349 GI-101A, a novel CD80-IgG4-IL2v2 fusion protein, promotes CAR-T expansion and enhances anticancer potential by increasing memory T cell population in a lymphoma model

<h3>Background</h3> Chimeric antigen receptor T cells (CAR-T) therapy has emerged as a groundbreaking treatment for various hematological malignancies. However, the persistence and expansion of CAR-T cells post-infusion remain critical challenges. Interleukin-2 (IL-2), a potent cytokine known for its role in T cell proliferation and survival, may enhance the efficacy of CAR-T therapy. This study investigates the combined effect of CAR-T therapy and GI-101A, a novel CD80-IgG4-IL2v2 fusion protein in lymphoma model. <h3>Methods</h3> The anti-tumor efficacy was evaluated using a Daudi-Luc lymphoma xenograft model in immunodeficient mice. Treatments were administered for up to 34 days (Part 1). Post-34 days, subjects with tumor recurrence following CAR-T therapy received additional GI-101A treatment to assess reinvigorated antitumor efficacy (Part 2). In the combination therapy group, treatment was discontinued, and a tumor rechallenge was performed to evaluate response durability (Part 3). Tumor growth was measured using the IVIS imaging system, and blood immune cell analysis was performed using flow cytometry. <h3>Results</h3> Compared to the control group, both the CAR-T alone and CAR-T with GI-101A groups demonstrated tumor reduction. After the day 20, however, the CAR-T alone group showed increasing tumors, whereas the combination group achieved complete remission. In Part 2, tumors worsened and led to death in the CAR-T only groups, but adding GI-101A upon recurrence reduced tumors. In Part 3, only the group that received GI-101A did not experience recurrence after tumors rechallenge. Blood analysis showed that combination of GI-101A increased the number of FMC63⁺CAR-T cells, and both CD4⁺ and CD8⁺CAR-T cells, compared to CAR-T alone. In the recurrence groups, CAR-T levels were very low, but after the administering GI-101A, significant CAR-T expansion was observed. Following tumor rechallenge, only the group that received GI-101A maintained increased CAR-T levels and complete remission. Memory T cell analysis revealed that while initial CAR-T cells were mostly naïve and terminally differentiated effector memory (TEMRA) cells, the GI-101A treated group exhibited a significant increase in central memory (CM) and effector memory (EM) cells. <h3>Conclusions</h3> The combination of CAR-T cell therapy with GI-101A, as well as the additional administration of GI-101A upon recurrence, significantly enhances the expansion and persistence of CAR-T cells and promotes the differentiation of memory T cells. These findings suggest that GI-101A can potentiate the antitumor efficacy of CAR-T cell therapy, offering a promising strategy to improve clinical outcomes for patients with lymphoid malignancies. Furthermore, GI-101A showed potential as a maintenance therapy following CAR-T treatment.