ALLO-501A With ALLO-647 Lymphodepletion Shows Early Efficacy in Relapsed/Refractory Large B-Cell Lymphoma

Treatment with the allogeneic CAR T-cell product ALLO-501A elicited encouraging signals of clinical activity when used with ALLO-647 lymphodepletion in patients with relapsed/refractory large B-cell lymphoma (LBCL) who did not previously receive autologous CAR T-cell therapy, according to findings from the phase 1/2 ALPHA2 study (NCT04416984) presented during the 2021 ASCO Annual Meeting.

Data showed that the objective response rate (ORR) with ALLO-501A in all patients (n = 9) was 56% (n = 5; 95% CI, 21%-86%), which included a 44% (n = 4; 95% CI, 14%-79%) complete response (CR) rate.

Specifically, in those who received ALLO-501A at the second dose level of 120 x 10⁶ CAR T cells (n = 4), the ORR was 50% (95% CI, 7%-93%) and both responses were CRs. For those who received ALLO-501A as a consolidation treatment (n = 5), the ORR was 60% (95% CI, 15%-95%) and the CR rate was 40% (95% CI, 5%-85%).

“Three patients had sufficient follow-up time to evaluate response after consolidation,” said Frederick L. Locke, MD, lead study author, vice chair of the Department of Blood and Marrow Transplant and Cellular Immunotherapy, and program co-leader of Immuno-Oncology at Moffitt Cancer Center, in a virtual presentation during the meeting. “Two out of 2 demonstrated responses deepening to CR by month 2, with the third maintaining a CR.”

Allogeneic CAR T-cell therapy has been identified as a method to address logistical and manufacturing challenges of autologous CAR T-cell products.

ALLO-501, an anti-CD19 CAR T-cell product, has rituximab (Rituxan) recognition domains. Prior data have demonstrated that ALLO-501 supported the clinical development of ALLO-501A, which is an allogeneic CAR T-cell therapy that excludes rituximab recognition domains.

ALLO-501A utilizes TALEN gene editing to disrupt the TCRα constant gene, which may reduce the risk of graft-vs-host disease (GVHD). Additionally, edited CD52 may permit the use of ALLO-647, a humanized anti-CD52 monoclonal antibody, to selectively deplete host T cells.

Previously, ALLO-501 produced deep responses in 32 patients with relapsed/refractory non-Hodgkin lymphoma in the phase 1 ALPHA trial (NCT03939026), with a 75% ORR (95% CI, 57%-89%) and a CR rate of 47% (95% CI, 29%-65%). In patients with follicular lymphoma (n = 21), the ORR was 81% (95% CI, 58%-95%) and the CR rate was 48% (95% CI, 26%-70%). In those with LBCL (n = 11), the ORR was 64% (95% CI, 31%-89%) and the CR rate was 46% (95% CI, 17%-77%). The longest ongoing remission persisted for at least 1 year, as of the patient’s last scan.

Additionally, the overall treatment failure-free survival rate (TFFS) at 6 months in all 32 patients was 63% (95% CI, 42%-78%). After the initial infusion, the 6-month CR rate was 29%; in those with follicular lymphoma and LBCL, the 6-month CR rates were 24% and 36%, respectively.

Among all autologous CAR T-cell therapy–naïve patients who achieved a CR, 3 patients remain in ongoing CR. The duration of response (DOR) in these patients is 5.1 months, while it was 11.1 months and 11.2 months in the follicular lymphoma and LBCL subgroups. In patients with follicular lymphoma and LBCL, the 1-year OS rates were 63% and 57%, respectively.

In the single-arm, open-label ALPHA2 study, investigators sought to determine whether ALLO-501A mirrored the efficacy results observed with ALLO-501 in the ALPHA trial.

In the study, ALLO-501 was examined in non-human leukocyte antigen–matched patients with relapsed/refractory LBCL, DLBCL, transformed follicular lymphoma, transformed marginal zone lymphoma (MZL), primary mediastinal B-cell lymphoma (PMBCL), and grade 3B follicular lymphoma.

Patients had to have received 2 or more prior lines of therapy, which included an anthracycline and anti-CD20 monoclonal antibody. The product was administered at the following doses: 40 x 106 (dose level 1 [DL1]; n = 1), 120 x 10⁶ (DL2; n = 5), and consolidation at 120 x 10⁶ plus 120 x 106 CAR T cells (n = 6).

Retreatment was permitted for progressive disease or stable disease (SD) with suboptimal CAR T-cell expansion. The study was recently amended to include a note that patients who had SD or better at day 28 received consolidation therapy with an additional 30-mg dose of ALLO-647, making a total dose of 90 mg, and cell infusion of ALLO-501A.

The primary end point of the trial was safety, tolerability, and cell kinetics of ALLO-501A following lymphodepletion; secondary end points comprised investigator-assessed ORR, as well as cell kinetics of ALLO-501A.

Of the 13 patients enrolled, the mean age was 55 years; 39% had stage IV disease, 69% of patients had an ECOG performance status of 1, and 69% had a baseline lactate dehydrogenase level that was greater than the upper limit of normal. Forty-six percent of patients had an International Prognostic Index of 3 or higher, and the mean number of prior regimens received was 3. Moreover, 31% of patients had previously received an anti-CD19 treatment. Fifty-four percent of patients had germinal center B type and 46% had double- or triple-hit lymphoma.

In the consolidation arm, a second dose of ALLO-647 and cell infusion was to be administered. No cases of cytokine release syndrome (CRS), immune effector cell–associated neurotoxicity syndrome (ICANS), dose-limiting toxicities, or dose reductions were reported, nor were any related serious adverse effects (AEs). Regarding AEs of special interest, 1 case of grade 3 or higher CRS was reported at the 40 x 106 CAR T-cell dose.

In the safety analysis set (n = 13), 10 treatment-emergent AEs occurred. The most common AEs reported with the product were neutropenia (n = 9), leukopenia (n = 8), lymphopenia (n = 7), thrombocytopenia (n = 6), and anemia (n = 5).

Potential benefits of consolidation dosing were suggested with in vivo expansion of CAR T cells following the second infusion of ALLO-501A, Locke added.

Across both the ALPHA and ALPHA2 trials, ALLO-501 and ALLO-501A in combination with ALLO-647 lymphodepletion were well tolerated, with no GVHD, 1 event AE each of grade 3 ICANS and grade 3 CRS.

“[These data include] patients who were treated with either 1 or 2 doses, suggesting that the safety profile with consolidative dosing was also tolerable,” Locke concluded. “Redosing at the time of disease progression, or up-front consolidation, can be safely administered with emerging evidence of meaningful clinical benefit.”

Reference

1. Locke FL, Malik S, Tees MT, et al. First-in-human data of ALLO-501A, an allogeneic chimeric antigen receptor (CAR) T-cell therapy and ALLO-647 in relapsed/refractory large B-cell lymphoma (R/R LBCL): ALPHA2 study. J Clin Oncol. 2021;39(suppl 15):2529. doi:10.1200/JCO.2021.39.15_suppl.2529