Phase I study results of novel humanized BCMA CAR T cells C-CAR088 in the treatment of RRMM

CAR T cell therapy is an important breakthrough in hematologic tumors, with BCMA CAR T cell therapy achieving an overall remission rate (ORR) of 85.

Study the design

The structure of the second-generation CAR targeting BCMA is shown in Figure 1A
.

Results of the study

Patient and disease characteristics

A total of 34 patients were screened, of which 31 patients received C-CAR088 (Figure 1B
).

The median age of patients was 61 years, 17 (54.

The median of previous treatment lines is 4
.

security

The median follow-up of 31 treated patients was 9.

The most common adverse events were hematologic toxicity, including neutropenia (100%), leukopenia (100%), thrombocytopenia (90.

Clinical efficacy

This study assessed the response to treatment on day 28 after reinfusion in patients with follow-up ≥ 1 month
.

Of the 28 patients who could be evaluated, the ORR was 96.

Of the intending to treat population (ITT, n = 31), the ORR was 87.

Of the 15 assessable patients with at least 2 high-risk gene abnormalities, the ORR was 93.

3.

The median follow-up time for the cohort receiving moderate + high doses was 9.

In subgroup analyses evaluating the effects of multiple factors, including baseline clinical and therapeutic features, on CR/sCR (Figure 2D), patients in the medium- and high-dose groups were more likely to achieve CR/sCR
.

MRD

The authors measured MRD
in patients with CR.

Pharmacokinetic and pharmacodynamic features of C-CAR088

The authors assessed the pharmacokinetic profile of C-CAR088 by measuring the copy number of the C-CAR088 gene in peripheral blood, and 30 patients had evaluative data
.

The median T_Max is 14 days, the median C_max is 750061 copy/μg genomic DNA (gDNA), and the median AUC_0-28 is 7558634 copy/μg gDNA/day
.
T_last ranges from 14+ to 566+ days
.
The differences in these indicators between groups were statistically significant
.
The pharmacokinetics of C-CAR088 between groups was analyzed using the Tukey True Significance Difference Test, with significantly shorter T_max in the medium dose group and the high dose group (p< 0.
05), and no significant difference in other kinetic parameters (Figure 3B–E).

Blood/urine M protein and changes in sFLC levels were compared
to baseline using changes in blood/urine M protein and sFLC levels as pharmacodynamic markers of CAR088 。 In the low-dose group, mean blood/urine M protein or sFLC levels decreased to 68±39%, 41±44%, 30±54%, 13±15%, and 5±7% of baseline at 2, 4, 8, 12, 12, and 16 weeks after infusion, respectively, while blood/urine M protein or sFLC levels were 12±16% and 55±12%
at baseline, respectively, at 20 weeks and 6 months after infusion.
These results suggest that the lowest dose cannot completely suppress tumor cells
.

In 12 patients in the moderate dose group, mean blood/urine M protein or sFLC levels decreased to baseline levels of 43±35%, 18±17%, 3±7%, 7±12%, 7±14%, 9±20%, 6±16%, and 3±8% at 12 and 18 months, respectively, and at 12 and 18 months, blood/urine M protein or sFLC could not be detected
.

In 14 patients in the high-dose group, mean blood/urine M protein or sFLC levels at 2, 4, 8, 12, 16, 20 weeks, 6 months, and 9 months decreased to 27%±29%, 19%, 33%, 16%, ±43%, 16%, 43%, 4%, 4%, 4±±5%, 3%±4%, 2%±3%, 0%±0%, 1% ±3%, respectively
, and no blood/urine M protein or sFLC was detected at 12 months after transfusion.
suggesting that decreased levels of M protein or sFLC in the blood/urine are inversely correlated with C-CAR088 amplification (Figure 3F)

Serum IL-6 and IFN-γ levels are transiently elevated
within 30 days of transfusion.
The peak levels of IL-6 and IFN-γ tend to correlate with CRS severity (Figure 3G
).

conclusion

This study shows that C-CAR088 has good safety and high anti-tumor activity in patients with RRMM, and is a promising treatment option for RRMM, but it is still necessary to conduct large multicenter clinical trials to further confirm this
.

References

Xiaoyan Qu, Gang An, Weiwei Sui,et al.
Phase 1 study of C-CAR088, a novel humanized anti-BCMA CAR T-cell therapy in relapsed/refractory multiple myeloma.
J Immunother Cancer .
2022 Sep; 10(9):e005145.
doi: 10.
1136/jitc-2022-005145.

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