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 PD‑1. It has been evaluated as monotherapy and in combination with the CTLA‑4 antibody zalifrelimab in previously treated recurrent/metastatic cervical cancer, with published phase 2 data. A U.S. BLA for second‑line cervical cancer was submitted in April 2021, accepted for Priority Review in June 2021, and voluntarily withdrawn in October 2021 after full approval of pembrolizumab in the same setting; development has continued in combinations. (pubmed.ncbi.nlm.nih.gov)

Mechanism of action

• Target: PD‑1 (programmed death‑1). Balstilimab binds PD‑1 with high affinity and blocks interactions with PD‑L1 and PD‑L2, restoring antitumor T‑cell activity. (ascopubs.org)
• Antibody class: Fully human IgG4 monoclonal antibody. Preclinical/meeting‑abstract work has described a differentiated activity profile compared with other PD‑1 inhibitors, though the mechanistic basis is still being investigated. (ascopubs.org)

Efficacy

Cervical cancer (previously treated, recurrent/metastatic)

• Balstilimab monotherapy (open‑label, single‑arm, phase 2; n=140 efficacy‑evaluable): Confirmed ORR 15.0% (95% CI, 10.0–21.8), including 3.6% complete responses; median duration of response (DoR) 15.4 months. ORR 20.0% in PD‑L1–positive tumors and 7.9% in PD‑L1–negative tumors. DCR 49.3%. Dosing: 3 mg/kg IV every 2 weeks (up to 24 months). (pubmed.ncbi.nlm.nih.gov)

• Balstilimab + zalifrelimab (open‑label, single‑arm, phase 2; n=125 efficacy‑evaluable): Confirmed ORR 25.6% (95% CI, 18.8–33.9), with 10 complete and 22 partial responses; median DoR not reached at median follow‑up 21 months (response durability 64.2% at 12 months). ORR 32.8% in PD‑L1–positive and 9.1% in PD‑L1–negative tumors. DCR 52%. Dosing: balstilimab 3 mg/kg Q2W + zalifrelimab 1 mg/kg Q6W (up to 24 months). (pubmed.ncbi.nlm.nih.gov)

Other tumor types (early signals)

• Soft tissue sarcoma (single‑arm phase 2 of doxorubicin + zalifrelimab + balstilimab): Best ORR 33.3% (95% CI, 17.3–52.8); the study did not meet its predefined PFS improvement endpoint. (pubmed.ncbi.nlm.nih.gov)

Note: Additional early‑phase combination studies with botensilimab (next‑generation CTLA‑4) have reported responses in ovarian and other solid tumors, but these are primarily from conference presentations and company communications and remain exploratory. (cancernetwork.com)

Safety

• Balstilimab monotherapy (phase 2 cervical cancer): Most common grade ≥3 treatment‑related AEs were immune‑mediated enterocolitis (3.1%) and diarrhea (1.9%). Overall safety was consistent with PD‑1 inhibitors. (pubmed.ncbi.nlm.nih.gov)

• Balstilimab + zalifrelimab (phase 2 cervical cancer): Grade ≥3 treatment‑related AEs occurred in 20.0%; common immune‑mediated AEs included hypothyroidism (14.2%) and hyperthyroidism (7.1%). Serious TRAEs occurred in 10.3%; three treatment‑related deaths (pneumonitis, immune‑mediated nephritis, diabetes mellitus) were reported. (ascopubs.org)

• Doxorubicin + zalifrelimab + balstilimab in soft tissue sarcoma: Grade 3/4 TRAEs in 45%; immune‑mediated AEs requiring immunosuppression in 9%. (pubmed.ncbi.nlm.nih.gov)

Further reading

• Phase 2 balstilimab monotherapy in cervical cancer (Gynecologic Oncology, 2021). (pubmed.ncbi.nlm.nih.gov)
• Phase 2 balstilimab + zalifrelimab in cervical cancer (Journal of Clinical Oncology, 2021/2022). (pubmed.ncbi.nlm.nih.gov)
• ASCO abstract: differentiated activity profile of balstilimab (mechanistic/meeting data). (ascopubs.org)
• Regulatory history: BLA acceptance/withdrawal (company notices). (investor.agenusbio.com)
• Soft tissue sarcoma combination study (PubMed, 2025). (pubmed.ncbi.nlm.nih.gov)

Notes: Balstilimab is not FDA‑approved as of October 7, 2025. Efficacy and safety summaries above reflect non‑randomized trials; comparative effectiveness versus approved PD‑1 inhibitors has not been established. (investor.agenusbio.com)

Last updated: Oct 2025

Overview

Botensilimab (AGEN1181; BOT) is an Fc‑engineered, next‑generation anti–CTLA‑4 monoclonal antibody being developed primarily in combination with the anti–PD‑1 antibody balstilimab (BAL). Early clinical activity has been reported across “cold” or immunotherapy‑refractory tumors, especially microsatellite‑stable (MSS) metastatic colorectal cancer (mCRC) without active liver metastases and in relapsed/refractory metastatic sarcomas. Fast Track designation has been granted by the FDA for BOT/BAL in non‑MSI‑H mCRC without active liver involvement. (pmc.ncbi.nlm.nih.gov)

