Summary
ALLO-501, an anti-CD19 allogeneic CAR T-cell therapy, shows promise among relapsed/refractory non-Hodgkin lymphoma patients, according to initial findings presented at the ASCO 2020 Annual Meeting (Abstract 8002).
“To be successful, allogeneic CAR T-cell should prevent graft-versus-host disease (GvHD) and should also prevent rejection of the donor cells by the host,” said study author Sattva S. Neelapu, MD, Professor in the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center.
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Original Article
Safety & Short-Term Efficacy of ALLO-501 for Lymphoma
Oncology Times
By Catlin Nalley
ALLO-501, an anti-CD19 allogeneic CAR T-cell therapy, shows promise among relapsed/refractory non-Hodgkin lymphoma patients, according to initial findings presented at the ASCO 2020 Annual Meeting (Abstract 8002).
“To be successful, allogeneic CAR T-cell should prevent graft-versus-host disease (GvHD) and should also prevent rejection of the donor cells by the host,” said study author Sattva S. Neelapu, MD, Professor in the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center.
“In order to minimize the risk of GvHD in ALLO-501, the TCR-alpha expression has been eliminated by TRAC knockout with the TALEN gene editing technology. And to improve persistence, CD52 has been knocked out to allow selective lymphodepletion with ALLO-647, which is an anti-CD52 monoclonal antibody that depletes the host cells but protects the donor cells, [and] allows CAR T-cell expansion and anti-tumor killing. ALLO-501, in addition, has the rituximab safety switch.
“Allogeneic CAR T-cell therapy may provide the benefits of autologous CAR T-cell therapy while also addressing its challenges. It has the potential to treat all eligible patients, the convenience of repeat dosing, and simplifies the logistics of manufacturing,” he continued. “In addition, since it is off-the-shelf, there is no wait period for the patients, and there is less product variability since it is made from healthy donor T cells.”
Study Specifics
The ALPHA study is an open-label, dose-escalation, phase I trial being conducted at six centers in the U.S. The primary endpoint is safety and dose-limiting toxicity. Secondary endpoints include overall response rate, as well as the PK/PD profile of ALLO-501 and ALLO-647, according to Neelapu.
Eligible patients include adults with relapsed/refractory large B-cell or follicular lymphoma who have received at least two prior lines of therapy. “Prior autologous CAR T-cell therapy was allowed if the tumors remained CD19-positive,” noted Neelapu. “Patients with donor-specific antibodies and rituximab levels greater than 15ng/mL were excluded.”
“Patients receive fludarabine 90 mg/m2, cyclophosphamide 900 mg/m2, and ALLO-647 39 or 90 mg followed by ALLO-501 at one of three dose levels in a 3+3 design: 40, 120, and 360 × 106 CAR+ T cells,” the study authors outlined.
Of the 22 enrolled patients, the median age was 63 years. Fourteen (64%) patients had diffuse large B-cell lymphoma and eight had follicular lymphoma.
“Almost all patients had advanced-stage disease with stage III or IV, but half the patients had high-risk or high intermediate-risk FLIPI or IPI scores,” Neelapu said. “These patients were heavily pretreated with a median number of prior regimens of four.
“Two-thirds of the patient were chemorefractory. About 40 percent of the patients had prior auto transplant, and four patients had prior autologous CAR-T,” he added. “Of these, two had short-lasting partial remission, and two had PD as best response with prior AutoCAR-T.”
As of the data cutoff (May 11, 2020), 22 patients were evaluable for safety and 19 for efficacy. To date, all but one enrolled patient has been treated on the study. The median time from enrollment to start of lymphodepletion was 5 days, which, according to Neelapu, reflects the potential advantage of allogeneic CAR T-cell therapy.
“The dose escalation has been completed for the CAR T cells at the low dose ALLO-647 and is ongoing on the high dose ALLO-647,” he said. “All patients treated to date on the study received CAR T-cells generated from a single healthy donor.”
Safety & Efficacy
Both ALLO-501 and ALLO-647 have been well-tolerated. To date, researchers have not observed any dose-limiting toxicities, GvHD, or neurological toxicity (ICANS), according to Neelapu.
“A third of the patients developed CRS, but most of these were grade 1 and grade 2, with only one patient having grade 3 CRS. All of these were reversible,” he reported. “About half the patients had infusion reactions attributable to ALLO-647, and another half had infections. Most of these were asymptomatic viral reactivations that were diagnosed during weekly PCR monitoring.”
Among the evaluable patients, the best overall response rate was 63 percent, and the best complete response rate was 37 percent, according to Neelapu. “The complete response rate appeared to be higher at the higher ALLO-647 dose, at 50 percent versus 27 percent,” he said. “The median follow-up time is still short at 3.8 months.”
Most patients achieved tumor shrinkage, Neelapu noted during his presentation. The three patients who were refractory to prior autologous CAR-T therapy did not have any response to ALLO-501.
The median time to response was 1 month, according to Neelapu, who noted that nine of the 12 responses are currently ongoing. One of the ongoing responders is a patient with an initial partial response who progressed by month 2. A CR was achieved after re-treatment with the same dose of ALLO-501 and higher dose (90 mg) ALLO-647.
“To conclude, ALLO-501 and ALLO-647-based lymphodepletion appears to be well-tolerated,” Neelapu shared. “To date, we have not observed any dose-limiting toxicity, GvHD, or ICANS. The CRS was manageable and there were no greater than grade 3 infections.
“AlloCAR T-cell expansion was associated with responses, and these responses were observed across all cell dose levels,” he continued. “Overall, these results suggest that the safety and the short-term efficacy, in terms of response rate, for this product is comparable to autologous CAR-T products that are currently in clinic.”
Further follow-up is necessary to determine the durability of those responses, Neelapu said, noting, “ALLO-647 delays host T-cell recovery and the higher dose of ALLO-647 appears to associate with deeper responses with almost a 50 percent complete response.”
Currently, optimization of the lymphodepletion regimen and patient follow-up is ongoing. Additionally, the phase I trial of ALLO-501A (ALLO-501 minus the rituximab switch) is now enrolling.
Catlin Nalley is a contributing writer.