Abstract 3190
Background
Despite mounting interest in combination immunotherapy including immune checkpoint inhibitors (ICIs) to improve anti-tumor responses, clinical translation has been disappointing. To address the significant unmet needs remaining, we designed GI101 comprising the extracellular domain of CD80 acting as a dual checkpoint (CTLA4/PD-L1) inhibitor, together with a long acting IL2v that preferentially binds to the IL2Rβ.
Methods
Affinity of GI101 for IL2Rs, CTLA4, and PD-L1 was determined by SPR. Immune cell proliferation was analyzed by CFSE assay and in vivo immune profiling. In vivo efficacy of GI101 were performed in a tumor-bearing mouse model.
Results
GI101 exhibits high affinity to both CTLA4 (Kd, 2.9 nM), PD-L1 (Kd, 8.5 nM), and preferential binding to IL2Rβ (Kd, 28.4 nM). GI101 induces the robust stimulation of in vitro and in vivo CD8+ T and NK cell proliferation without a significant increase in Treg cells. GI101 has high binding affinity to CTLA4 acting as a decoy ligand, thereby enhancing the interaction between endogenous CD80 and CD28, leading to the activation of T cells. GI101 elicits improved restoration of immune functions compared to a CD80-Fc in in vitro settings using human PBMCs co-cultured with PD-L1hi tumor cells. In the CT26 tumor-bearing mice, GI101 was superior at inhibiting tumor growth when compared to a combination of aPD-1/aCLTA4 in association with a profound increase in CD8+ T and NK cells without causing an increase in Tregs in the TME. In addition, a dose-dependent anti-tumor effect was observed in CT26 syngeneic models. Furthermore, isolated mortality was observed in the aPD-1/aCTLA4 combo-treated group whereas GI101-treated group has no evidence for toxicity associated with IL2 activity including vascular leakage syndrome and cytokine storm.
Conclusions
The complementary modes of action of GI101 via dual checkpoint blockade with IL2 activity to enhance the proliferation and activation of Teff and NK cells is projected to translate into superior clinical efficacy and safety as indicated even in ‘cold tumor’ models. GI101 has promising potential to replace first-generation ICIs as a monotherapy or in combination with chemo/radiotherapies and other immunotherapies.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
GI innovation.
Funding
GI innovation.
Disclosure
J.C. Park: Shareholder / Stockholder / Stock options, Full / Part-time employment: GI innovation. K.H. Pyo: Research grant / Funding (institution): Yonsei Medical Center. Y.J. Song: Shareholder / Stockholder / Stock options, Full / Part-time employment: GI innovation. W.J. Lee: Shareholder / Stockholder / Stock options, Full / Part-time employment: GI innovation. J. Kim: Shareholder / Stockholder / Stock options, Full / Part-time employment: GI innovation. H.N. Ji: Full / Part-time employment: GI innovation. S.S. Park: Full / Part-time employment: GI innovation. Y.J. Koh: Full / Part-time employment: GI innovation. K. Lee: Shareholder / Stockholder / Stock options, Full / Part-time employment: GI innovation. B. Cho: Research grant / Funding (institution): Yonsei Medical Center. B. Chun: Shareholder / Stockholder / Stock options, Full / Part-time employment: GI innovation. Y.M. Oh: Shareholder / Stockholder / Stock options, Full / Part-time employment: GI innovation. B. Yang: Shareholder / Stockholder / Stock options, Full / Part-time employment: GI innovation. S.Y. Nam: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: GI innovation. M.H. Jang: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: GI innovation.
Resources from the same session
3252 - Genes involved in DNA replication, chromatin remodeling and cell cycle as potential biomarkers for therapy outcome to immune therapy in patients with metastatic cutaneous malignant melanoma
Presenter: Fernanda Costa Svedman
Session: Poster Display session 3
Resources:
Abstract
5545 - Phase Ib/II Study (SENSITIZE) assessing safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical outcome of domatinostat in combination with pembrolizumab in patients with advanced melanoma refractory/non-responding to prior checkpoint inhibitor therapy
Presenter: Jessica Hassel
Session: Poster Display session 3
Resources:
Abstract
5213 - Genomic landscape of primary malignant melanoma of esophagus
Presenter: Jie Dai
Session: Poster Display session 3
Resources:
Abstract
2716 - A phase III, randomised, double-blind study of adjuvant cemiplimab versus placebo post-surgery and radiation in patients with high-risk cutaneous squamous cell carcinoma (CSCC)
Presenter: Danny Rischin
Session: Poster Display session 3
Resources:
Abstract
3550 - ILLUMINATE 301: A randomized phase 3 study of tilsotolimod in combination with ipilimumab compared with ipilimumab alone in patients with advanced melanoma following progression on or after anti-PD-1 therapy
Presenter: Marcus Butler
Session: Poster Display session 3
Resources:
Abstract
1645 - PRIME002 - Early phase II study of Azacitidine and Carboplatin priming for Avelumab in patients with advanced melanoma who are resistant to immunotherapy
Presenter: Andre Van Der Westhuizen
Session: Poster Display session 3
Resources:
Abstract
4440 - Pembrolizumab (pembro) Plus Lenvatinib (len) for First-Line Treatment of patients (pts) With Advanced Melanoma: Phase 3 LEAP-003 Study
Presenter: Alexander Eggermont
Session: Poster Display session 3
Resources:
Abstract
3454 - Proof of concept study with the histone deacetylase inhibitor vorinostat in patients with resistant BRAFV600 mutated advanced melanoma
Presenter: Sanne Huijberts
Session: Poster Display session 3
Resources:
Abstract
1832 - A phase Ia/Ib clinical study to evaluate the safety, pharmacokinetics (PK) and preliminary anti-tumor activity of FCN-159 in patients with advanced melanoma harboring NRAS-aberrant (Ia) and NRAS-mutation (Ib).
Presenter: Lu Si
Session: Poster Display session 3
Resources:
Abstract
3996 - A Phase I Clinical Trial Investigating the Therapeutic Cancer Vaccine UV1 in Combination with Pembrolizumab as First-Line Treatment of Patients with Malignant Melanoma
Presenter: Sanjiv Agarwala
Session: Poster Display session 3
Resources:
Abstract