Agenus highlights durable survival and immune reprogramming in PD-1 refractory gastroesophageal cancer with Botensilimab combo
Agenus Inc., a company focused on advancing immuno-oncology innovation, has reported new clinical findings from an investigator-initiated Phase II study evaluating a multi-agent immunotherapy-based regimen in patients with advanced gastroesophageal adenocarcinoma who have progressed after prior PD-1 inhibitor treatment. The data, presented at the American Association for Cancer Research Annual Meeting 2026 held in San Diego, highlight the potential of combining botensilimab (BOT), balstilimab (BAL), and agenT-797—an allogeneic invariant natural killer T (iNKT) cell therapy developed by MiNK Therapeutics—alongside ramucirumab and paclitaxel, to improve disease control and survival outcomes in a patient population with significant unmet medical need.
The study was conducted at Memorial Sloan Kettering Cancer Center and represents the first clinical investigation to evaluate this specific combination in patients with gastroesophageal cancer who are refractory to PD-1 inhibitors. These patients typically face poor prognoses and limited therapeutic options, making the development of novel strategies critically important.
Gastroesophageal adenocarcinoma is a challenging malignancy, particularly in advanced stages. While immune checkpoint inhibitors targeting PD-1 have transformed treatment paradigms in several cancers, a substantial proportion of patients either do not respond or eventually develop resistance. Once resistance occurs, treatment options are limited, and outcomes are often poor. The Phase II trial led by Agenus sought to address this gap by exploring whether a combination of immune-modulating agents, including cellular therapy, could overcome resistance and enhance anti-tumor responses.
The trial enrolled 17 patients and was designed not only to evaluate efficacy but also to investigate the role of immune priming and treatment sequencing. Patients were assigned to different treatment approaches: some received an induction phase with agenT-797 alone or in combination with BOT and BAL, followed by the full regimen, while others initiated treatment directly with the full combination without induction. This design allowed researchers to assess whether priming the immune system before administering the complete regimen could improve clinical outcomes.
The results demonstrated encouraging signals of efficacy, particularly in terms of disease control and survival. Across the entire study population, the disease control rate (DCR) reached 77 percent, indicating that a majority of patients experienced either tumor shrinkage or disease stabilization. Additionally, a subset of patients achieved long-term survival extending beyond 20 months, a notable outcome in this heavily pretreated population.
One of the most striking findings from the study was the apparent benefit of the induction strategy. Patients who received an induction cycle exhibited significantly improved progression-free survival (PFS) compared to those who did not. Median PFS was 6.9 months in the induction cohort versus 3.5 months in the non-induction group, corresponding to a hazard ratio of 0.19 and a statistically significant p-value of 0.015. These results suggest that immune priming may play a critical role in enhancing the effectiveness of subsequent combination therapy.
Overall survival (OS) outcomes further supported the potential value of the induction approach. Patients in the induction cohort achieved a median OS of 9.5 months, compared to 5.2 months for those who did not receive induction. Moreover, 43 percent of patients in the induction group remained alive at both 12 and 18 months, compared with 20 percent and 0 percent, respectively, in the non-induction group. These findings highlight the potential for durable clinical benefit, which is particularly meaningful in a population where long-term survival is rare.
Although the study did not meet its primary endpoint of objective response rate (ORR), the observed disease control and survival benefits suggest that traditional response metrics may not fully capture the therapeutic impact of this regimen. In immuno-oncology, durable disease stabilization and prolonged survival are increasingly recognized as important indicators of clinical benefit, especially in treatment-refractory settings.
According to Dhan Chand, Ph.D., Vice President of Research at Agenus, the findings illustrate the mechanistic synergy between agenT-797 and the checkpoint inhibitors botensilimab and balstilimab. He explained that the induction approach appeared to enhance immune activation within the tumor microenvironment, leading to improved clinical outcomes.
Correlative biomarker analyses provided further insight into the underlying mechanisms of action. Treatment with the combination regimen was associated with significant increases in intratumoral T-cell and dendritic cell infiltration, indicating enhanced immune engagement within the tumor. Additionally, researchers observed the formation of organized tertiary lymphoid structures in on-treatment biopsy samples from a patient who experienced durable clinical benefit. These structures are considered important sites of immune activation and have been linked to improved responses to immunotherapy.
Beyond the tumor microenvironment, the therapy also appeared to activate systemic immune responses. Peripheral blood analyses revealed increased activation of both CD4 and CD8 T-cell populations, suggesting that the treatment may promote a broad and coordinated immune response against cancer cells. Together, these findings support the hypothesis that immune priming and reprogramming of the tumor microenvironment are key drivers of the observed clinical benefits.
