Off-the-shelf CAR-T regimen safe for advanced lymphoma
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An allogeneic chimeric antigen T-cell therapy plus an anti-CD52 monoclonal antibody appeared safe for certain patients with large B-cell or follicular lymphoma, according to study data presented during the ASCO20 Virtual Scientific Program.
The combination therapy also showed clinically relevant antitumor activity, according to the researchers.
For allogeneic CAR T-cell therapies to be successful, they must be engineered to reduce the likelihood of graft-versus-host disease, according to Sattva S. Neelapu, MD, professor and deputy chair of the department of lymphoma/myeloma in the division of cancer medicine at The University of Texas MD Anderson Cancer Center.
The anti-CD19 CAR T-cell product (ALLO-501; Allogene Therapeutics, Servier) used in the phase 1 ALPHA trial was genetically modified to knock out T-cell receptor (TCR)-alpha gene expression and reduce incidence of GVHD.
Prior to infusion, trial participants received fludarabine dosed at 90 mg/m2 and cyclophosphamide dosed at 900 mg/m2 for lymphodepletion, followed by ALLO-647 (Allogene Therapeutics, Servier) — an investigational monoclonal antibody that targets CD52 on most T cells.
“By giving ALLO-647, we deplete the hosts’ T cells without affecting the donor T cells in ALLO-501 because it lacks the TCR-alpha gene,” Neelapu told Healio. “This leads to better persistence by the donor T cells, better expansion of the cells, and improved clinical outcomes and durability.”
The open-label, dose-escalation ALPHA trial enrolled 22 adults (median age 63 years; range, 34-73; 77% men), with relapsed or refractory large B-cell or follicular lymphoma who had received at least two previous lines of therapy. Patients who received previous anti-CD19 cell therapies were eligible for the trial.
Fourteen patients (64%) had diffuse large B-cell lymphoma and eight (36%) had follicular lymphoma. Most patients (59%) had stage IV disease by Lugano 2014 criteria, whereas 36% had stage III disease.
Patients had a median four (range, 2-8) previous lines of treatment, with 41% having undergone previous hematopoietic stem cell transplantation.
After lymphodepletion, patients received ALLO-647 dosed at 39 mg or 90 mg. They then received an IV infusion of ALLO-501 at one of three dose levels — 40 × 106 CAR T cells/kg, 120 × 106 CAR T cells/kg or 360 × 106 CAR T cells/kg — 5 to 7 days after lymphodepletion.
Safety and dose-limiting toxicity of the regimen served as the study’s primary endpoints. Key secondary endpoints included overall response rate and cell kinetics after infusion with ALLO-501.
Median follow-up was 3.8 months (range, 0.7-6.1).
Neelapu presented data on 19 patients in the efficacy analysis and 22 patients in the safety analysis.
The safety analysis showed the most common treatment-related adverse event was neutropenia (68% overall, 32% grade 3, 32% grade 4). Seven patients (32%) experienced cytokine release syndrome, including one grade 3 case.
No patients showed evidence of GVHD or symptoms resembling immune effector cell-associated neurotoxicity syndrome (ICANS).
“Thus far we have not seen any dose-limiting toxicities or evidence of any GVHD, which is a concern with allogeneic CAR-T products,” he told Healio. “We have not seen any incidence of neurotoxicity or ICANS, but we have seen cytokine release syndrome in about a third of patients.”
According to Neelapu, the rate of cytokine release syndrome in the ALPHA trial is comparable to or better than that seen with autologous CAR T-cell products.
Neelapu warned that the process of depleting the hosts’ T cells in this trial leaves patients more susceptible to subsequent infections. Half of patients in the safety analysis experienced infections, but these were easily resolved through monitoring and medication Neelapu said.
The efficacy analysis showed a 63% (95% CI, 38-84) ORR and a 37% (95% CI, 16-62) complete response rate. Nine of the 12 patients who responded remained in response at data cutoff May 11.
The ORR was comparable (64% vs. 63%) for patients who received the lower and higher ALLO-647 dose.
Higher complete response rates were achieved with higher doses of ALLO-647, Neelapu told Healio. Patients who received the lower ALLO-647 dose had a 27% complete response rate, compared with 50% with the higher ALLO-647 dose.
“The complete and overall response rates we have seen are in the same ballpark as what we have seen with autologous CAR-T cell therapy,” he said. “What we don’t know at this time is whether its durability will be as lasting as autologous CAR T-cell products.”
Perspective
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Samantha M. Jaglowski, MD, MPH
One of the problems with autologous CARs is the manufacturing time, which is potentially several weeks — especially for patients whose disease is progressing. They may no longer have the time to benefit from the CAR T cells once they are ready.
The promise of allogeneic therapies is that you can obtain a more robust and healthier CAR for patients immediately, which has led to much anticipation and excitement in the field. The problem with this approach is the risk for GVHD when you take cells from a donor and use them in a product. The primary reason why these allogeneic therapies are being modified using CRISPR technology is to abrogate some of this risk.
Neelapu and colleagues have begun a very exciting study and — although it is in its early stage and, thus far, has treated a small number of patients — it is encouraging to see this treatment regimen is relatively safe and induces a good response rate compared with historical numbers.
In terms of safety, the rate of grade 4 or higher CRS was lower in this study than we usually would see with autologous CARs. The same can be said for neurotoxicity. With response rates comparable to currently available treatments, the value of this approach remains to be determined based the accumulation of more efficacy data.
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Neelapu SS, et al. Abstract 8002. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
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