Background CAR T cell therapy has demonstrated improved outcomes for patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). Despite this, it results in a cure for only a subset of patients, with over half experiencing relapses. The effectiveness of CAR T therapy is closely linked to the robust expansion of CAR T cells. Therefore, developing strategies to enhance the proliferation and maintain the fitness of these cells would significantly improve treatment options and patient outcomes.

GI-102 (CD80/IL2v3) is a novel, clinical-stage immunocytokine designed to target and deliver the IL-2 variant (IL-2v3) specifically to immune and tumor cells. GI-102 targets CD8+ T and NK cells via IL-2Rβγ affinity and uses CD80-PD-L1 cis-binding as an anchoring domain to enhance binding avidity and rigidity. IL-2v3 of GI-102 has abolished affinity to IL-2Rα to minimize the impact of IL-2 on Tregs. In the ongoing study involving patients with solid tumors failed on available therapies (NCT05824975), GI-102 was found to be generally safe and well-tolerated up to 0.45 mg/kg (Q3W), resulting in robust expansion and activation of CD8+ T and NK cells. Additionally, GI-102 demonstrated strong activity as a monotherapy 1.

IL-2 is a potent cytokine known for its role in T cell proliferation and survival, and it may enhance the efficacy of CAR T therapy. In an in vivo Daudi-Luc lymphoma xenograft model using immunodeficient mice, GI-102 plus anti-CD19 CAR T cells resulted in a higher rate of complete responses, which were associated with a significant expansion of CAR T cells compared to the control group on CAR T cells without GI-102.

Study Design and Methods Based on these observations, we have designed an open-label, multi-center trial (KCT0009580) in R/R DLBCL patients to evaluate the PK profile of CAR T cells, safety, and anti-cancer activity of GI-102 post anti-CD19 CAR T therapy. Up to 29 eligible patients diagnosed with R/R DLBCL post ≥ 2 lines of systemic therapy will be enrolled. Patients will receive intravenous GI-102 (Q3W) approximately 4 weeks after anti-CD19 CAR T treatment. GI-102 will be given for 3 cycles as mandatory and administration beyond Cycle 4 is based on the investigator's decision. The primary objective is to assess the level of CAR T cell expansion over time post GI-102 treatment. The secondary objectives are to evaluate the anti-tumor activity, safety, and tolerability of GI-102 as a consolidation therapy. Efficacy endpoints include best overall response, complete response (CR) rate, duration of response or CR, overall response rate (ORR) at 3, 6, and 12 months, upgrade in response, median progression-free survival and overall survival. Biomarkers will be analyzed to characterize changes in immune responses after treatment of GI-102 utilizing flow cytometer, circulating tumor DNA, single cell RNA sequencing, T cell receptor repertoire, etc.

This study consists of safety run-in (Part A) and dose-expansion (Part B) phases. In Part A, 0.12 and 0.24 mg/kg of GI-102 will be evaluated using a conventional 3+3 design to determine the combination recommended phase 2 dose (cRP2D) of GI-102 when used as a consolidation therapy of CAR T treatment. CAR T cell PK profile, safety, tolerability, and efficacy data from DLT evaluation period (3 weeks post injection of GI-102) will be comprehensively reviewed to determine cRP2D.

In Part B, 17 subjects will be enrolled into one of two cohorts: the observation cohort (N=5) or the GI-102 cRP2D cohort (N=12). The observation cohort is designed to assess the CAR T cell PK profile without intervention. Analysis will be conducted by pooling data from subjects receiving cRP2D of GI-102 in Part A and B.

Significance: This study represents a novel approach to potentially enhance the efficacy of CAR T therapy in R/R DLBCL. By evaluating GI-102 as a consolidation therapy, we aim to address the critical need for improved long-term outcomes in this challenging patient population. The results of this trial may pave the way for new strategies to optimize CAR T therapy in hematologic malignancies.

Reference 1 Lee J et al. J Clin Oncol 42;16_suppl, 2024

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2025
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