Immunomodulators are effective in controlling haematological malignancy by initiating host anti-tumor immunity to otherwise poorly immunogenic and immune suppressive cancers. We aimed to boost anti-tumor immunity against B cell lymphoms by developing a tumor cell vaccine incorporating alpha-galactosylceramide (α-GalCer) that targets the immune adjuvant properties of NKT cells. In the Eµ-myc transgenic mouse model, single therapeutic vaccination using irradiated, α-GalCer-loaded autologous tumor cells was sufficient to significantly inhibit growth of established tumors and prolong survival. Vaccine-induced anti-lymphoma immunity required early activation and peripheral expansion of NKT cells and NK cells, leading to IL-12-dependent production of IFN-gamma, an important effector cytokine in this response. CD8 T cells were also important for therapeutic efficacy, however there was no evidence for prolonged CD8 T cell activation or memory formation with vaccination alone. An increase in expression of the immune checkpoint molecule 4-1BB (CD137) on CD8 T cells following vaccination provided strong rationale for combining the vaccine with an agonistic monoclonal antibody (mAb) targeting 4-1BB. We observed potent synergy with vaccine + anti-4-1BB mAb treatment combination resulting in significantly enhanced survival of mice harbouring Eµ-myc tumors, including durable complete responses in over 50% of mice. Elimination of lymphoma burden was associated with increased numbers and persistence of KLRG1+ CD8 T cell effector subsets upon combination treatment. ‘Cured’ mice were also resistant to lymphoma re-challenge 80 days later indicating effective immunological memory formation. Overall, our results demonstrate a potent immune adjuvant effect of an NKT cell ligand in therapeutic anti-cancer vaccination against B cell lymphomas, which can be boosted by antibody-mediated signalling through the immune checkpoint molecule 4-1BB in CD8 T cells. Outcomes from assessing the therapeutic benefit of this multipronged immunotherapeutic strategy in pre-clinical mouse models will provide the evidence for future clinical studies in patients with treatment-resistant B cell lymphomas and other haematological malignancies.