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Background While checkpoint immunotherapy has revolutionized cancer treatment, responses are observed only in a subset of patients. The finite capacity of a patient’s immune system to recognize tumor mutations as foreign antigens is a major factor limiting the benefit of approved immunotherapies. Diacylglycerol kinases alpha (DGKα) and zeta (DGKζ) are expressed in T cells and play key non-redundant roles modulating the intensity of T cell receptor (TCR) signalling. Through phosphorylation of the critical secondary messenger diacylglycerol (DAG) to form phosphatidic acid, DGKs act as intracellular checkpoints attenuating T cell activation, limiting recognition of tumor antigens. DGKα cooperates with DGKζ to regulate the levels of DAG, suggesting that dual DGKα/ζ inhibition would result in the maximal biologic effect. Preclinically, inhibition of DGKα with BAY2862789 increases T cell activation and resistance to immune suppression that is further elevated in conjunction with inhibition of DGKζ by BAY2965501, to levels above either monotherapy. This suggests that BAY2862789 has the potential to strengthen patient anti-tumor responses which could be further enhanced in combination with BAY2965501.Methods Monotherapy BAY2862789 treatment is currently under investigation in a FIH dose escalation study ( NCT05858164) evaluating safety, tolerability, pharmacokinetics, and pharmacodynamics. To assess the capacity of BAY2862789 to modulate a patient’s immune responses, changes in T cell activation were tracked in peripheral blood by flow cytometry and with ex vivo assays to measure TCR downstream ERK phosphorylation and cytokine production during treatment (n≥30). A Limited number of paired biopsies were also evaluated. Additionally, to understand if BAY2862789 exposure in patients was sufficient to observe effects of DGKα/ζ dual inhibition, DGKζ inhibitor BAY2965501 was spiked into ex vivo assays to compare changes on treatment to baseline.Results BAY2862789 was able to achieve blood exposure above preclinically defined EC80, however, no consistent increase >2-fold from baseline was observed in ERK phosphorylation or cytokine production. Despite this, a low frequency of patients did display T cell activation in situ (>2-fold increases in Ki67+), suggesting potential pharmacologic activity. Accordingly, ex vivo assays performed on a subset of patients (n=>10), including the addition of BAY2965501, demonstrated synergistic elevation in IFNγ and IL2 production on-treatment compared to baseline.Conclusions Specific inhibition of DGKα by BAY2862789 alone does not lead to substantial immune modulation in patients, despite reaching sufficient exposure to synergize with BAY2965501 in ex vivo assays. Data suggests that BAY2862789 should be combined with DGKζ inhibition to achieve the greatest T cell activation in patients.