A Phase II Study of agenT-797 (Invariant Natural Killer T Cells), Botensilimab, a Novel Fc-enhanced CTLA-4 Inhibitor, Plus Balstilimab (Anti-PD-1) With Ramucirumab and Paclitaxel for Patients With Previously Treated, Advanced Esophageal, Gastric, or Gastro-esophageal Junction Adenocarcinoma

Overview

Balstilimab (AGEN2034; BAL) is an investigational, fully human IgG4 monoclonal antibody targeting programmed cell death protein 1 (PD-1). It has been studied as monotherapy and in combinations—particularly with the CTLA-4 inhibitors zalifrelimab and botensilimab—in cervical, colorectal and other solid tumors. It is not FDA-approved; a biologics license application for recurrent/metastatic cervical cancer was voluntarily withdrawn in 2021 after the FDA recommended against pursuing accelerated approval following full approval of pembrolizumab in the same setting. (investor.agenusbio.com)

Mechanism of action

Balstilimab binds PD-1 and blocks its interaction with PD-L1 and PD-L2, preventing inhibitory PD-1 signaling and potentially restoring cytotoxic T-cell activity against tumors. (cancer.gov)

Efficacy

Cervical cancer monotherapy: In a single-arm phase I/II study, 140 efficacy-evaluable patients with previously treated recurrent or metastatic cervical cancer received balstilimab 3 mg/kg every two weeks. The confirmed objective response rate (ORR) was 15.0% (95% CI, 10.0–21.8%), including 3.6% complete responses and 11.4% partial responses. The disease-control rate was 49.3%, and median response duration was 15.4 months. ORR was 20.0% in PD-L1-positive and 7.9% in PD-L1-negative disease. (pmc.ncbi.nlm.nih.gov)

Randomized cervical-cancer study: In the phase II RaPiDS trial, investigator-assessed ORR was 24% with balstilimab–zalifrelimab and 15% with balstilimab–placebo; blinded independent review found ORRs of 24% and 26%, respectively. Because the study was non-comparative and the investigator and independent assessments differed, it did not establish that adding zalifrelimab improved efficacy. (annalsofoncology.org)

Colorectal cancer combination: In a peer-reviewed phase I study of 101 response-evaluable patients with heavily pretreated, microsatellite-stable metastatic colorectal cancer, botensilimab plus balstilimab produced a 17% ORR (95% CI, 10–26%) and 61% disease-control rate. Median response duration was not reached and median progression-free survival was 3.5 months. These results apply to the combination and do not isolate balstilimab’s contribution. (pubmed.ncbi.nlm.nih.gov)

Safety

With cervical-cancer monotherapy, 71.4% of patients experienced treatment-related adverse events; commonly reported events included asthenia and diarrhea. The most frequent grade ≥3 treatment-related events were immune-mediated enterocolitis (3.1%) and diarrhea (1.9%). (pmc.ncbi.nlm.nih.gov)

In RaPiDS, treatment-related adverse events occurred in 71% of patients receiving balstilimab–zalifrelimab and 64% receiving balstilimab–placebo; grade 3 events occurred in 23% and 15%, respectively. No treatment-related deaths were reported. (annalsofoncology.org)

With botensilimab–balstilimab in metastatic colorectal cancer, 89% experienced treatment-related adverse events, most commonly fatigue (35%), diarrhea (32%) and fever (24%). Twelve percent discontinued because of treatment-related toxicity, and no grade 5 treatment-related events occurred. (pubmed.ncbi.nlm.nih.gov)

Further reading

• Balstilimab monotherapy in recurrent/metastatic cervical cancer — Gynecologic Oncology
• Balstilimab plus zalifrelimab in advanced cervical cancer — Journal of Clinical Oncology
• Botensilimab plus balstilimab in microsatellite-stable metastatic colorectal cancer — Nature Medicine
• NCI Drug Dictionary: balstilimab

Last updated: Sep 2026

Overview

Botensilimab (AGEN1181; BOT) is an investigational, fully human, Fc-engineered IgG1 monoclonal antibody targeting CTLA-4. It is being studied both alone and—more commonly—in combination with the investigational anti-PD-1 antibody balstilimab. Clinical development includes colorectal, ovarian, liver and other difficult-to-treat solid tumors. Evidence remains preliminary because most results come from small, non-randomized phase 1–2 studies; a randomized phase 2 colorectal-cancer trial is ongoing and has not posted results. (cancer.gov)

