Background Targeted cancer therapy aims to eradicate cancer cells while preserving healthy tissue, significantly improving the therapeutic index compared to conventional treatments. Antibodies are crucial in these targeted therapies due to their exceptional specificity for target antigens.

Advancements in T-cell biology have led to the development of immune checkpoint inhibitors (ICIs), which indirectly kill cancer cells by activating T-cells. To enhance this approach, combination therapies involving multiple ICIs are frequently explored. More recently, bispecific antibodies have been designed to redirect a patient‘s T-cells to attack cancer cells.

Although combination checkpoint blockade regimens and bispecific engagers have shown improved response rates and overall survival, they also result in increased severe toxicities, dose limitations, and higher-grade treatment-related adverse events (TRAEs). Furthermore, these approaches face challenges such as poor infiltration of immune effectors into tumors and immunosuppressive, heterogeneous tumor microenvironments (TME).

Our research has demonstrated that invariant Natural Killer T (iNKT)-cells home to the tissues, modulate the TME, harness the host’s immune system, and be administered without lymphodepletion, resulting in minimal TRAEs. Additionally, we have developed a scalable in-house manufacturing process using iNKTs from healthy donors to generate our clinical product AgenT-797, addressing supply, cost, and product consistency issues.

We propose combining next-generation ICIs or bispecific engagers with AgenT-797 to enhance efficacy, reduce off-target effects, and decrease toxicity.

Methods We used a Staphylococcal Enterotoxin Toxin A (SEA toxin)-based approach to explore synergy between next-generation CPMs BOT and BAL, targeting CTLA-4 and PD-1 respectively, and AgenT-797 in modulating other immune cells. Additionally, we combined clinical-stage third-party engagers in in vitro co-culture models to compare AgenT-797 engagement with that of conventional T-cells.

Results We show that AgenT-797 can enhance the effect of CPMs in activating T-cells, decreasing T-regs and activate dendritic cells. We, also demonstrate that AgenT-797 can be engaged by clinical stage engagers to boost their efficacy showing a favorable activation profile in comparison to conventional T-cells.

Conclusions While combining cell therapy with antibody-based regimens has shown promise, particularly for immune-refractory tumors, adoptive cell therapy still faces several challenges. AgenT-797, with its intrinsic immunomodulatory and tumor-targeting capabilities, robust manufacturing process, and favorable safety profile, provides a strong platform to enhance the efficacy of clinical-stage treatments, making them beneficial to a significantly larger number of patients.