Off-the-Shelf CAR Therapy Shows Early Promise in Multiple Myeloma

Sham Mailankody, MBBS

ALLO-715, an off-the-shelf chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen (BCMA), elicited responses in heavily pretreated patients with relapsed/refractory multiple myeloma in early findings from a first-in-human study presented at the 2020 ASH Meeting.¹

The therapy generated responses in 6 of 10 patients (60%), including a very good partial-plus response (VGPR+) in 4 patients (40%), who were treated with ALLO-715 at a dose of 320 x 10⁶ CAR cells plus a lymphodepleting regimen that included ALLO-647, an anti-CD52 monoclonal antibody, during the ongoing phase 1 UNIVERSAL study (NCT04093596).¹

The findings mark the first results for an allogeneic CAR therapy directed at BCMA, said lead study author Sham Mailankody, MBBS, a medical oncologist and investigator in the Cellular Therapeutics Center at Memorial Sloan Kettering Cancer Center in New York, New York. BCMA, which is highly expressed on plasma and multiple myeloma cells, has sparked intensive research interest.²

“These results demonstrate the feasibility and safety of an off-the-shelf CAR T cell therapy for multiple myeloma. In this first report of an allogeneic BCMA CAR T-cell therapy, we show that nearly 90% of patients were treated within 5 days of enrollment and without needing any bridging therapy,” Mailankody said.

Allogeneic CAR therapy offers the potential for scalable manufacturing for on-demand treatment with shorter waiting times, which would overcome some of the logistical challenges posed by autologous CAR therapy, Mailankody said. The T cells needed for ALLO-715 are harvested from healthy donors and genetically engineered to express CARs aimed at specific cancer targets, according to Allogene Therapeutics, the company developing the therapy.³

ALLO-715 includes a human-derived single-chain variable fragment anti-BCMA cell with a 4-1BB costimulatory domain. Mailankody said the “2 key attributes” of the construct are a knockout of CD52, which allows for selective lymphodepletion with ALLO-647 to prevent graft rejection without affecting the CAR T cells, and a knockout of the TRAC gene, which also minimizes the risk of graft-versus-host disease (GVHD).¹

The UNIVERSAL study, which is being conducted at 11 cancer centers in the United States, is recruiting patients with multiple myeloma who have received 3 or more prior therapies, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 agent, and are refractory to their last treatment. Participants must have an ECOG performance status score of 0 or 1.

The dose escalation portion of the study is testing ALLO-715 as a single infusion across 4 doses: 40, 160, 320, or 480 x 10⁶ CARs. Lymphodepletion regimens consist of fludarabine (F; 30 mg/m²/day) plus cyclophosphamide (C; 300 mg/m²/day) given on 3 days with ALLO-647 (A; 13-30 mg x 3 days; FCA) or cyclophosphamide plus ALLO-647 (CA).

Among the 35 patients enrolled at the time of the presentation, 4 became ineligible because of organ failure due to rapidly progressing disease. Of 31 patients in the safety population, the median age was 65 years (range, 46-76). Nearly half of the patients (48%) have high-risk cytogenetics and 23% had extramedullary disease. The efficacy population at data cutoff on October 30, 2020, comprised 26 patients across the 4 dosing levels, with a median follow-up of 3.2 months.¹

The overall response rate (ORR) varied across dosing cohorts and lymphodepleting regimens. No responses were observed among 3 patients each who received CARs at 40 x 10⁶ with FCA or 160 x 106 with CA, both with low-dose ALLO-647. The ORRs were 50% in 4 patients who received CARs at 160 x 10⁶ with low–ALLO-647 FCA; 33% in 3 at 480 x 10⁶ with low–ALLO-647 FCA; and 67% in 3 at 320 x 10⁶ with low–ALLO-647 CA.

The most robust responses were seen among those who received ALLO-647 at 320 x10⁶. For this cohort, the ORR was 60% among 10 patients, including 3 of 6 who received CARs with low–ALLO-647 FCA and 3 of 4 who had the therapy with high–ALLO-647 FCA. Overall, 6 patients had a VGPR+, defined as stringent complete response, complete response, or VGPR. These included 1 at 160, 4 at 320, and 1 at 480 10 x 10⁶ CARs. Of the VGPR+ patients, 5 were negative for measurable residual disease. Additionally, 6 of 9 patients treated at the 320 or 480 x 10⁶ dose levels remain in response.

Mailankody highlighted the experience of 1 participant, a 71-year-old man whose myeloma had progressed after undergoing 9 prior lines of therapy including autologous stem cell transplant and an experimental BCMA-targeted therapy. The patient received a conditioning regimen of FCA with low-dose ALLO-647 and ALLO-715 at 320 x 10⁶. He reached a VGPR on day 14 that deepened to a stringent complete response by day 28 that remains in effect at 6 months, while experiencing grade 1 cytokine release syndrome (CRS).

“The patient is clinically doing very well and is back at work,” Mailankody said.

Among 31 patients in the safety population, most adverse effects were of grade 1 or 2 severity. These included CRS in 14 patients (45%) and infusion-related reactions to ALLO-647 in 7 patients (23%). The use of drugs to manage CRS also was low, at 19% for tocilizumab and 10% for steroids.

All-grade infections were reported in 13 patients (42%), including grade 3 events in 4 (13%). One patient (3%) died from a presumed fungal pneumonia related to progressive disease and the CA conditioning regimen but unrelated to ALLO-715. There were no instances of neurotoxicity or GVHD.

“Notably, the fact that we did not see any GVHD is encouraging for an off-the-shelf allogeneic product,” Mailankody said.

In response to a question from a conference attendee, Mailankody said it is too soon to compare efficacy levels seen with this allogeneic CAR therapy with those observed with investigational autologous CARs, which have been under study for several years.

Moving forward, investigators are continuing to evaluate dosing levels for ALLO-715. UNIVERSAL is enrolling patients to the 480 x 10⁶ cohort, Mailankody said, adding that the appropriate dose likely would land between 320 and 480 x 10⁶.

References

1. Mailankody S, Matous JV, Liedtke M, et al. Universal: an allogeneic first-in-human study of the anti-Bcma ALLO-715 and the Anti-CD52 ALLO-647 in relapsed/refractory multiple myeloma. Presented at: 2020 American Society of Hematology Annual Meeting and Exposition. December 5-8, 2020; Virtual. Abstract 129. Accessed December 5, 2020. https://ash.confex.com/ash/2020/webprogram/Paper140641.html
2. Cho SF, Anderson KC, Tai YT. Targeting B cell maturation antigen (BCMA) in multiple myeloma: potential uses of BCMA-based immunotherapy. Front Immunol. 2019;9:1821. doi:10.3389/fimmu.2018.01821
3. AlloCAR T Therapy. Allogene Therapeutics. Accessed December 5, 2020. https://www.allogene.com/allocar-t-therapy