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

Balstilimab (AGEN2034, BAL) is a fully human monoclonal IgG4 antibody that binds with high affinity to programmed death 1 (PD-1), preventing its interaction with PD-L1 and PD-L2 ligands. The drug is designed to enhance T cell activation and effector function [1]. It is being developed by Agenus Inc. as both a monotherapy and in combination with other immunotherapy agents, particularly botensilimab (an anti-CTLA-4 antibody).

Clinical Trial Results

As a monotherapy, balstilimab showed activity in a phase II trial for recurrent/metastatic cervical cancer, with an objective response rate (ORR) of 15% and median duration of response of 15.4 months. In PD-L1 positive patients with squamous cell carcinoma, the ORR was 21%. The drug also showed some activity in PD-L1 negative patients [2]. When combined with zalifrelimab (anti-CTLA-4), the ORR increased to 25.6% in cervical cancer patients, with a disease control rate of 52% [3].

Safety Profile

The safety profile appears manageable based on clinical trials. In combination therapy with zalifrelimab for cervical cancer, the most common treatment-related adverse events were hypothyroidism (16.8%), diarrhea (14.2%), fatigue (11.6%), and nausea (9.0%) [3]. Development history includes a withdrawn BLA for cervical cancer in 2021, but the drug continues to be studied in various combinations and indications, particularly with botensilimab in colorectal cancer and other solid tumors [4].

Sources:

[1] Phase II Trial Results in Journal of Clinical Oncology [2] Clinical Trial Results in Gynecologic Oncology [3] Phase II Combination Trial Results in Journal of Clinical Oncology [4] Recent Development Update from BioSpace

Last updated: Dec 2024

Botensilimab is an investigational Fc-enhanced anti-CTLA-4 monoclonal antibody being developed by Agenus Inc. for cancer immunotherapy. It is designed to boost both innate and adaptive anti-tumor immune responses through multiple mechanisms: enhanced T cell priming and activation, depletion of regulatory T cells (Tregs) in the tumor microenvironment, activation of myeloid cells, and induction of long-term memory responses [1]. The drug's novel Fc-enhanced design allows it to bind more effectively to both high and low-affinity FcγRIIIA variants, potentially extending its benefits to a broader patient population compared to first-generation CTLA-4 inhibitors. Additionally, botensilimab is engineered to reduce complement-mediated toxicity through reduced C1q binding [2].

Clinical Efficacy

The drug has shown promising results in clinical trials, particularly in combination with the PD-1 inhibitor balstilimab. In a phase 1 trial of patients with microsatellite stable (MSS) metastatic colorectal cancer without liver metastases, the combination achieved a 23% objective response rate with a median overall survival of 21.2 months [3]. More recently, in the neoadjuvant NEST-1 trial for resectable colorectal cancer, the combination showed impressive pathologic response rates, with tumor shrinkage of ≥50% observed in 67.5% of MSS CRC patients [4]. The drug has demonstrated clinical responses across nine different types of metastatic, late-line cancers, including traditionally immunotherapy-resistant tumors.

Safety

The safety profile of botensilimab appears manageable based on clinical trial data. In the phase 1 trial combining botensilimab with balstilimab, the most common treatment-related adverse events were diarrhea/colitis, fatigue, and decreased appetite. Grade 3-4 adverse events occurred in approximately 39% of patients, with diarrhea/colitis being the most frequent serious adverse event. Notably, unlike some other CTLA-4 inhibitors, no cases of hypophysitis were reported in the monotherapy arm, which may be attributed to the drug's reduced complement activation [2]. As of 2024, approximately 1100 patients have been treated with botensilimab in phase 1 and phase 2 clinical trials.

