Genetic and pharmaceutical targeting of HIF1α allows combo-immunotherapy to boost graft vs. leukemia without exacerbation graft vs. host disease

Tipping the GVH/GVL balance by targeting HIF1α

“…evaluated HIF1α as a therapeutic target alone or in combination with ICI in the treatment of hematological malignancies after allo-HCT. 1 The clinical relevance of HIF1α in aGVHD pathogenesis was shown by elevated expression of HIF1α and its target genes in peripheral blood mononuclear cells (PBMCs) from the patients with aGVHD. By using genetic and pharmacologic approaches in clinically relevant murine and humanized GVH/GVL models, they convincingly demonstrated that targeted deletion of Hif1a in donor T cells or systemic inhibition of HIF1α with echinomycin significantly ameliorated GVHD and reduced mortality.…”

“…The other important finding is that targeting HIF1α allowed for anti-CTLA4 treatment to augment GVL effects without exacerbating GVHD. 1 While blocking CTLA4 exacerbated GVHD severity by increasing T cell infiltration in GVHD target organs, this adverse effect was largely abrogated when Hif1a was deficient in donor T cells or HIF1α was inhibited with echinomycin, which was likely attributed to elevated PD-L1 in these target organs, causing inhibition of the infiltrated donor T cells. On the other hand, blocking CTLA4 enhanced the expansion and activation of donor T cells presumably in hematologic and lymphatic compartments.…”

“…Such a discrepancy deserves further investigation and reconciliation, given that IFNγ/PD-L1 was demonstrated as a key pathway in regulating GVHD. 1 …”

“…demonstrates that targeting HIF1α confers GVHD protection without affecting GVL effect and that HIF1α inhibition allows ICI in combination with allo-HCT to improve therapeutic efficacy against hematologic malignances while limiting GVHD development. 1 …”

“…demonstrate that targeting HIF1α can favor GVL activity while limiting GVHD after allo-HCT even in combination with immune checkpoint inhibition. 1 …”