, made from healthy donor T cells, can provide the benefits of autologous CAR T therapy while increasing patient access, the study’s lead author, Sattva S. Neelapu, MD, of The University of Texas MD Anderson Cancer Center in Houston, explained. He added that providing an off-the-shelf version of CAR T-cell therapy makes it available to patients more quickly, including on occasions when repeat dosing is necessary.
ALL0-501 is a genetically modified anti-CD19 CAR T-cell product in which the protein TCR alpha is disrupted to reduce the risk of graft-versus-host disease (GvHD). To support the effectiveness of the 2-pronged approach, the protein CD52 has been knocked out in ALLO-501 so that its partner therapy, the anti-CD52 monoclonal antibody ALLO-647, can be used successfully in lymphodepletion.
ALPHA’s primary endpoint was the safety and dose-limiting toxicity of ALL0-647 followed by ALLO-501. A secondary endpoint was ORR.
Eligible participants had advanced disease, an ECOG status of 0 or 1 and had been treated with at least 2 previous lines of therapy. Prior treatment with an anti-CD20 monoclonal antibody or with autologous CAR T therapy was permitted, as long as the patient’s tumor remained CD19-positive.
A total of 22 patients, whose median age was 63 years, were treated. Approximately two-thirds had diffuse large B-cell lymphoma and the rest had follicular lymphoma. Approximately half had high-risk disease. Their median number of previous treatments was 4.
Patients underwent lymphodepletion that included fludarabine, cyclophosphamide and ALLO-647; 3 regimens of varying doses were tested, which included ALLO-647 doses of 39 mg and 90 mg. This was followed by infusion of ALLO-501 at CAR-T cell doses of 40 million, 120 million, or 360 million, Neelapu said.
All the medication in the trial was made from the T cells of a single healthy donor, he said.
At a median follow-up of 3.8 months, 63% of patients (n = 12) demonstrated a response to treatment (95% CI, 38%-84%), including 37% (n = 7) who had complete responses (95% CI, 16%-62%). Most patients experienced tumor shrinkage, Neelapu said. The median time until response was 1 month, and 9 patients continue to respond. One patient achieved a complete response after a second infusion of ALLO-501, Neelapu reported.
He noted that 10 of 16 patients evaluated to date showed evidence of CAR-T cell expansion, which was associated with better response.
No dose-limiting toxicity or GvHD was observed in any of the patients treated. The most common adverse events of grade 3 or higher were neutropenia (55.6%), leukopenia (33.3%), and anemia (22.2%). Seven patients developed cytokine release syndrome, 2 of them at grade 1, 4 at grade 2 and 1 at grade 3, all reversible without steroids or tocilizumab (Actemra), according to the researchers. About half the patients had infusion reactions, most grade 2 or lower. Eleven infections reported were grade 3 and lower, mostly asymptomatic and diagnosed during weekly monitoring, Neelapu said. Finally, 1 patient developed a grade 1 neurotoxicity that resolved without treatment.
Neelapu said the safety of the 2 drugs appears comparable to that of autologous CAR T products currently approved for use.
Researchers noted that higher doses of ALLO-647 could have a potential association with deeper responses, as a larger proportion of patients on the greater dose saw a complete response. Follow-up is ongoing as researchers seek to enroll more patients to test for further response.
Neelapu SS, Munoz J, Locke FL, et. al. First-in-human data of ALLO-501 and ALLO-647 in relapsed/refractory large B-cell or follicular lymphoma: ALPHA study. Presented at: 2020 ASCO Virtual Scientific Program; May 29, 2020. Abstract 8002.