Mechanism of action

• Target: CTLA‑4.
• Engineering: Human IgG1 with enhanced Fcγ receptor binding to amplify Fc‑dependent effector functions.
• Proposed immunobiology: Improves antigen‑presenting cell/T‑cell co‑engagement, expands effector/memory T cells, depletes intratumoral Tregs via FcγR‑mediated mechanisms, repolarizes myeloid cells, and shows activity independent of tumor neoantigen burden; FcγRIIA/IIIa expression may serve as response biomarkers. (aacrjournals.org)

Efficacy

Microsatellite‑stable metastatic colorectal cancer (MSS mCRC)

• Phase 1 (expanded) Nature Medicine report (NCT03860272): In heavily pretreated MSS mCRC, responses were concentrated in patients without active liver metastases (NLM). Among 77 NLM patients with median 13‑month follow‑up, confirmed ORR was 22% (later noted as 23% with an additional response), disease control 73%, and median duration of response (DOR) not reached. (pmc.ncbi.nlm.nih.gov)
• ASCO 2024 update (abstract 3556): In the same NLM cohort, ORR 22–23%, DCR 73%, and estimated median OS 20.9 months; activity observed across multiple non‑liver sites (peritoneum, soft tissue, pleura, brain). (ascopubs.org)
• Randomized phase 2 (ASCO GI 2025, NCT05608044): BOT±BAL vs standard of care (regorafenib or trifluridine/tipiracil) in refractory NLM MSS mCRC. Confirmed ORR was higher with BOT+BAL than BOT alone; the 75 mg BOT + BAL arm achieved ORR 19% (95% CI 10–31), while SOC had 0% responses. These data informed selection of 75 mg BOT Q6W + BAL for further study. (ascopubs.org)
• ESMO‑GI 2025 (Phase 1 expansion, n=123 NLM): Confirmed ORR 20%, DCR 69%, median OS 20.9 months, with 42% two‑year survival. (biospace.com)

Relapsed/refractory metastatic sarcomas

• Phase Ib (JCO 2025): BOT (1 or 2 mg/kg Q6W) + BAL in 64 patients; among 52 evaluable, ORR 19.2% (all PRs), DOR median 21.7 months, median PFS 4.4 months, and 12‑month OS 69%. Subtype activity included angiosarcoma ORR 27.8%. (pmc.ncbi.nlm.nih.gov)

Neoadjuvant, resectable colorectal cancer

• NEST‑1 (phase 2, ASCO GI 2024): Single pre‑op dose of BOT 75 mg plus two doses of BAL was feasible and did not delay surgery; pathologic tumor regression was observed in both pMMR/MSS and dMMR/MSI‑H disease, with several major/complete pathologic responses reported. (ascopubs.org)

Combination with chemotherapy

• ASCO GI 2025 (FOLFOX‑3B phase 1): In MSS mCRC, BOT + BAL added to FOLFOX/bevacizumab showed high preliminary response rates (partial responses in 4/7 at BOT 25 mg and 6/7 at BOT 75 mg; median PFS ~8 months overall, not reached at higher dose) with acceptable tolerability in a small cohort. (ascopubs.org)

Safety

• Immune‑related toxicities typical of checkpoint blockade predominate. In the randomized phase 2 MSS mCRC study, grade ≥3 treatment‑related AEs occurred in 35% with BOT 75 mg + BAL and 42% with BOT 150 mg + BAL; treatment‑related immune‑mediated diarrhea/colitis was more frequent at the higher BOT dose. No treatment‑related deaths were reported. (ascopubs.org)
• In metastatic sarcomas (JCO 2025), the safety profile was manageable; grade 3 treatment‑related diarrhea/colitis occurred in ~6% and responses were durable. (pmc.ncbi.nlm.nih.gov)
• In early neoadjuvant CRC (NEST‑1), treatment was delivered safely without surgical delays. (ascopubs.org)

Development status and next steps

• Regulatory: FDA Fast Track designation for BOT/BAL in non‑MSI‑H mCRC without active liver metastases. Following End‑of‑Phase 2 discussions, FDA advised proceeding to a randomized phase 3 trial and did not support accelerated approval based on response rates alone; the selected registrational dose is BOT 75 mg Q6W + BAL. (investor.agenusbio.com)
• Planned/ongoing trials: A global phase 3 study in refractory NLM MSS mCRC is planned with BOT 75 mg + BAL vs standard of care. (agenus2023ir.q4web.com)

Further reading

• Nature Medicine phase 1 MSS mCRC (open access): Botensilimab + balstilimab in relapsed/refractory MSS mCRC. (pmc.ncbi.nlm.nih.gov)
• Cancer Discovery mechanistic study of Fc‑enhanced anti–CTLA‑4 (botensilimab). (aacrjournals.org)
• ASCO 2024 abstract: Non‑liver metastatic MSS mCRC efficacy update. (ascopubs.org)
• ASCO GI 2025 abstract: Randomized phase 2 BOT±BAL vs SOC in refractory NLM MSS mCRC. (ascopubs.org)
• JCO 2025 full article: BOT + BAL in relapsed/refractory metastatic sarcomas (open access). (pmc.ncbi.nlm.nih.gov)
• ASCO GI 2025 abstract: BOT/BAL with FOLFOX/bevacizumab in MSS mCRC (FOLFOX‑3B). (ascopubs.org)
• ASCO GI 2024 abstract: NEST‑1 neoadjuvant BOT/BAL in resectable CRC. (ascopubs.org)

