FDA approved CD38 monoclonal antibodies (mAb) daratumumab and isatuximab are used to treat MM in patients, and have been tested to treat other CD38 expressing malignancies...Here, we generated multiple CD38 scFv based on isatuximab sequences and generated fratricide-resistant primary CD38-CAR NK cells using CRISPR/Cas9 genome editing and AAV6 gene delivery...Finally, we investigated the need for a CD38KO to develop a fratricide-resistant therapy by comparing the cytolytic and metabolic functions of CD38+/AAVS1KO and CD38KO CD38-CAR NK cells. We conclusively report a CD38-CAR NK cell therapy with enhanced metabolism and cytotoxicity toward a variety of hematologic malignancies, which can be further augmented by combination treatment with ATRA to target CD38-low malignancies.
1 year ago
IO biomarker
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CD8 (cluster of differentiation 8) • CD38 (CD38 Molecule)
Anti-CD38 monoclonal antibodies increase efficacy when added to standard-of-care (SOC) regimens as reflected by minimal residual disease-negativity (MRD-neg) rates of >50 % after induction therapy in newly diagnosed MM (NDMM) patients treated with SOC plus isatuximab within the GMMG-HD7 trial (Goldschmidt et al...NDMM patients were treated with lenalidomide/bortezomib/dexamethasone (RVd) alone or in combination with isatuximab (isa-RVd, NCT03617731)...BME signatures at baseline and during treatment as defined by our reference atlas enable risk stratifications of MM patients and can identify patients at high risk for early relapse. Longitudinal monitoring of the BME can support clinical decision making, as a compromised CD8+ memory compartment in patients may impact on the efficacy of novel immunotherapies.
These updated results with longer follow-up of SC Isa administration via OBDS at the RP2D of 1400 mg showed a safety profile consistent with IV administration, with no IRs, excellent local tolerability and efficacy comparable to that observed in the phase 3 ICARIA study with IV Isa, in combination with Pd. Isa SC administration by OBDS is well tolerated, has a short duration of injection, and provides a convenient hands-free option with controlled delivery. Based on these results and OBDS performance, a non-inferiority phase 3 trial of Isa-SC with OBDS versus Isa-IV is ongoing (NCT05405166).