Sources:

[1] Cancer Discovery Article on Botensilimab Mechanism and Clinical Results [2] OncoDaily Detailed Review of Botensilimab [3] Phase 1 Trial Results in OncoLive [4] NEST-1 Trial Results Press Release

Last updated: Dec 2024

Overview

AgenT-797 is an allogeneic, off‑the‑shelf invariant natural killer T (iNKT) cell therapy being developed by MiNK Therapeutics. It is in clinical development for cancer, virally induced acute respiratory distress syndrome (ARDS), and graft‑versus‑host disease (GvHD). Early human data include an open‑label phase 1/2 ARDS study and peer‑reviewed oncology case reports, with an ongoing randomized phase 2 study in second‑line gastroesophageal cancers (NCT06251973). (pmc.ncbi.nlm.nih.gov, pubmed.ncbi.nlm.nih.gov, targetedonc.com)

Mechanism of action

iNKT cells express a semi‑invariant T‑cell receptor that recognizes glycolipid antigens presented by the non‑polymorphic CD1d molecule, enabling HLA‑unrestricted, allogeneic administration. Upon activation, iNKTs can exert direct cytotoxicity and coordinate innate and adaptive immunity (e.g., dendritic cells, macrophages, NK cells, and conventional T cells), potentially remodeling the tumor microenvironment. (frontiersin.org, jci.org, pmc.ncbi.nlm.nih.gov)

Efficacy

• ARDS (COVID‑19): In a phase 1/2 open‑label study of 21 mechanically ventilated patients (including 5 on VV‑ECMO), agenT‑797 showed signals of benefit with 70% survival (14/20) in the main trial cohort versus 10% in a contemporaneous single‑site historical control; VV‑ECMO subgroup survival was 80% at 30 days and 60% at 6 months. These exploratory data are non‑randomized. (pmc.ncbi.nlm.nih.gov)

• Oncology case reports (peer‑reviewed, Oncogene):

• Gastric cancer (MSI‑H, anti‑PD‑1–refractory): durable RECIST‑confirmed partial response after a single infusion of agenT‑797 combined with nivolumab; biologic correlates included increased immune cell infiltration. (pubmed.ncbi.nlm.nih.gov)

• Metastatic testicular germ‑cell tumor (heavily pretreated): complete clinical/radiographic/biochemical remission persisting beyond 2 years after a single infusion of agenT‑797 with nivolumab. (pubmed.ncbi.nlm.nih.gov)

• Ongoing randomized phase 2 (2L gastroesophageal cancer): investigator‑sponsored trial at MSK evaluating agenT‑797 with checkpoint blockade and chemotherapy (NCT06251973); active and enrolling. (targetedonc.com)

Conference presentations (AACR/SITC) have described additional signals of disease control and long‑term iNKT persistence without lymphodepletion; these are not peer‑reviewed publications. (investor.minktherapeutics.com)

Safety

• ARDS study: No dose‑limiting toxicities; most adverse events were consistent with severe COVID‑19/ARDS. No cytokine release syndrome (CRS) was observed; one possible grade 4 treatment‑related dyspnea was reported. Infused iNKTs persisted with only transient donor‑specific antibodies. (pmc.ncbi.nlm.nih.gov)

• Oncology case reports: Treatments were well tolerated; reports note absence of CRS and no graft‑versus‑host disease. (pubmed.ncbi.nlm.nih.gov)

Overall, across early studies and case reports, agenT‑797 has been administered without lymphodepletion and with a generally favorable tolerability profile; larger controlled trials are needed to characterize safety and efficacy. (pmc.ncbi.nlm.nih.gov, investor.minktherapeutics.com)

Further reading

• Nature Communications (phase 1/2 ARDS study, mechanistic and clinical signals): A phase 1/2 clinical trial of invariant natural killer T cell therapy in moderate‑severe ARDS. (pmc.ncbi.nlm.nih.gov)
• Oncogene (gastric cancer case report): Overcoming resistance to PD‑1 blockade with allogeneic invariant natural killer T‑cells. (pubmed.ncbi.nlm.nih.gov)
• Oncogene (testicular cancer case report): Salvage therapy with allogeneic invariant natural killer T cells in a heavily pre‑treated germ cell tumor. (pubmed.ncbi.nlm.nih.gov)
• Trial listing and status (2L gastroesophageal cancer, phase 2): NCT06251973. (targetedonc.com)
• Background on iNKT/CD1d biology and lipid antigen recognition. (frontiersin.org)

Notes: Reported oncology outcomes are limited to individual case reports and conference updates; no peer‑reviewed, controlled efficacy datasets in cancer are yet available as of September 2, 2025. (pubmed.ncbi.nlm.nih.gov, investor.minktherapeutics.com)

Last updated: Sep 2025

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