talacotuzumab (JNJ-56022473)

We used the known co-crystal structure of CD123 bound to the mAb CSL362 (talacotuzumab) for computer-aided protein engineering...Variant IL-3 receptor engineered HSPC's and paired immunotherapies could enable novel and targeted therapeutic interventions post HSCT to either treat minimal residual disease or be used as a salvage therapy. Such approaches could expand the therapeutic window and broaden indications and applications for targeted immunotherapies for various malignant and benign conditions.

Here, we develop third-generation anti-CD123 CAR T cells with a humanized CSL362-based ScFv and a CD28-OX40-CD3ζ intracellular signaling domain...CD123 expression on leukemia cells increases upon 5'-Azacitidine (AZA) treatment...Functionally, the CTLA-4 anti-CD123 CAR T cells exhibit superior cytotoxicity against AML cells, accompanied by higher TNFα production and enhanced downstream phosphorylation of key T cell activation molecules. Our findings indicate that AZA increases the immunogenicity of AML cells, enhancing recognition and elimination of malignant cells by highly efficient CTLA-4 anti-CD123 CAR T cells.

Median (95% CI) OS was 5.36 (4.27-7.95) months for combination therapy versus 7.26 (6.47-8.64) months for decitabine alone (hazard ratio: 1.04; 95% CI: 0.79-1.37; p = 0.78). Combination therapy showed no improvement in efficacy versus decitabine alone, resulting in the Independent Data Monitoring Committee's recommendation of early termination of enrollment and discontinuation of talacotuzumab treatment.

Chimeric antigen receptor T-cells (CAR Tc) have yielded impressive remission rates in treatment-refractory B-cell malignancies (B-ALL and B-lymphomas) by targeting CD19, resulting in the first FDA approved CAR Tc therapies, Kymriah and Yescarta...The anti-CD123 CAR was constructed with the humanized CSL362-based ScFv and the CD28-OX40-CD3ζ signaling domain, encoded in a third-generation lentiviral vector and expressed in CD3+ Tc from healthy donors...This is the first demonstration that HMAs and CAR Tc immunotherapy can be used synergistically to treat AML. Considering HMAs are currently under clinical investigation in AML, our data encourage further clinical evaluation of this dual treatment in r/r AML, including high-risk patients that are chemotherapy or allogeneic transplantation ineligible.