Preclinical Rationale for Targeting the PD-1/PD-L1 Axis in Combination with a CD38 Antibody in Multiple Myeloma and Other CD38-Positive Malignancies.

Simple Summary The CD38-targeting antibody daratumumab mediates its anti-myeloma activities not only through direct effects on tumor cells, but also by its effects on T-cell immunity through depletion of CD38(+) immune suppressor cells. We hypothesized that combining daratumumab with modulators of other potent immune inhibitory pathways, such as the PD-1/PD-L1 axis, may further improve its efficacy. We show that during MM progression there is increased expression of the PD-1/PD-L1 pathway components in the bone marrow microenvironment. Although nivolumab (a PD-1 checkpoint inhibitor) moderately increased T-cell frequencies in ex vivo experiments with bone marrow samples from MM patients, no single agent activity was observed, and addition of nivolumab did not enhance the activity of daratumumab in these short-term assays. However, with a longer treatment duration, in mouse experiments, we demonstrate that anti-CD38 and anti-PD-1 antibodies synergize to eradicate MM cells. In addition, our results suggest that this combined immunotherapeutic approach may also be beneficial in other CD38-positive malignancies. The CD38-targeting antibody daratumumab mediates its anti-myeloma activities not only through Fc-receptor-dependent effector mechanisms, but also by its effects on T-cell immunity through depletion of CD38(+) regulatory T-cells, regulatory B-cells, and myeloid-derived suppressor cells. Therefore, combining daratumumab with modulators of other potent immune inhibitory pathways, such as the PD-1/PD-L1 axis, may further improve its efficacy. We show that multiple myeloma (MM) cells from relapsed/refractory patients have increased expression of PD-L1, compared to newly diagnosed patients. Furthermore, PD-1 is upregulated on T-cells from both newly diagnosed and relapsed/refractory MM patients, compared to healthy controls. In short-term experiments with bone marrow samples from MM patients, daratumumab-mediated lysis was mainly associated with the MM cells' CD38 expression levels and the effector (NK-cells/monocytes/T-cells)-to-target ratio, but not with the PD-L1 expression levels or PD-1(+) T-cell frequencies. Although PD-1 blockade with nivolumab did not affect MM cell viability or enhanced daratumumab-mediated lysis in short-term ex vivo experiments, nivolumab resulted in a mild but clear increase in T-cell numbers. Moreover, with a longer treatment duration, PD-1 blockade markedly improved anti-CD38 antibody-mediated cytotoxicity in vivo in murine CD38(+) tumor models. In conclusion, dual targeting of CD38 and PD-1 may represent a promising strategy for treating MM and other CD38-positive malignancies.