Clinical responses and pharmacokinetics of fully human BCMA targeting CAR T-cell therapy in relapsed/refractory multiple myeloma.

Abstract

8013 Background: Previous studies indicate patients with relapsed/refractory multiple myeloma (RRMM) who receive high-dose BCMA-targeting CAR-T cells may achieve better remission but have worse adverse events. Moreover, once the disease progresses again, the re-infusion of CAR-T cells is not effective. To solve this dilemma, we have developed a novel BCMA-targeting CAR-T (CT103A) with a lentiviral vector containing a CAR structure with a fully human scFv, CD8a hinger and transmembrane, 4-1BB co-stimulatory and CD3z activation domains. Methods: ChiCTR1800018137 is a single-center and single-arm trial of CT103A in patients with RRMM. The primary objectives are to characterize the safety and tolerability in patients with R/R MM. The secondary objectives include evaluation of anti-myeloma activity, cytokines, CAR-T cell persistence, and pharmacokinetics. Between September 21, 2018, and January 21, 2019, nine patients (including 3 patients having relapsed after being given a murine BCMA CAR-T) received CT103A in 3+3 dose-escalation trial (three doses at 1, 3, 6 ×106/kg) after a conditioning chemotherapy regimen of cyclophosphamide and fludarabine. All Patients had received a median of 4 prior lines (range 3 - 5) of MM therapy. Results: At the time of the February 4, 2019 data analysis, the overall response rate was 100% (Table), and all patients had a rapid response within 14 days, with 67% (2/3) reaching CR/sCR at the lowest dose. The pharmacokinetics of CT103A were assessed by a digital polymerase chain reaction. Robust expansions were seen even at the lowest dosage level. In addition, Cmax and AUC0-28 reached levels comparable to reported CD19 CAR-T. In the first two dose groups, the grade of cytokine release syndrome (CRS) was 0 - 2. In the 6 ×106 /kg dose group, DLT had been observed in one patient. Conclusions: Data from this early-stage clinical study showed the unparalleled safety and efficacy of CT103A. Major AEs were transient, manageable, and reversible. three patients who relapsed the murine BCMA CAR-T were treated with CT103A, two patients achieved CR, and one patient achieved VGPR. 100% ORR and a rapid response within 2 weeks, suggests CT103A could be developed as a competitive therapeutic to treat patients with RRMM. Treatment Response (Case 1,5 and 7 are patients who relapsed the murine BCMA CAR-T). Clinical trial information: ChiCTR1800018137. [Table: see text]

B cell maturation antigen‐specific chimeric antigen receptor T cells for relapsed or refractory multiple myeloma: A meta‐analysis

“…Out of these, 47 studies were excluded: 20 were still recruiting and without outcome data or were not restricted to CAR T‐cell therapy, 21 reported outcomes only on a single case basis, and 6 studies evaluated safety and efficacy of CAR T cells targeting antigens other than BCMA. Of the remaining 18 studies, 3 were included only in the qualitative review because they evaluated CAR T products that, in addition to BCMA, targeted other antigens such as CD19 and CD38 . The remaining 15 studies were included in the quantitative systematic review and meta‐analysis .…”

“…shows the PRISMA flow diagram of the study selection process. Out of 18 identified studies, three were included only in the qualitative review because they evaluated CAR T products that, in addition to BCMA, targeted other antigens such as CD19 and CD38 . The remaining 15 studies were included in the quantitative systematic review and meta‐analysis…”

BCMA-targeted immunotherapy for multiple myeloma

“…No NTX was observed. One patient died of lung infection at day 19 post-infusion [111,138]. Despite this encouraging preliminary result, further studies are still warranted to evaluate the safety and efficacy of this fully human BCMA-targeted CT103A.…”

Emerging agents and regimens for multiple myeloma

“…Currently, there are many ongoing CAR-T studies for BCMA, such as JCARH125 [ 103 ], CT053 [ 104 ], MCARH171 [ 105 ], and CT103A [ 106 ]. These studies also showed a good response rate, and no new treatment toxicity and side effect was observed.…”