Researchers are launching a pioneering Phase II clinical trial combining two novel immunotherapy approaches to tackle advanced gastroesophageal cancer, a devastating disease that ranks as the third most common cancer worldwide and claims 1.3 million lives annually.
The study will evaluate the combination of agenT-797, an allogeneic invariant natural killer T (iNKT) cell therapy, with botensilimab, an engineered anti-CTLA-4 antibody, addressing the significant unmet need for effective treatments beyond current standard options.
Current Treatment Landscape and Unmet Needs
While PD-1 inhibitors combined with chemotherapy are approved for frontline treatment of advanced gastroesophageal cancer, most patients eventually experience disease progression. Second-line therapy with ramucirumab and paclitaxel offers limited benefit, achieving a median progression-free survival of only 4.4 months and an objective response rate of 28%.
Innovative Mechanism of AgenT-797
AgenT-797 represents a novel approach to cellular therapy, utilizing allogeneic unmodified iNKT cells derived from healthy donors. These specialized lymphocytes operate through a dual mechanism:
- Direct tumor cell killing via T cell receptor recognition of CD1d, a molecule commonly expressed in gastrointestinal tumors
- Indirect cytotoxicity through stimulation of dendritic cell maturation and immune system activation
Early clinical evidence from a Phase I trial has already demonstrated the safety and preliminary efficacy of agenT-797 when combined with PD-1 inhibition in patients with refractory disease, including promising responses in gastric cancer.
Botensilimab: Enhanced Anti-CTLA-4 Engineering
The trial's second component, botensilimab, is an advanced version of CTLA-4 inhibition, featuring enhanced Fc engineering that sets it apart from first-generation drugs like ipilimumab. Key advantages include:
- Stronger binding to Fc gamma receptors on immune cells
- Enhanced antigen-specific T cell responses
- Improved targeting of immunosuppressive regulatory T cells
- Reduced complement-mediated toxicity
Phase I results have shown botensilimab's potential when combined with the PD-1 inhibitor balstilimab, demonstrating both safety and efficacy in heavily pretreated patients, including those with immunotherapy-resistant tumors.
Scientific Rationale for Combination
The combination strategy leverages complementary immune-activating mechanisms: agenT-797's direct tumor-killing capacity and immune system stimulation, alongside botensilimab's enhanced ability to prime T cell responses and deplete regulatory T cells. This dual approach aims to overcome the limitations of existing immunotherapies and address the complex immune evasion mechanisms in gastroesophageal cancer.
