Allogeneic CAR-T Shows Promise in R/R Multiple Myeloma

Allogene Therapeutics’ ALLO-715, an investigational allogeneic chimeric antigen receptor T-cell (CAR-T) therapy that targets B-cell maturation antigen (BCMA), has demonstrated an encouraging safety profile and evidence of efficacy in patients with relapsed/refractory (r/r) multiple myeloma (MM), according to data from part A of the phase 1 UNIVERSAL clinical trial (NCT04093596) recently published in Nature Medicine.¹

The results included data from 43 patients who were treated with ALLO-715 at various doses following lymphodepletion with a regimen containing the anti-CD52 antibody ALLO-647. The overall response rate (ORR) for these patients was 55.8%. Among 24 patients who received lymphodepletion regimens containing fludarabine, cyclophosphamide, and ALLO-647 and subsequent treatment with a dose of 320x10⁶ CAR T-cells, the ORR was 70.8%, with 45.8% achieving a very good partial response or better and 25% achieving a complete response (CR) or stringent CR. This group of 24 patients had a median duration of response of 8.3 months. The median time from enrollment to the start of treatment for the 43 treated patients was 5 days. It was noted that 24 patients discontinued treatment due to progressive disease, 7 discontinued due to death, and 2 discontinued due to withdrawal of consent.

In terms of safety, 38 (88%) of the 43 treated patients experienced grade 3 or greater adverse events (AEs). Twenty-four patients (55.8%) experienced cases of cytokine release syndrome (CRS), with only 1 CRS event being grade 3 or higher. Neurotoxicity AEs were observed in 6 patients (14%); none of these events were grade 3 or greater. Infections were reported in 23 patients (53.5%), with 10 (23.3%) of these AEs being grade 3 or higher. There were no cases of graft versus host disease observed.

“While new autologous CAR-T therapies are a significant advance for patients with MM, challenges inherent to those treatments remain, including manufacturing constraints and out-of-specification product, lengthy vein-to-vein time requiring bridging therapy or prolonged courses of treatment,” first author Sham Mailankody, MBBS, Clinical Director of Cellular Therapy Service and Associate Attending Physician, Memorial Sloan Kettering Cancer Center in New York, New York, said in a statement.² “These groundbreaking results demonstrate the potential for an off-the-shelf cell therapy to be delivered on demand to patients at scale. It is my hope that this publication demonstrating significant proof-of-concept for allogeneic CAR-T will set the stage for many more advances in the field of cell therapy for myeloma.”

As of the October 14, 2021, data cutoff, the trial had treated 27 male patients and 16 female patients aged 46 to 77 years (median, 64). Twenty-one patients had an Eastern Cooperative Oncology Group (ECOG) score of 0 while 22 had an ECOG score of 1. It was noted that the number of previously-received treatment regimens ranged from 3 to 11 (median, 5), with 91% of the patients being refractory to at least 1 proteasome inhibitor (PI), 1 immunomodulator (IMiD), and 1 anti-CD38 monoclonal antibody and 42% of the patients being refractory to 2 PIs, 2 IMiDs, and 1 anti-CD38 monoclonal antibody. BCMA-targeted treatment had been previously administered to 3 patients. ALLO-715 was administered at 4 dose levels: 40x10⁶ (n=3), 160x10⁶ (n=7), 320x10⁶ (n=27), and 480x10⁶ (n=6). Various ALLO-647-containing lymphodepleting regimens were used, and none of the patients received bridging therapy during the trial. 

“It should be noted that viral reactivations, in particular cytomegalovirus (CMV) viral reactivations, were noted in 33% of patients in UNIVERSAL highlighting the importance of CMV monitoring and consideration of anti-infective prophylaxis,” Mailankody and colleagues wrote.¹ “Reassuringly, only 2 grade 3 CMV reactions requiring the use of intravenous antiviral therapy were reported and no grade 4 or 5 reactivations or infections were reported. Given the small sample size and the lack of a control arm, it is difficult to ascertain what role fewer or shorter courses of prophylaxis may have played at the cohort or even individual level. Per the National Comprehensive Cancer Network (NCCN) guidelines on infectious prophylaxis, patients who are treated with anti-CD52 therapeutic anti- bodies are considered at high risk for CMV reactivation, which may differentiate the UNIVERSAL patient population from those in trials of autologous CAR-T therapies. However, most trials for autologous CAR-T products to date have categorized infections broadly as bacterial, viral, or fungal, which makes it difficult to tease out the individual viral types for comparison to the CMV rates in the UNIVERSAL trial.”

Mailankody and colleagues pointed out that enrollment in UNIVERSAL’s part A is ongoing. However, it was concluded that the interim results reported provide support for the feasibility, safety, and efficacy of ALLO-715. The investigators also noted that while UNIVERSAL used an in-patient approach to treatment, an outpatient approach to administration with ALLO-715 may be feasible. Comparison between the phenotypic characteristics of T-cells derived from healthy donors versus those derived from patients with r/r disease was additionally highlighted as an area of interest for further study.

REFERENCES

1. Mailankody S, Matous JV, Chhabra S, et al. Allogeneic BCMA-targeting CAR T cells in relapsed/refractory multiple myeloma: phase 1 UNIVERSAL trial interim results. Nat Med. Published online January 23, 2023:1-8. Doi: doi.org/10.1038/s41591-022-02182-7

2. Allogene Therapeutics announces publication in Nature Medicine of data from its phase 1 UNIVERSAL study of ALLO-715 for the treatment of relapsed/refractory multiple myeloma. News release. Allogene Therapeutics, Inc. January 24, 2023. Accessed February 6, 2023. https://ir.allogene.com/news-releases/news-release-details/allogene-therapeutics-announces-publication-nature-medicine-data