Therapeutic vaccination with 4-1BB co-stimulation eradicates mouse acute myeloid leukemia

Oncoimmunology. 2018 Jul 26;7(10):e1486952. doi: 10.1080/2162402X.2018.1486952. eCollection 2018.

Abstract

Immunomodulatory therapies can effectively control haematological malignancies. Previously we reported the effectiveness of combination immunotherapies that centre on 4-1BB-targeted co-stimulation of CD8 + T cells, particularly when simultaneously harnessing the immune adjuvant properties of Natural Killer T (NKT) cells. The objective of this study was to assess the effectiveness of agonistic anti-4-1BB antibody-based combination therapy against two aggressive forms of acute myeloid leukemia (AML). Anti-4-1BB treatment alone resulted in transient suppression of established AML-ETO9a tumor growth in 50% of mice, however the majority of these mice subsequently succumbed to disease. Combining alpha-galactosylceramide (α-GalCer)-loaded tumor cell vaccination with anti-4-1BB antibody treatment increased the proportion of responding mice to 100%, and protection led to long-term, tumor-free survival, demonstrating complete eradication of AML. This finding was extended to established mixed lymphocytic leukemia (MLL)-AF9 tumors, whereby vaccine plus anti-4-1BB combination similarly resulted in 100% protection. The addition of anti-PD-1 to anti-4-1BB treatment, although improving survival outcomes compared to anti-4-1BB alone, was not as effective as NKT cell vaccination. The effectiveness of 4-1BB combination therapies was dependent on IFN-γ signaling within host cells, but not tumors. Vaccine plus anti-4-1BB therapy elicited potent generation of functional effector and memory CD8 + T cells in all tumor-associated organs. Therapy induced KLRG1+ effector CD8 T cells were the most effective at controlling disease. We show that combining NKT cell-targeting vaccination with anti-4-1BB provides excellent therapeutic responses against AML and MLL in mice, and these results will guide ongoing efforts in finding immunotherapeutic solutions against acute myeloid leukemias.

Keywords: Acute myeloid leukemia; CD8 T cells; NKT cells; alpha-galactosylceramide; anti-4-1BB; anti-PD-1; cancer vaccine; immunotherapy; mixed lineage leukemia; monoclonal antibody.

Publication types

  • Research Support, Non-U.S. Gov't

Grant support

This work was supported by Project Grant (APP1044355) from the National Health and Medical Research Council (NHMRC) of Australia. TK and M.D.N were supported by an Australian Government Research Training Program (RTP) Scholarship. PL was supported by a University of Queensland International Scholarship. S.R.M. was supported by an NHMRC Career Development Fellowship (APP1061429).