Cellular immunotherapy has traditionally centered on autologous, genetically engineered T-cell platforms, which—despite transformative efficacy in selected settings—are limited by toxicity, manufacturing complexity, and restricted patient eligibility. AgenT-797 represents a distinct immunotherapeutic strategy built on invariant natural killer T (iNKT) cell biology. AgenT-797 is an allogeneic, off-the-shelf cellular therapy designed to deliver coordinated antitumor immune activation with a reduced risk of cytokine release syndrome, neurotoxicity, and graft-versus-host disease.
The program is being developed by Agenus, with early clinical development focused on hematologic malignancies characterized by immune dysfunction, treatment resistance, and limited tolerance for highly toxic therapies.
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What Is AgenT-797?
AgenT-797 consists of ex vivo–expanded invariant natural killer T cells derived from healthy donors. Unlike conventional αβ T cells, iNKT cells express a semi-invariant T-cell receptor that recognizes lipid antigens presented by CD1d rather than peptide antigens presented by classical HLA molecules. This HLA-independent recognition enables safe allogeneic administration without genetic engineering and largely eliminates the risk of alloreactive expansion.
From a translational perspective, iNKT cells are uniquely suited to cancer therapy because they can exert both direct cytotoxic effects and broad immunomodulatory functions. These properties form the biological foundation for AgenT-797’s clinical development as a scalable, repeat-dose cellular immunotherapy.
Mechanism of Action and Immune Effects
Upon activation, iNKT cells rapidly secrete interferon-γ, tumor necrosis factor-α, and interleukin-2. This cytokine burst leads to downstream activation of natural killer cells, CD8-positive cytotoxic T lymphocytes, and dendritic cells, enhancing antigen presentation and amplifying antitumor immune responses.
Preclinical studies supporting AgenT-797 demonstrated increased NK-cell cytotoxicity, expansion of effector T-cell populations, and partial reversal of immunosuppressive features of the tumor microenvironment, including suppression mediated by regulatory T cells and myeloid-derived suppressor cells. These findings provide a rationale for both monotherapy use and combination strategies with immune checkpoint blockade or antibody-based therapies.
Clinical Uses in Cancer: Current Situations
AgenT-797 remains investigational and is not FDA-approved. Clinical development to date has focused primarily on relapsed or refractory hematologic malignancies, where patients often have limited therapeutic options and reduced tolerance for aggressive immune-activating treatments.
In this setting, AgenT-797 is being evaluated as a low-toxicity immune-activating therapy for patients who have progressed after multiple prior lines of treatment, including chemotherapy, targeted agents, and, in some cases, stem cell transplantation. Exploratory investigations in solid tumors are also being considered, particularly in scenarios characterized by immune exclusion or resistance to checkpoint inhibitors, where broad immune orchestration may be advantageous.
Dedicated Clinical Trials
Clinical evaluation of AgenT-797 has been conducted through early-phase studies designed to assess safety, feasibility, and immune activation in heavily pretreated populations.
The first-in-human Phase 1 clinical trial of AgenT-797 (registered on ClinicalTrials.gov as NCT04754100) evaluated intravenous administration of allogeneic iNKT cells in patients with relapsed or refractory hematologic malignancies. Eligible patients were adults with advanced blood cancers who had exhausted standard therapeutic options and were not candidates for curative therapy. Key inclusion criteria included adequate organ function, measurable or evaluable disease, and prior exposure to multiple lines of therapy. Exclusion criteria focused on uncontrolled infections, active autoimmune disease requiring systemic therapy, and conditions associated with high baseline risk for immune-related toxicity.
In this trial, AgenT-797 was administered using a dose-escalation design, with primary endpoints centered on safety, dose-limiting toxicities, and feasibility of repeat dosing. Secondary and exploratory endpoints included immune activation markers, cytokine profiles, and preliminary signals of antitumor activity. Early results demonstrated successful manufacturing and infusion of allogeneic iNKT cells, evidence of immune engagement, and an absence of dose-limiting toxicities, enabling exploration of repeat dosing schedules.
Additional ongoing and planned studies are evaluating AgenT-797 in similar relapsed or refractory hematologic malignancy settings, including multiple myeloma and acute myeloid leukemia, with continued emphasis on safety, immune modulation, and identification of biomarkers such as CD1d expression and NK-cell activation signatures. These trials are designed for patients who are unsuitable for CAR T-cell therapy due to age, comorbidities, prior toxicities, or lack of target antigen expression.
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Dosage and Administration
In clinical trials, AgenT-797 has been administered as an intravenous infusion without mandatory lymphodepleting chemotherapy. This distinguishes it from many autologous T-cell therapies and reduces treatment complexity. Dose selection has been guided by immune pharmacodynamic readouts and tolerability rather than by a conventional maximum tolerated dose framework.
The ability to administer repeat doses has been a key feature of the clinical program, reflecting the favorable safety profile and low immunogenicity observed in early studies. This repeat-dose potential supports investigation of AgenT-797 as a platform therapy rather than a one-time intervention.
Safety Profile and Side Effects
Safety has been a defining characteristic of AgenT-797 development. Across early-phase clinical trials, treatment-related adverse events have predominantly been low grade and transient.
Cytokine release syndrome has been uncommon and limited to mild cases, without progression to severe or life-threatening events. Importantly, no consistent signal of immune effector cell–associated neurotoxicity syndrome has been observed. Due to the invariant nature of the iNKT-cell receptor, graft-versus-host disease has not been reported, supporting the feasibility of allogeneic administration.
Other observed side effects have included transient infusion-related symptoms, fatigue, low-grade fever, and laboratory changes consistent with immune activation. No cumulative toxicity has been identified with repeat dosing in early studies.
Expectations and Future Directions
AgenT-797 represents a cellular immunotherapy strategy centered on immune coordination rather than single-antigen targeting. Its off-the-shelf availability, favorable safety profile, and repeat-dose feasibility position it as a potential option for patients who are not candidates for CAR T-cell therapy and as a partner for combination immunotherapy regimens.
Ongoing clinical development aims to refine patient selection, identify predictive biomarkers, and clarify the durability of immune effects. Combination strategies with immune checkpoint inhibitors and antibody-based therapies are of particular interest, given preclinical evidence of immune priming and tumor microenvironment modulation.
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Written by Armen Gevorgyan, MD