Abstract Text: The epichaperome is a tightly integrated protein network with critical roles in tumor-associated microenvironment and cancer cell survival. The epichaperome inhibitor PU-H71 is under development in clinical trials.
We tested the effects of PU-H71 on C57BL/6 mice responses to OVA. When administered at the time of priming, PU-H71 significantly increased the number of IFNγ-secreting T cells but had no effect once the OVA-specific T cell response was ongoing. PU-H71 improved in vivo anti-tumor immune responses in OVA-primed mice challenged with E.G7 (OVA+) but not EL4 parental cells (OVAneg).
Lethally-irradiated B6C3F1 mice received bone marrow and splenocytes from C57BL/6 mice and were treated with PU-H71 at first signs of GvHD. We found that PU-H71 did not aggravate GvHD.
We evidenced that epichaperome indeed forms in human CD19.4-1Bb.3z CAR-T cells upon activation. In vitro cytotoxicity of CAR-T cells toward NALM6 B-ALL cells was significantly improved by PU-H71. Finally, the therapeutic effect of the combination of PU-H71 and CAR-T cells was evaluated in NSG mice using NALM6-BLIV cells, with bioluminescence imaging and flow cytometry monitoring. PU-H71 administration increased CAR-T cell numbers in the bone marrow and improved their in vivo antileukemic efficacy against NALM6.
These results show that PU-H71 augments antigen-specific T cell responses during priming, such as CAR-T cell cytotoxicity, with little effect on ongoing immune responses, including GvHD. PU-H71 also has an adjuvant effect on anti-tumor T cell responses while not aggravating GvHD, supporting its clinical evaluation in the post-transplant setting or in combination with CAR-T cells.