Mechanism of action

Botensilimab blocks CTLA-4-mediated suppression of T-cell activation. Its engineered Fc region has increased affinity for activating Fcγ receptors on antigen-presenting and natural-killer cells. Preclinical and translational studies indicate that this design may strengthen T-cell priming and memory, activate innate immunity, and promote depletion of intratumoral regulatory T cells. Whether these properties produce better clinical outcomes than established CTLA-4 antibodies has not yet been demonstrated in randomized trials. (pmc.ncbi.nlm.nih.gov)

Efficacy

The most extensive published evidence is for botensilimab plus balstilimab:

• Previously treated microsatellite-stable metastatic colorectal cancer: In a phase 1 trial, 101 response-evaluable patients had a confirmed objective response rate (ORR) of 17%, including one complete response, and a disease-control rate of 61%. Median progression-free survival was 3.5 months; median duration of response was not reached. All responses occurred in patients without active liver metastases. The study was single-arm, and efficacy data for 47 additional treated patients were immature at publication. (pmc.ncbi.nlm.nih.gov)
• Localized colorectal cancer: In the 24-patient phase 2 NEST study, neoadjuvant treatment produced major pathological responses in 41% of mismatch-repair-proficient tumors and 100% of mismatch-repair-deficient tumors. Treatment did not delay planned surgery. These results are promising but derive from a small, non-randomized study using pathological rather than long-term survival outcomes. (aacrjournals.org)
• Treatment-refractory ovarian cancer: A phase 1b cohort reported an ORR of 23% among 35 efficacy-evaluable patients, including one complete and seven partial responses; the 24-week clinical-benefit rate was 31%. (pubmed.ncbi.nlm.nih.gov)
• Treatment-refractory hepatocellular carcinoma: Among 18 efficacy-evaluable patients, the ORR was 17%, the 18-week clinical-benefit rate was 50%, median progression-free survival was 4.4 months, and median overall survival was 12.3 months. (pmc.ncbi.nlm.nih.gov)
• Responses have also been reported in phase 1 sarcoma cohorts, particularly angiosarcoma, but sample sizes were small and histologies heterogeneous. (pmc.ncbi.nlm.nih.gov)

Safety

Toxicity resembles that expected from CTLA-4/PD-1 checkpoint inhibition, particularly immune-mediated gastrointestinal and hepatic events. In the 148-patient metastatic colorectal-cancer safety population, 89% experienced a treatment-related adverse event; 31% had grade 3 and 1% had grade 4 events. Common events included fatigue (35%), diarrhea (32%) and fever (24%). Immune-mediated diarrhea/colitis occurred in 33%, including grade 3–4 events in approximately 11%. Twelve percent discontinued both drugs because of toxicity, and no treatment-related deaths were reported. (pmc.ncbi.nlm.nih.gov)

Further reading

• Phase 1 metastatic colorectal-cancer trial in Nature Medicine
• Mechanistic and translational study in Cancer Discovery
• NEST phase 2 neoadjuvant colorectal-cancer study
• Phase 1b ovarian-cancer study
• ClinicalTrials.gov randomized colorectal-cancer study

Last updated: Sep 2026

Overview

AgenT-797 is an investigational, off-the-shelf cell therapy made from invariant natural killer T (iNKT) cells collected from healthy donors and expanded in the laboratory. It has been studied in solid tumors and in acute respiratory distress syndrome (ARDS). The human results available so far come mainly from small, early-stage studies; clinical benefit has not been established. (nature.com)

Mechanism of action

The infused cells are unmodified. Their receptors recognize lipid antigens presented by CD1d; iNKT cells can also recognize other signals on abnormal cells. The proposed effects include direct tumor-cell killing and regulation of other immune cells, including T cells and antigen-presenting cells. In ARDS, researchers are investigating whether these cells can alter harmful inflammation and support antimicrobial immunity. (nature.com)

