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Oncoimmunology. 2015 Jan 7;4(3):e990793. eCollection 2015.

NKT cell-targeted vaccination plus anti-4-1BB antibody generates persistent CD8 T cell immunity against B cell lymphoma.

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1
The University of Queensland Diamantina Institute; The University of Queensland; Translational Research Institute, Brisbane ; Queensland, Australia.

Abstract

Harnessing the immune adjuvant properties of natural killer T (NKT) cells is an effective strategy to generate anticancer immunity. The objective of this study was to increase the potency and durability of vaccine-induced immunity against B cell lymphoma by combining α-galactosylceramide (α-GalCer)-loaded tumor cell vaccination with an agonistic antibody targeting the immune checkpoint molecule 4-1BB (CD137). We observed potent synergy when combining vaccination and anti-4-1BB antibody treatment resulting in significantly enhanced survival of mice harboring Eμ-myc tumors, including complete eradication of lymphoma in over 50% of mice. Tumor-free survival required interferon γ (IFNγ)-dependent expansion of CD8+ T cells and was associated with 4-1BB-mediated differentiation of KLRG1+ effector CD8+ T cells. 'Cured' mice were also resistant to lymphoma re-challenge 80 days later indicating successful generation of immunological memory. Overall, our results demonstrate that therapeutic anticancer vaccination against B cell lymphoma using an NKT cell ligand can be boosted by subsequent co-stimulation through 4-1BB leading to a sustainable immune response that may enhance outcomes to conventional treatment.

KEYWORDS:

4–1BB; B cell lymphoma; CRs, complete responses; DPEC, double positive effector cells; EEC, early effector cells; KO, knock-out; MPEC, memory precursor effector cells; NKT cells; SLEC, short-lived effector cells; WT, wild-type.; cIg: isotype control immunoglobulin; cancer vaccine; hematological malignancies; immune checkpoint molecule; immunotherapy; mAb, monoclonal antibody; monoclonal antibody; α-GalCer, α-galactosylceramide; α-galactosylceramide

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