Combining CAR T cells and the Bcl-2 family apoptosis inhibitor ABT-737 for treating B-cell malignancy

Karlsson, S. C. HannahUppsala universitet,Science for Life Laboratory, SciLifeLab,Klinisk immunologi (författare)

B-cell malignancies upregulate the B-cell lymphoma 2 (Bcl-2) family inhibitors of the intrinsic apoptosis pathway, making them therapy resistant. However, small-molecule inhibitors of Bcl-2 family members such as ABT-737 restore a functional apoptosis pathway in cancer cells, and its oral analog ABT-263 (Navitoclax) has entered clinical trials. Gene engineered chimeric antigen receptor (CAR) T cells also show promise in B-cell malignancy, and as they induce apoptosis via the extrinsic pathway, we hypothesized that small-molecule inhibitors of the Bcl-2 family may potentiate the efficacy of CAR T cells by engaging both apoptosis pathways. CAR T cells targeting CD19 were generated from healthy donors as well as from pre-B-ALL (precursor-B acute lymphoblastic leukemia) patients and tested together with ABT-737 to evaluate apoptosis induction in five B-cell tumor cell lines. The CAR T cells were effective even if the cell lines exhibited different apoptosis resistance profiles, as shown by analyzing the expression of apoptosis inhibitors by PCR and western blot. When combining T-cell and ABT-737 therapy simultaneously, or with ABT-737 as a presensitizer, tumor cell apoptosis was significantly increased. In conclusion, the apoptosis inducer ABT-737 enhanced the efficacy of CAR T cells and could be an interesting drug candidate to potentiate T-cell therapy.

Lindqvist, A. C.Uppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab (författare)
Fransson, MoaUppsala universitet,Klinisk immunologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)moafr634 (författare)
Paul-Wetterberg, GabriellaUppsala universitet,Klinisk immunologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)gabrpaul (författare)
Nilsson, BoUppsala universitet,Klinisk immunologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)bonils (författare)
Essand, MagnusUppsala universitet,Klinisk immunologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)magnessa (författare)
Nilsson, KristinaUppsala universitet,Klinisk immunologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)krisnil (författare)
Frisk, PerUppsala universitet,Pediatrik(Swepub:uu)pefri226 (författare)
Jernberg-Wiklund, HelenaUppsala universitet,Hematologi och immunologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)helenajw (författare)
Loskog, S. I. A.Uppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab (författare)
Uppsala universitetScience for Life Laboratory, SciLifeLab (creator_code:org_t)

Ingår i:Cancer Gene Therapy: Springer Science and Business Media LLC20:7, s. 386-3930929-19031476-5500

Av författaren/redakt...: Karlsson, S. C. ...; Lindqvist, A. C.; Fransson, Moa; Paul-Wetterberg, ...; Nilsson, Bo; Essand, Magnus; visa fler...; Nilsson, Kristin ...; Frisk, Per; Jernberg-Wiklund ...; Loskog, S. I. A.; visa färre...

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