Efficacy

• Solid tumors: An updated phase 1 abstract reported a complete remission in one patient with metastatic testicular cancer treated with agenT-797 plus anti-PD-1 therapy, a confirmed partial response in one patient with gastric cancer, and disease stabilization in nine others. These observations do not establish an overall response rate or show how much benefit was attributable to agenT-797. (jitc.bmj.com)
• Gastroesophageal cancer: In a phase 2 study combining agenT-797 with two checkpoint inhibitors and chemotherapy/ramucirumab, 0 of 15 patients with measurable disease had a complete or partial response; 11 of 15 (73%) had stable disease. Median progression-free survival was 4.4 months. The investigators reported no improvement in response rate or median survival outcomes against historical comparisons. (aacrjournals.org)
• COVID-19–related ARDS: In an open-label phase 1/2 study, 14 of 20 (70%) mechanically ventilated trial participants survived after treatment. Without a randomized comparison, survival cannot be attributed to agenT-797. (nature.com)

Safety

The phase 1 solid-tumor abstract reported no new safety signals with agenT-797 alone or alongside anti-PD-1 therapy. In the ARDS study, there were no dose-limiting toxicities or observed cytokine-release syndrome; one patient had a possible grade 4 treatment-related episode of breathing difficulty. In the five-drug gastroesophageal regimen, all 17 patients had an adverse event and 9 (53%) had a grade 3 or higher event; those findings cannot be assigned to agenT-797 alone. (jitc.bmj.com)

Further reading

• Peer-reviewed ARDS phase 1/2 study
• Updated solid-tumor phase 1 conference abstract
• Gastroesophageal cancer phase 2 conference abstract

Last updated: Sep 2026

Inclusion Criteria:

* Metastatic or advanced unresectable adenocarcinoma of esophageal, gastric, or gastroesophageal junction

* Disease progression on one prior line of therapy for metastatic disease. Patients with previously untreated advanced unresectable or metastatic disease may be included if disease progressed or recurred during neoadjuvant or adjuvant therapy or within 6 months of completion of those treatments.

* Patients must have histologically or cytologically confirmed esophageal, gastric, or gastroesophageal junction adenocarcinoma

* Patients must have measurable or evaluable disease as defined by RECIST v1.1 criteria. Patients with evaluable disease must be eligible to begin with an induction cycle

* Age 18 years or older

* ECOG performance status 0 to 1

* Adequate organ function as defined in Table 2

Table 2. Organ function requirements for eligibility Hematological Absolute neutrophil count: ≥1000/mcL Platelets: ≥90,000/mcL Hemoglobin: ≥8 g/dL Renal Serum creatinine: ≤1.5X ULN Hepatic Serum total bilirubin: ≤1.5X ULN OR Direct bilirubin ≤ULN for subjects with total bilirubin levels \>1.5X ULN, except patients with Gilbert's disease (≤3X ULN) AST and ALT: ≤2.5X ULN Albumin: ≥3 mg/dL

Exclusion Criteria:

* Received prior therapy with ramucirumab at any time

* Received paclitaxel or docetaxel-based therapy within 6 month of study enrollment

* Had a prior grade \>3 immune related adverse event due to anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA4 therapy at any time

* Diagnosis of immunodeficiency or receipt of systemic steroid therapy or any other form of immunosuppressive therapy within 7 days before the first dose of trial treatment. Replacement therapy (ie physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic immunosuppressive therapy and is allowed.

* History of gastrointestinal perforation or fistulae

* A known history of active Bacillus tuberculosis

* Known active central nervous system metastases and/or carcinomatous meningitis

* History of or any evidence of active, non-infectious, immune-mediated pneumonitis. Patients with radiation-induced pneumonitis who are asymptomatic are permitted on study.

* Peripheral neuropathy limiting ADLs

* A known history of human immunodeficiency virus (HIV 1/2 antibodies)

* Known active hepatitis B (e.g., HBsAg reactive) or hepatitis C (e.g., HCV RNA \[qualitative\] is detected). Patients with HBsAg reactive on entecavir may be eligible after consultation with hepatologist and study team.

* Received a live vaccine within 30 days of planned start of study therapy

* Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial

* Pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the prescreening or screening visit through 5 months after the last dose of trial treatment

* Unwilling to give written, informed consent, unwilling to participate, or unable to comply with the protocol for the duration of the study