Notes: Reported efficacy in MSS mCRC is largely confined to patients without active liver metastases in early‑phase studies; definitive benefit will require results from randomized phase 3 testing. (pmc.ncbi.nlm.nih.gov)

Last updated: Oct 2025

Overview

AgenT-797 is an allogeneic, off‑the‑shelf invariant natural killer T (iNKT) cell therapy being developed by MiNK Therapeutics. It has been tested in phase 1 trials for advanced solid tumors (alone and with anti–PD‑1 therapy) and in a phase 1/2 study for viral ARDS (COVID‑19). A randomized phase 2 trial combining agenT‑797 with botensilimab, balstilimab, ramucirumab, and paclitaxel is recruiting in previously treated gastric/GEJ/esophageal adenocarcinoma (NCT06251973). The completed phase 1 solid‑tumor study enrolled ~34 patients (NCT05108623). (mskcc.org)

Mechanism of action

iNKT cells recognize glycolipid antigens presented by the non‑polymorphic CD1d molecule, enabling donor‑unrestricted activity. They can exert direct cytotoxicity and orchestrate antitumor immunity via rapid cytokine release and activation/recruitment of other immune cells. Unlike many allo‑cell therapies, iNKTs can be given without HLA matching or lymphodepletion in current trials. (pubmed.ncbi.nlm.nih.gov)

Efficacy

Solid tumors - Phase 1 (monotherapy or with pembrolizumab/nivolumab): an AACR 2023 abstract reported, among 29 evaluable patients, a confirmed partial response in PD‑1–refractory MSI‑H gastric cancer (agenT‑797 + nivolumab) and stable disease in 8 patients; the objective response rate in the combination cohort was 20% (1/5). (providence.elsevierpure.com) - Peer‑reviewed case reports from the same program describe: - A durable confirmed partial response (42% tumor shrinkage) in PD‑1–refractory MSI‑H gastric adenocarcinoma after a single infusion of agenT‑797 with nivolumab. (pubmed.ncbi.nlm.nih.gov) - A complete and durable remission in metastatic, heavily pretreated germ‑cell (testicular) cancer after one infusion of agenT‑797 plus nivolumab. (pmc.ncbi.nlm.nih.gov)

ARDS (COVID‑19) - Open‑label phase 1/2 study (NCT04582201): in 21 ventilated patients (including 5 on VV‑ECMO), agenT‑797 produced rapid immune activation with no dose‑limiting toxicities and signals of improved survival and fewer secondary infections; infused cells persisted and only transient donor‑specific antibodies were detected. (pubmed.ncbi.nlm.nih.gov)

Note: Beyond these reports and abstracts, controlled efficacy data in oncology have not yet been published; the phase 2 gastric/GEJ/esophageal trial is ongoing. (mskcc.org)

Safety

• Solid tumors (phase 1): across dose levels (single infusion, no lymphodepletion), early reports noted no dose‑limiting toxicities and favorable tolerability; abstracts described absence of severe cytokine release syndrome (CRS) or neurotoxicity. (providence.elsevierpure.com)
• ARDS (phase 1/2): no dose‑limiting toxicities were reported; the therapy was administered safely to critically ill, ventilated patients, including those on VV‑ECMO. (pubmed.ncbi.nlm.nih.gov)

Further reading

• Phase 1 solid‑tumor update (AACR 2023 abstract). (aacrjournals.org)
• Case report: overcoming PD‑1 resistance with allogeneic iNKT cells in MSI‑H gastric cancer (Oncogene, 2024). (pubmed.ncbi.nlm.nih.gov)
• Case report: complete remission in refractory germ‑cell tumor after agenT‑797 plus nivolumab (Oncogene, 2025; open access). (pmc.ncbi.nlm.nih.gov)
• ARDS trial: iNKT therapy in moderate–severe COVID‑19 ARDS (Nature Communications, 2024). (pubmed.ncbi.nlm.nih.gov)
• Trial listings: phase 1 solid tumors (NCT05108623); phase 2 gastric/GEJ/esophageal (NCT06251973). (cdek.pharmacy.purdue.edu)
• Background on iNKT cells and allogeneic iNKT platforms. (pubmed.ncbi.nlm.nih.gov)

Summary: AgenT‑797 is an unmodified, allogeneic iNKT cell therapy with a mechanistically distinct, donor‑unrestricted approach. Early oncology data consist of an AACR abstract and peer‑reviewed case reports suggesting activity in PD‑1–refractory tumors, alongside favorable safety; a randomized phase 2 study in gastric/GEJ/esophageal cancer is in progress. A separate peer‑reviewed trial in COVID‑19 ARDS indicates biological activity and acceptable safety in critical illness. (aacrjournals.org)

Last updated: Oct 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