Therapeutic vaccination and immune checkpoint blockade regresses haematological and solid tumours respectively. Irradiated alpha-galactosylceramide-loaded tumour cells (vaccine) stimulate Natural Killer T cells, which also contribute to Natural Killer (NK) and T cell activation. We have shown that tumour vaccines induce effector CD8+ T cells in a Eμ-myc mouse model of B cell lymphoma, resulting in tumour suppression. Such vaccines can be greatly enhanced in the presence of co-stimulatory agents like anti-4-1BB. However, their therapeutic potential can be mitigated under conditions of immune exhaustion, suggesting that combinational therapies involving immune checkpoint blockade (e.g. PD-1) may increase anti-tumour efficacy. This study evaluated and determined the effectiveness of different therapies against acute myeloid leukemia.
Irradiated C57BL/6J female mice were inoculated with GFP-labelled AML-ETO9a-expressing tumours. Mice received a vaccine, anti-PD-1, anti-4-1BB or in combination with the vaccine or anti-PD-1; and CD8b and NK cell depleting antibodies followed by flow cytometric analysis. Mice exhibited the following tumour levels 50 days post-tumour inoculation (PI): (a) control group, 13/13 mice (83.16±2.3% tumour); (b) vaccinated, 7/9 (6.02±3.1%), 2/9 (85.02±4.2%); (c) anti-4-1BB, 7/13 (0.91±0.8%), 6/13 (88.40±3.1%); (d) anti-PD-1 (day 36 PI), 7/7 (control-61.44±7.1%; 63.81±4.7%); (e) anti-PD-1+anti-4-1BB (variable); and (f) vaccine+anti-4-1BB, 9/9 (0.11%±0.03%).
Anti-PD1 had no effect, and the results from anti-PD1+anti-4-1BB therapy varied between experiments. The vaccine or anti-4-1BB alone suppressed tumour growth with relapses in some mice. Interestingly, vaccine+anti-4-1BB therapy eradicated the tumour with 100% mouse survival. This therapy strongly elicited CD8+ T cells, with a decline in NK cells. Unexpectedly, modest (5.06±3.8%) and significant (45.62±17.3%) tumour rebound was reported in CD8b and NK cell depleted mice, respectively; suggesting that the effectiveness of CD8+ T cells is largely NK cell dependent. We reveal potent therapeutic strategies for AML, and these results will be invaluable to the efforts needed in finding treatments against haematological malignancies.