A first patient has been dosed with a novel, allogeneic, off-the-shelf, invariant natural killer T (iNKT) cell therapy to treat cancer and other immune-mediated diseases. In an open-label phase I study, patients with solid tumors are receiving the investigational therapy, called AgenT-797, alone or in combination with approved anti-PD-1 checkpoint inhibitors. The study will enroll approximately 30 patients.

The drug is being developed by MiNK Therapeutics, Agenus’s cell therapy subsidiary.

Invariant natural killer T (iNKT)-cells are an innate-like T-cell subset that expresses an invariant T-cell receptor (TCR) α-chain and recognizes lipids presented on CD1d.  They have a dual mechanism of action with an internal targeting and homing device (iTCR) that modulates both arms of immunity, NK cells (innate immunity), and T-cells (adaptive immunity). This unique feature combines the killing features of natural killer (NK) cells with the durable memory response of T-cells. [1]

iNKT-cells secrete diverse cytokines and can influence many types of immune responses. Despite having highly similar TCR specificities, iNKT cells differentiate in the thymus into distinct subsets that are analogous to T helper 1 (TH1), TH2, and TH17 cell subsets.[1]

Jennifer Buell, Ph.D., President and Chief Executive Officer of MiNK Therapeutics. Photo Courtesy: © 2018 – 2022. MiNK Therapeutics. Used with permission.

iNKTs naturally home to tissues, promote tumor killing, viral clearance, suppress inflammatory cytokines, and naturally suppress GvHD.

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In pre-clinical studies, iNKT cells have been demonstrated to be highly effective in treating solid tumor cancers in their native form. Scientists at MiNK Therapeutics have demonstrated that these cells can be further engineered or edited for super-targeting.

Preclinical studies
Data from preclinical studies have demonstrated that MiNK’s iNKTs can penetrate tissues, giving them a critical advantage in targeting solid tumors not currently served by approved cell therapies. The same data also showed that the combination of checkpoint antibodies and iNKT cell triggering therapy shows curative potential in cancer models that are refractory to available therapies.

“This is the first study to evaluate the use of native, allogeneic iNKTs in combination with approved checkpoint inhibitors in patients with solid tumor cancers,” said Jennifer Buell, Ph.D., President and Chief Executive Officer of MiNK.

iNKT Cells for Anti-Cancer Immunity Tumor lysis via TCR dependent and independent mechanisms • CD1d ligands through the TCR • Stress-signals through activating NK receptors, NKG2D, DNAM1 • Counteracts myeloid suppressor cells • Recruits and activates NK & T cells • Cytokine secretion (e.g. IFNg, IL-4). Image courtesy: © 2018 – 2022. MiNK Therapeutics. Used with permission.

“The favorable safety profile and encouraging signals of early clinical activity demonstrated to date, paired with our preclinical data showing tumor eradication when AgenT-797 is combined with standard of care checkpoint antibodies, underscore the potential of this therapy in solid tumor cancers.”

Ongoing studies
In the ongoing clinical trials, it has been demonstrated that AgenT-797 can be administered tolerably in up to 1 billion cells per dose without lymphodepletion, with no evidence of cytokine release syndrome or neurotoxicity. Pre-clinical data has demonstrated the persistence, trafficking, and anti-cancer activity of AgenT-797, in both solid and liquid cancers.

This phase 1 study is evaluating the safety, tolerability, and preliminary clinical activity of AgenT-797, an unmodified, allogeneic iNKT cell therapy, alone and in combination with approved immune checkpoint inhibitors in patients with relapsed/refractory solid tumors

Clinical trials
A Study Investigating agenT-797 in Participants With Relapsed/Refractory Solid Tumors – NCT05108623
AGENT-797 in Participants With Relapsed/Refractory Multiple Myeloma – NCT04754100
An Experiment to Evaluate the Safety of agenT-797 in COVID-19 Patients With Severe Difficulty Breathing – NCT04582201

[1] Crosby CM, Kronenberg M. Tissue-specific functions of invariant natural killer T cells. Nat Rev Immunol. 2018 Sep;18(9):559-574. doi: 10.1038/s41577-018-0034-2. PMID: 29967365; PMCID: PMC6343475.

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