Immunotransplant modulates the IL-2/7/15 axis and increases anti-cancer efficacy compared to checkpoint blockade or BMT alone
Netonia Marshall, PhD1, Keino Hutchinson1, Tom Marron, MD/PHD1, Mark Aleynick1, Ranjan Upadhyay1, Judith Agudo, PhD 1, Brian Brown, PhD 1, Joshua Brody, MD2
1Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, United States
The identification of immune checkpoints inhibitors CTLA-4 and PD-1 and the subsequent development of checkpoint blockade antibodies has revolutionized the field of cancer therapy. Checkpoint blockade therapy has been used to treat a wide array of cancers, such as melanoma, non-small cell lung carcinoma, renal cell cancer; checkpoint blockade, showing response rates from ~17-40%.
While these results are promising, the majority of patients do not respond to checkpoint blockade therapy; thus, there is a need to identify ways to increase the efficacy of checkpoint blockade therapy.
One approach to potently increase the anti-tumor potential of a T cell therapy is to combine the T-cell therapy with adoptive T-cell transfer into lymphodepleted recipients. Here, we have developed a novel therapy combining these approaches which we termed Immunotransplant. Immunotransplant is comprised of:
-treatment and priming of tumor-bearing host with anti-CTLA-4 and/or anti-PD-1 antibodies
-splenocyte harvest and transfer to lymphodepleted recipient
Whereas checkpoint blockade alone has minimal anti-tumor effect in the pre-clinical model, our results show that the combined therapy results in superior anti-tumor immunity as seen by increased production of tumor-reactive IFNγ positive NK and T-cells. We have shown this therapy can be used to treat a wide array of preclinical cancer models.
Mechanistic studies have revealed that Immunotransplant cures recipients in a CD8-, NK-, and IFNγ-dependent manner. Furthermore, we have demonstrated that T and NK cells exposed to checkpoint blockade and transfer into the lymphopenic host demonstrate greater:
-in vivo serum levels of IL-2/7/15 and surface expression levels of receptor IL-15RA, IL-15RB, and common gamma receptor
-in vitro STAT5 phosphorylation and proliferation in response to common gamma chain cytokines
This work has been translated to a Phase Ib/II trial for relapsed lymphoma. Ongoing studies aim to confirm the role of IL-2/7/15 and guide the development to optimize the anti-tumor immunity of Immunotransplant.