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745 IMP-MEL: a phase 1 first-in-human dose-finding study of a novel invariant natural killer T-cell agonist (iNKT) IMM60 in advanced melanoma and non-small-cell lung cancer (NSCLC)
  1. Nicholas Coupe1,
  2. Ian Walters2,
  3. Justin Fairchild2,
  4. Matthew Parkes3,
  5. David Thompson3,
  6. Robert Kramer2,
  7. Uzi Gileadi3 and
  8. Mark Middleton3
  1. 1Oxford University Hospitals, Oxford, UK
  2. 2Portage BioTech, Westport, CT, USA
  3. 3University of Oxford, Oxford, UK


Background Invariant natural killer T-cells (iNKTs) share features of innate cells (NK-like) and T-cells. The importance of this relatively rare lymphocyte subset has generated increased interest due to its dual ability to have a direct cytotoxic effect on CD1d-expressing tumors and its ability to induce long-lasting antitumor CD8 T-cell responses mediated by cross priming and licensing of dendritic cells. Various clinical approaches involving the use of allogeneic iNKT cells are in development; here we describe an initial clinical study with IMM60, a synthetically derived agonist of iNKT cells which is formulated in a liposome (PORT-2). In preclinical studies, IMM-60 treatment results in maturation of DCs and B cells and potent stimulation of iNKT cell-derived IFN-g. In efficacy studies, IMM60 demonstrated monotherapy activity in PD-1 resistant models, (e.g., B16-F10), and upregulation of PD-L1 expression on cancer cells as a consequence of its priming effect.

Methods IMP-MEL is an open-label first-in-human phase 1/2 study, currently enrolling adult subjects with advanced NSCLC and melanoma. IMM60-containing liposomes were administered IV Q3W at 3 escalating dose levels for 6 doses. The study seeks to assess the safety and efficacy of IMM-60 alone, as well as in combination with a PD-1 inhibitor. Pharmacodynamic analyses were performed, including circulating cytokines and flow cytometry.

Results Six patients with advanced melanoma (n=3) or NSCLC (n=3) have been enrolled in the monotherapy dose cohorts, having a median of 4.5 prior therapies (min 2, max 5). The drug was well tolerated with no treatment-related SAEs or Grade 3-5 adverse events to date. Cytokine analysis and flow cytometry of pre- and on-study blood samples revealed evidence of iNKT activation as well as NK and dendritic cell activation. [MP1] One patient achieved >50% reduction in select target and non-target lesions. The MTD has not been reached.

Conclusions This trial provides early proof of concept for using a small molecule iNKT agonist to promote both innate and adaptive immune responses. PORT-2 (liposomal IMM60) is well tolerated at 1 and 3 mg/m2. Pharmacodynamic measurements support a broad immune mechanism. Once the Phase 2 dose is defined the trial is designed to accrue six Phase 2 arms testing PORT-2 alone or combined with a PD-1 inhibitor, compared to PD-1 inhibitor monotherapy. Further data on pharmacokinetics and biopsy analyses will be presented.

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.

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