Pre-sensitization of Malignant B Cells Through Venetoclax Significantly Improves the Cytotoxic Efficacy of CD19.CAR-T Cells

Abstract

Chimeric antigen receptor (CAR) T cell therapy has shown promising responses in patients with refractory or relapsed aggressive B-cell malignancies that are resistant to conventional chemotherapy or stem cell transplantation. A potentially combinatorial therapeutic strategy may be the inhibition of anti-apoptotic Bcl-2 family proteins, overexpressed in most cancer cells. In this study we investigated the combination of 3rd-generation CD19.CAR-T cells and the BH3 mimetics venetoclax, a Bcl-2 inhibitor, or S63845, a Mcl-1 inhibitor, under three different treatment conditions: pre-sensitization of cancer cells with BH3 mimetics followed by CAR-T cell treatment, simultaneous combination therapy, and the administration of BH3 mimetics after CAR-T cell treatment. Our results showed that administration of CAR-T cells and BH3 mimetics had a significant effect on the quantity and quality of CD19.CAR-T cells. The administration of BH3 mimetics prior to CAR-T cell therapy exerted an enhanced cytotoxic efficacy by upregulating the CD19 expression and pro-apoptotic proteins in highly sensitive tumor cells, and thereby improving both CD19.CAR-T cell cytotoxicity and persistence. In simultaneous and post-treatment approaches, however, the quantity of CAR-T cells was adversely affected. Our findings indicate pre-sensitization of highly sensitive tumor cells with BH3 mimetics could enhance the cytotoxic efficacy of CAR-T cell treatment.

Pediatric multicellular tumor spheroid models illustrate a therapeutic potential by combining BH3 mimetics with Natural Killer (NK) cell-based immunotherapy

“…Thereby, we provide the first report showing that BH3 mimetics may synergize with NK cell-based immunotherapy. In a similar approach, it has recently been shown that the BH3 mimetics ABT-737, ABT-199, and S63845 synergized with CAR-T cells to kill malignant B cells [ 47 , 48 ]. Our study demonstrates that BH3 mimetics may synergize with allogeneic activated NK cells to kill solid tumor spheroids.…”

Transcriptome Characterization of Short Distance Transport Stress in Beef Cattle Blood

“…The other hub genes were associated with the function of immune, differentiation, proliferation, survival, and apoptosis. Combing with the results of GO and KEGG enrichment, the function of hub genes was centered around B cell function ( Hu et al, 2018 ; Gazon et al, 2018 ; Karin and Razon, 2018 ; Tokunaga et al, 2018 ; Xiao et al, 2019 ; Huang et al, 2020 ; Yang et al, 2020 ). Considering fold change of qPCR was easier to detect in practical production and the gene function of B cell receptor signal pathway, SMC3 , JUN and CXCL10 could be suggested as molecular markers in transportation stress.…”

Born to survive: how cancer cells resist CAR T cell therapy

“…In a coculture model containing B-ALL and CD19 CAR T cells, Bcl-2 inhibition decreased the apoptosis threshold in leukemic cells leading to an enhanced CAR T cell cytotoxicity [ 86 ]. Moreover, in vitro pre-sensitization of B-ALL cells with the Bcl-2 inhibitor venetoclax resulted in an enhanced CAR T cell mediated cytotoxicity by upregulating the CD19 expression and pro-apoptotic proteins [ 87 ]. However, these strategies are yet to be tested in clinic.…”