Background: Invariant natural killer T-cells (iNKTs) share features of NK-like cells and T-cells, playing a role in both innate and adaptive immune responses. The importance of this relatively rare lymphocyte subset has generated interest due to its dual ability to have a direct cytotoxic effect on CD1d expressing tumors as well as to induce long-lasting antitumor CD8 T cell responses mediated by cross-priming and licensing of dendritic cells. While many current clinical approaches involve the use of allogeneic iNKT cells, here we describe initial clinical studies with IMM60, a synthetically derived agonist of iNKT cells formulated in a liposome (PORT-2). In preclinical studies, IMM60 treatment results in maturation of DCs and B cells and a potent stimulation of iNKT cell-derived IFN-g. In murine efficacy studies, IMM60 demonstrated monotherapy activity in multiple PD-1 resistant models (e.g., B16-F10), as well as upregulation of PD-L1 expression on cancer cells and re-sensitization to PD-1 inhibition. Methods: The IMPORT-201 trial is a multicenter, international expansion of an open-label first-in-human phase I/II investigator initiated study (IMP-MEL). Ph 1 is currently enrolling patients with NSCLC or melanoma. IMM60-containing liposomes are administered IV Q3W at 3 escalating dose levels for 6 doses as monotherapy or with pembrolizumab 200mg Q3W. The Ph I portion of the study seeks to establish the recommended Ph 2 dose of IMM60 alone and in combination with pembrolizumab. The Ph 2 evaluates IMM60 monotherapy, PD-1 monotherapy, and the combination. Results: Eight patients with melanoma (n=4) or NSCLC (n=4) have been enrolled in the IMM60 monotherapy dose cohorts. These patients were heavily pretreated, having a median of 3.5 prior therapies (range 2-7). One patient with NSCLC has been enrolled to the IMM60 + pembrolizumab combination cohort. IMM60 was well tolerated with no treatment-related SAEs or G3-5 AEs, and no MTD was determined. The most common related AE is G1-2 fatigue, reported in 2 patients. In the monotherapy cohort, a preliminary review of individual target lesions showed 2 lesions that completely resolved, 1 lesion with 69% decrease in size, 10 lesions that were stable, and 6 lesions with >20% increase in size. Serum biomarker analysis demonstrated evidence of iNKT and NK activation, as well as increases in dendritic and CD86+ B cells. Pharmacokinetics demonstrate dose proportionality with a terminal half-life of ~8 hours. Conclusions: IMM60 is well tolerated as monotherapy and in combination with pembrolizumab at the doses tested. These data show that a single agent iNKT agonist can be safely administered in a heavily pre-treated population and initiate immune activation. The combination with pembrolizumab is ongoing, and updated results of the Ph 1 portion of the study will be reported. Clinical trial information: NCT05709821.