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 inserted into the shell of a liposome (PORT-2). In preclinical studies, IMM60 treatment results in maturation of DCs and B cells and potent stimulation of iNKT cell-derived IFN-g. In murine efficacy studies, IMM60 demonstrated monotherapy activity in multiple PD-1 resistant models, 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). Ph1 is currently enrolling patients with NSCLC or melanoma. IMM60-containing liposomes are administered IV Q3W at escalating dose levels as monotherapy or with pembrolizumab 200mg Q3W. Cohorts of 1, 3 and 9 mg/m² have been enrolled, and the study is being amended to add a fixed 36 mg dose cohort. Once a recommended Ph2 dose is established, Ph2 will evaluate PORT-2 monotherapy, PD-1 monotherapy, and the combination. Flow cytometry and pharmacokinetic analyses have been performed in Ph1.

Results Twelve patients with melanoma (n=6) or NSCLC (n=6) have been enrolled in the IMM60 monotherapy dose cohorts. These patients were heavily pretreated (median = 4 prior therapies; range 2–7). One patient with NSCLC has been enrolled to the IMM60 + pembrolizumab cohort. IMM60 was well-tolerated with no treatment-related SAEs or G3–5 AEs; no MTD was determined. The majority of related AEs have been G1, with the only related G2 events being hypertension and fatigue. Reduction in the size of target lesions has been observed and updated efficacy results will be presented. Results of flow cytometry analyses will be presented along with the PK profile for IMM60.

Conclusions PORT-2 is well tolerated 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. Combination with pembrolizumab is ongoing, and updated Ph1 results, along with PK and pharmacodynamic analyses, will be reported.

Trial Registration ClinicalTrials.gov: NCT05709821

Ethics Approval This University of Oxford study has received ethical approval by a UK Research Ethics Committee, approval number 20/SC/0367. All participants provided informed consent before taking part in this clinical trial.