First-in-Human Trial Shows Synthetic Immune Cell Activator IMM60 Is Safe in Advanced Cancer

A first-in-human clinical trial has delivered the earliest glimpse of how a next-generation immune-activating drug behaves in the bodies of patients with advanced cancer, and the results suggest the approach is both safe and biologically active. The study, known as IMP-MEL, tested a synthetic compound called IMM60, delivered in microscopic fatty bubbles called liposomes, in people with advanced melanoma and non-small cell lung cancer who had already been through standard treatments. Published in the Journal of Translational Medicine, the phase I trial was designed primarily to establish safety, but it also captured molecular fingerprints showing that the drug did exactly what its designers hoped: it switched on a rare but powerful population of immune cells known as invariant natural killer T cells, or iNKT cells.

The science behind IMM60 begins with a molecule that has fascinated immunologists for decades. Alpha-galactosylceramide, a lipid originally isolated from a marine sponge, is the archetypal activator of iNKT cells. These cells occupy a peculiar niche in the immune system: they carry an invariant T cell receptor, a fixed molecular sensor that recognizes lipid fragments displayed by a specialized presenting molecule called CD1d. When the right lipid locks into CD1d and engages the iNKT cell receptor, the result is a rapid, coordinated burst of immune activity. Unlike conventional T cells, which need weeks to expand and specialize against a new threat, iNKT cells respond within hours, releasing signaling proteins that recruit and energize other immune players, including cells that kill tumors directly.

Alpha-galactosylceramide itself, however, has proved awkward as a drug. It is chemically unstable, difficult to formulate, and its potency fades during storage and in the bloodstream. IMM60 was engineered to be a more robust cousin: a synthetic lipid agonist with enhanced potency and stability, encapsulated within liposomes to protect it from degradation and deliver it efficiently to the CD1d presentation machinery. The idea is that a stable, liposomal formulation could finally translate the dramatic immune activation seen in laboratory studies into a therapy that works reliably in patients, potentially priming tumors for attack by the immune system and working hand in hand with existing immunotherapies.

The IMP-MEL trial enrolled fifteen patients with advanced melanoma or non-small cell lung cancer, and fourteen of them received treatment, six with melanoma and eight with lung cancer. Together they received sixty-six infusions of liposomal IMM60, with a median of five infusions per patient and a range of two to six. Some patients received the drug on its own, while others received it in combination with pembrolizumab, an antibody that blocks the PD-1 checkpoint and is already a mainstay of immunotherapy for both tumor types. The combination strategy rests on a simple logic: IMM60 sounds the immune alarm, while pembrolizumab removes the molecular brakes that tumors use to silence the responding cells.

Safety was the trial’s central question, and the answer was reassuring. No dose-limiting toxicities were observed at any of the doses tested, and the study did not need to define a maximum tolerated dose, the ceiling that phase I trials exist to find. Treatment-related adverse events did occur, affecting ten of the fourteen treated patients, or seventy-one percent, but every one of them was graded as mild or moderate, meaning grade one or two on the standard toxicity scale, and all were self-limiting. For a drug designed to deliberately provoke the immune system, the absence of severe inflammatory side effects is a notable achievement, since excessive immune activation has derailed many immunotherapy candidates before them.

The pharmacokinetic data, which track how the drug moves through the body, showed clean, predictable behavior. Exposure increased in proportion to dose, with the maximum plasma concentration showing a strong linear fit across dose levels, and the drug lingered in circulation with a mean residence time of about seven hours. That predictability matters enormously for a first-in-human agent, because it means clinicians can anticipate how the body will handle each dose rather than contending with erratic spikes or unexpected accumulation. The liposomal delivery appears to have tamed a molecule that, in its earlier form, was notoriously difficult to manage pharmacologically.

More important than how the drug circulated was whether it engaged its biological target, and here the trial provided direct molecular evidence. Within twenty-four hours of infusion, the researchers observed downregulation of the iNKT cell T cell receptor on the surface of circulating cells, a well-recognized sign that the cells have encountered their target ligand and internalized their sensor, confirming that IMM60 reached and stimulated its intended audience in living patients. Alongside this, the drug triggered a measurable wave of chemokines, the signaling molecules that guide immune cells to sites of inflammation and tumors. Monocyte chemoattractant protein-1, known as MCP-1 or CCL2, peaked at twenty-four hours with a geometric mean fold-change of 4.2 times baseline, a statistically significant rise. Interferon-gamma-inducible protein 10, or IP-10, rose faster, peaking at four hours with a 2.4-fold increase, also statistically significant.

Notably, the broad family of pro-inflammatory cytokines, the molecules most associated with the dangerous systemic immune storms that can accompany overzealous immunotherapy, showed no consistent elevation over baseline. This pattern, a targeted rise in chemokines that recruit immune cells without a indiscriminate inflammatory surge, is precisely the profile a rational iNKT agonist should produce. It suggests the drug can orchestrate immune traffic toward tumors while sparing patients the collateral damage of systemic inflammation, a balance that has been the holy grail of this therapeutic class since alpha-galactosylceramide first entered human testing years ago.

On the clinical side, the trial was small and early-stage, so dramatic tumor shrinkage was never the realistic expectation, particularly in a population this heavily pretreated. Even so, the signals were encouraging. Stable disease was the best overall response in the majority of assessed patients, and when the investigators examined individual tumor lesions, they found reductions in thirty percent of the lesions evaluated. Among these was a patient with melanoma whose cancer had resisted both BRAF and MEK inhibitor targeted therapy and PD-1 checkpoint blockade, one of the hardest treatment scenarios in modern oncology. Median progression-free survival across the treated group was 2.9 months, a modest figure that nonetheless reflects the refractory nature of the disease in these patients and the fact that the trial’s dose-escalation design was built to find a safe dose, not to maximize efficacy.

The authors conclude that liposomal IMM60 is well tolerated, shows clear evidence of iNKT cell target engagement and early chemokine induction, and produced signs of disease control in heavily pretreated and PD-1-refractory patients, findings they say support further evaluation of the drug in combination with checkpoint inhibition. The trial, sponsored and funded by iOx Therapeutics and conducted at sites including the Churchill Hospital in Oxford and Hammersmith Hospital in London, was prospectively registered in January 2021. As with any phase I study, the road ahead is long: larger trials will need to determine whether the immune activation seen in blood tests translates into meaningful extension of survival, and which doses and schedules best combine IMM60 with checkpoint blockade. But for a therapeutic concept that has struggled for years to make the leap from laboratory promise to clinical reality, this first-in-human dataset offers something precious: proof that a next-generation iNKT agonist can be given safely to cancer patients, can be seen doing its molecular job, and may be stirring the immune system in tumors that have run out of options.

Subject of Research: A first-in-human phase I trial of the liposomal iNKT cell agonist IMM60 with or without pembrolizumab in advanced melanoma and non-small cell lung cancer

Article Title: IMP-MEL: a phase I first-in-human study of IMM60 with or without pembrolizumab in advanced melanoma and non-small cell lung cancer (NSCLC)

Article References: IMP-MEL: a phase I first-in-human study of IMM60 with or without pembrolizumab in advanced melanoma and non-small cell lung cancer (NSCLC). (n.d.). https://doi.org/10.1186/s12967-026-08980-8

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08980-8

Keywords: IMM60, iNKT cells, cancer immunotherapy, melanoma, non-small cell lung cancer, pembrolizumab, phase I trial, liposomal formulation, alpha-galactosylceramide, CD1d, checkpoint inhibitor, chemokines