The safety profile of the regimen was consistent with the known effects of its individual components. The most commonly reported treatment-emergent adverse events included fatigue, fever, diarrhea, anorexia, nausea, and mucositis. Immune-related adverse events were also observed, including dermatitis, colitis, gastritis, enteritis, hepatitis, and hypothyroidism. While these side effects are typical of immunotherapy-based treatments, their management remains an important consideration in clinical practice.
The study’s findings also underscore the growing importance of combination strategies in oncology. By integrating multiple therapeutic modalities—checkpoint inhibition, cellular therapy, and chemotherapy—the regimen aims to address different aspects of tumor biology and immune evasion. This multifaceted approach may be particularly valuable in overcoming resistance to single-agent therapies.
The inclusion of agenT-797, an allogeneic iNKT cell therapy, adds a novel dimension to the treatment strategy. iNKT cells are a unique subset of immune cells with the ability to rapidly produce cytokines and bridge innate and adaptive immunity. By introducing these cells into the patient, the therapy seeks to enhance immune surveillance and amplify anti-tumor responses. When combined with checkpoint inhibitors that release immune brakes, this approach may create a more favorable environment for sustained tumor control.
The presentation of these data at AACR 2026, delivered by Samuel L. Cytryn, M.D., a gastrointestinal medical oncologist at Memorial Sloan Kettering Cancer Center, highlights the collaborative nature of this research. Investigator-initiated trials such as this play a critical role in exploring innovative treatment strategies and generating early evidence that can inform future clinical development.
Further analyses of the study’s biospecimen dataset are ongoing and are expected to provide deeper insights into immune mechanisms, optimal treatment sequencing, and potential biomarkers. Identifying biomarkers that predict response could be particularly valuable in selecting patients most likely to benefit from this complex regimen, thereby improving treatment outcomes and minimizing unnecessary toxicity.
Looking ahead, the findings from this Phase II study support continued investigation of the BOT, BAL, and agenT-797 combination in larger clinical trials. While the current study is limited by its small sample size, the consistency of the observed signals across multiple endpoints provides a strong rationale for further development.
In the broader context of immuno-oncology, these results contribute to a growing body of evidence supporting the importance of immune system modulation and combination therapy. As researchers continue to refine these approaches, the goal is to develop treatments that not only extend survival but also offer durable and meaningful responses for patients with difficult-to-treat cancers.
For patients with PD-1 refractory gastroesophageal adenocarcinoma, the need for new therapeutic options remains urgent. The data presented by Agenus at AACR 2026 offer a promising glimpse into a potential new strategy that leverages immune priming, cellular therapy, and combination treatment to overcome resistance and improve outcomes.
As the field moves forward, continued innovation and collaboration will be essential in translating these early findings into clinically meaningful advances. If validated in larger studies, this approach could represent an important step toward redefining the standard of care for patients facing one of the most challenging forms of cancer.
About Agenus
Agenus is a leading immuno-oncology company targeting cancer with a comprehensive pipeline of immunological agents. The company was founded in 1994 with a mission to expand patient populations benefiting from cancer immunotherapy through combination approaches, using a broad repertoire of antibody therapeutics, adoptive cell therapies (through MiNK Therapeutics) and adjuvants.
Agenus has robust end-to-end development capabilities, across commercial and clinical cGMP manufacturing facilities, research and discovery, and a global clinical operations footprint. Agenus is headquartered in Lexington, MA. For more information, visit www.agenusbio.com or @agenus_bio. Information that may be important to investors will be routinely posted on our website and social media channels.
About Botensilimab (BOT)
Botensilimab (BOT) is a human Fc enhanced multifunctional anti-CTLA-4 antibody designed to boost both innate and adaptive anti-tumor immune responses. Its novel design leverages mechanisms of action to extend immunotherapy benefits to “cold” tumors which generally respond poorly to standard of care or are refractory to conventional PD-1/CTLA-4 therapies and investigational therapies. Botensilimab augments immune responses across a wide range of tumor types by priming and activating T cells, downregulating intratumoral regulatory T cells, activating myeloid cells and inducing long-term memory responses.
Approximately 1,200 patients have been treated with botensilimab and/or balstilimab in phase 1 and phase 2 clinical trials. Botensilimab alone, or in combination with Agenus’ investigational PD-1 antibody, balstilimab, has shown clinical responses across nine metastatic, late-line cancers. For more information about botensilimab trials, visit www.clinicaltrials.gov.
About Balstilimab (BAL)
Balstilimab is a novel, fully human monoclonal immunoglobulin G4 (IgG4) designed to block PD-1 (programmed cell death protein 1) from interacting with its ligands PD-L1 and PD-L2. It has been evaluated in more than 900 patients to date and has demonstrated clinical activity and a favorable tolerability profile in several tumor types.
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