A pair of off-the-shelf CAR T-cell agents have shown promise for the treatment of relapsed/refractory large B-cell or follicular lymphoma, according to the phase 1 ALPHA study.
First-in-human findings show that ALLO-501, an allogeneic chimeric antigen receptor (CAR)-T cell therapy plus ALLO-647, a monoclonal antibody, has clinical activity and is tolerable in patients with relapsed/refractory large B-cell or follicular lymphoma, according to results reported in an oral presentation during the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program.
The two treatments were used sequentially in the open-label, phase 1 ALPHA study that occurred at six sites across the United States, demonstrating an overall response rate of 63%, including a 37% complete response rate, in 19 evaluable, previously treated adults in this population.
Researchers believe that allogeneic CAR T-cell therapy, made from healthy donor T cells, can provide the benefits of autologous CAR T-cel 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 on May 29. He said 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 two-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 overall response rate.
Eligible participants had advanced disease, an ECOG performance status of 0 or 1 and had been treated with at least two previous lines of therapy. Prior treatment with an anti-CD20 monoclonal antibody or with autologous CAR T-cell 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; three 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 two drugs appears comparable to that of autologous CAR T-cell 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.