Background PD1+ CD38+ CD8 T-Cells have been shown to be induced during α-PD1 treatment, and show an inverse correlation with therapeutic response in melanoma patients. Additionally, Two Clinical trials have recently investigated the potential of α-CD38 to enhance PD1/PDL-1 blockade therapy in a variety of solid tumors based on the potential of CD38 to contribute to adenosine signaling mediated inhibition of T cells, or the potential of tumors to increase CD38 expression following PD1/PD-L1 blockade. Both NCT03367819 and NCT03637764 utilized isatuximab (α-CD38) on a continuous schedule (every week for 3 weeks followed by once every 3 weeks). Both trials confirmed that while CD38+ immune cells were cleared from the TME, there was no effect on Clinical outcomes.
Methods Briefly, 70,000 TC-1 tumor cells were injected subcutaneously to C57BL/6 mice, vaccine was be administered 10 days post inoculation and CD38 treatments was scheduled around this time. Mice were randomized to receiving a Single α-CD38 dose, or repeated α-CD38 (w/α-PD1 every three days) or appropriate single and double agent controls. Tumor response was monitored for these groups and day 27 was selected for Immune profiling. Abundance and phenotypic analysis of tumor infiltrating lymphocytes, splenocytes, and PBMC was distinguished by CyTOF. In order to confirm these results, tumor volume, survival, and immunological analysis was repeated in B16 tumor model and key markers were confirmed via flow cytometry.
Results Our data demonstrated that a single dose of α-CD38 reversed resistance while continuous dosing failed to change tumor or survival outcomes which is consistent with the result obtained from clinical trial data. This data is encouraging for clinical translatability as together it demonstrates the potential of this combination, regardless of type of resistance, when dosed properly. Immunological analysis revealed an increase in activated CD8 T cells in blood and TME in multiple tumor models in single dose α-CD38 therapy but not in continuous α-CD38 dosing.
Conclusions α-CD38 combination therapy has the ability to reduce tumor volume and improve survival in α-PD1 resistant murine models, and increase functional CD8 and CD4 T cells in the TME in multiple tumor models. In addition, we replicate the failure of recent clinical trials attempting this combination as a consequence of prolonged CD38 depletion resulting in reversal of aforementioned functional immune response. Future clinical trials should take into account dosing strategies that avoid prolonged α-CD38 administration.
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