CT103A: Improving persistence of CAR T-cell therapy in MM

Whilst durable responses are often observed for CD19-directed CAR T-cell therapies in acute lymphoblastic leukemia, it has proven challenging to achieve durable responses to BCMA-directed CAR T-cell therapy in multiple myeloma (MM).¹ The degree of proliferation and persistence of CAR T cells in the blood may influence the duration of response to treatment, and it has been suggested that fully human or humanized CAR T-cell constructs may promote persistence by reducing immune-mediated CAR T-cell clearance.²

CT103A is a second generation, fully human CAR T-cell therapy targeting BCMA which has been granted IND approval in China for the treatment of relapsed/refractory MM, based on the results of an open label, single arm phase I clinical study designed to evaluate safety and preliminary efficacy (ChiCTR1800018137). An overview of the study design and early results have been summarized previously on the Multiple Myeloma Hub and have since been published by Wang, et al. in Blood.³ In this summary we report the latest data from the trial, presented at the European Hematology Association (EHA)2021 Virtual Congress,² focusing on the results suggesting improved persistence compared with existing BCMA CAR T-cell products, and those highlighting the possibility for retreatment with CAR T-cell therapy.

Safety updates³

By the data cutoff date of May 1, 2021, 35 patients had been followed up for a median of 291 days (range, 21–954 days). All but three patients (91%) experienced cytokine release syndrome (CRS) but only 16% of CRS cases were Grade ≥3. Most cases of Grade ≥3 CRS occurred at the highest dose level (6 × 10⁶ CAR T cells/kg) and at this dose one patient experienced Grade 4 CRS, which was considered a dose-limiting toxicity. Immune effector cell-associated neurotoxicity syndrome was observed in only one patient (Grade 2). The incidences of CRS and serious adverse events are shown in Table 1.

Table 1. Incidence of CRS and SAEs*

Efficacy updates³

Response and survival data after a median follow-up time of 291 days are summarized in Table 2. The overall response rate was 97.1% and a complete response or stringent complete response was achieved in 57.1% of patients. The median progression free survival was 20 months, suggesting more durable responses than for other trials with non-human BCMA-targeted CARs (with median progression free survival rates of ~7 to 15 months).²

Table 2. Summary of trial outcomes*

Persistence of CT103A³

The duration of CAR T cell persistence may be one determinant of durable responses, and particularly noteworthy was the persistence of the CT103A CAR T cells reported in this study. CT103A expansions were rapid and robust, with peak concentrations reached in a median of 12 days after infusion. CT103A levels remained high in most patients for at least 3 months, and in three patients CT103A persisted for >24 months.

The investigators considered that the following features might contribute to the observed persistency of CT103A²:

• The human single-chain variable fragment (scFv) of the CAR, which may reduce CAR-directed cellular and humoral immune responses compared with murine scFvs, although the role of this potential immunogenicity in CAR T-cell treatment failure is unknown.
• The binding properties of the CAR scFv, which appears to bind BCMA more slowly, remain longer, and dissociate more slowly compared with another BCMA CAR T-cell construct, bb2121.
• A less heavily pre-treated patient population than for other BCMA CAR T-cell trials, which may confer a more favorable efficacy.
• A higher dose of cyclophosphamide than that administered for lymphodepletion in other BCMA CAR T-cell trials, which they speculate may reduce tumor burden prior to CAR T-cell infusion.

Efficacy after prior murine CAR T-cell treatment²

Another noteworthy element of this study was the inclusion of patients who had previously been treated with murine BCMA-directed CAR T cells and had either relapsed or had progressive disease. At the data cutoff date of July 8, 2019, four patients who had received prior murine BCMA-directed CAR T-cell therapy were enrolled on the trial and received CT103A. CT103A expansion did not appear to be affected by prior murine BCMA CAR treatment, with successful expansion in all four patients. Three patients achieved a stringent complete response which was maintained for ≥455 days. The fourth patient, who had extramedullary myeloma and secondary plasma cell leukemia, achieved a very good partial response and survived for 255 days. This data poses for the first time a possibility of retreatment with BCMA CAR T cells in MM.

Conclusion

Although the ideal BCMA-directed CAR T-cell therapy for the treatment of MM is yet to be established, this study has made some important findings. Firstly, the increased cellular persistence reported with CT103A holds promise for more durable responses and, secondly, the benefit from CT103A for patients previously treated with murine BCMA CAR T cells adds weight to the prospect of retreatment with BCMA-directed CAR T-cell therapy.