CYAD-211 Induces Favorable Safety, Supports Proof of Concept in Patients With Relapsed/Refractory Myeloma
Safety and the recommended dose of CYAD-211 and the lymphodepletion regimen served as the primary end point of the study.
CYAD-211 demonstrated a favorable safety profile across 3 dose levels, with limited observations of graft-versus-host disease (GvHD) in adult patients with relapsed/refractory multiple myeloma, according to data from the phase 1 IMMUNICY-1 trial (NCT04613557) presented at the 2021 ASH Annual Meeting and Exposition.
“CYAD-211 is the first non-gene edited allogeneic [B-cell maturation antigen (BCMA)] CAR T-cell product based on [short hairpin (sh)] RNA technology targeting the CD3 zeta subunit,” Samer Al-Homsi, MD, MBA, NYU Langone Health, said during a virtual presentation of the data. “A favorable safety profile for CYAD-211 was observed at the 3 dose levels. The lack of observed GvHD despite engraftment of CYAD-211 provides proof of concept of the safe administration of allogeneic CAR T using a shRNA-allogeneic platform.”
In the ongoing, open label, multicenter phase 1 IMMUNICY-1 trial, investigators evaluated CYAD-211 – a non-gene edited allogeneic CAR T-cell product co-expressing a CAR directed against BCMA, a single optimized shRNA to downregulate the expression of the T-cell receptor (TCR) CD3 zeta, and a cell surface selection marker (tCD34) – in 12 adult patients with relapsed/refractory multiple myeloma.
During the dose-escalation portion, patients received non-myeloablative preconditioning, consisting of 300 mg/m2 cyclophosphamide per day and 30 mg/m2 fludarabine per day for 3 days. They were then infused with CYAD-211 at 3 dose levels, following a 3+3 design:
- 30x106 cells/infusion (DL1),
- 100x106 cells/infusion (DL2), and
- 300x106 cells/infusion (DL3
Safety and the recommended dose of CYAD-211 and the lymphodepletion regimen served as the primary end point of the study. Secondary end points included clinical anti-tumor activity, and CYAD-211 cell expansion, persistence, and trafficking.
Median age was 68.5 years (range, 49-82). The majority of patients were heavily pretreated, with a median of 4 prior lines of therapy received. Of note, 83% of patients has previously received treatment with all 3 major drug classes in myeloma: proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibody therapy. In addition, most patients had high-risk cytogenetics, and 25% had extramedullary disease.
CYAD-211 demonstrated an acceptable safety profile, with no dose-limiting toxicities, GvHD, or CAR T-cell-related encephalopathy syndrome.
Ten patients (83%) reported with an adverse event (AE) related to treatment with CYAD-211.
In the DL1 cohort, 1 patient developed grade 1 fever, which was associated with cytokine release syndrome, that required hospitalization. The adverse event occurred 10 days after CYAD-211 infusion.
In addition, 3 patients experienced a grade 3/4 AE (anemia, decreased lymphocyte count, neutropenia, decreased neutrophil count, and decreased white blood cell count), possibly related to the CAR T-cell therapy.
Per IMWG criteria, 3 of 12 patients experienced a partial response – 1 in each dose level. Eight patients reported with stable disease, 1 of which showed evidence of a reduction in the size of plasmacytomas at 4.5 months.
The investigators noted that all patients had detectable CYAD-211 cells in their peripheral blood; however, it was short lasting.
Among DL2 and DL3, no dose-dependency was observed, “suggesting the expansion and persistence of cells might be more dependent on the depth and period of the lymphodepletion induced by the preconditioning regimen,” they investigators wrote.
Lastly, clearance of CYAD-211 was associated with the recovery of endogenous lymphocyte populations, “as suggested by the averaged absolute lymphocyte counts (ALC) kinetics,” they added.
Next, investigators will evaluate enhanced lymphodepleting regimens and potential CYAD-211 redosing has been initiated.
“This may overcome many hurdles associated with autologous and gene edited allogeneic CAR T-cell approaches,” Al-Homsi said. “The absence of dose-dependency at the higher CYAD-211 doses and the lack of sustained engraftment of CYAD-211 can be explained by rejection of the allogeneic cells by the recovering immune system of patients. The next segment of the IMMUNICY-1 trial will evaluate enhanced lymphodepleting regimens and potential CYAD-211 redosing.”
