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
4822 - Efficiacy of different nutritional intervention on nutritional status and quality of life for local advanced nasopharyngeal carcinoma patients: a prospective clinical trial
Presenter: Yuan-yuan Chen
Session: Poster Display session 3
Resources:
Abstract
2628 - Apatinib in treating patients with platinum-resistant or platinum-refractory recurrent or metastatic nasopharyngeal carcinoma
Presenter: Changjuan Tao
Session: Poster Display session 3
Resources:
Abstract
4887 - Impact of tumor site and adjuvant radiotherapy on survival of adenoid cystic carcinoma: a SEER database analysis
Presenter: Jason Tasoulas
Session: Poster Display session 3
Resources:
Abstract
2634 - Efficacy and safety of anlotinib for patients with recurrent and/or metastatic salivary gland carcinomas
Presenter: Wen Jiang
Session: Poster Display session 3
Resources:
Abstract
3568 - ACCURACY a phase (P) 2 trial of AL101, a pan-Notch inhibitor, in recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC) patients (pts) with Notch activating mutations (Notch act mut): preliminary safety and efficacy data.
Presenter: Renata Ferrarotto
Session: Poster Display session 3
Resources:
Abstract
683 - Pathologic Staging Changes in Oral Cavity Squamous Cell Carcinoma—Stage Migration and Implications for Adjuvant Treatment
Presenter: Zain Husain
Session: Poster Display session 3
Resources:
Abstract
563 - Expression of immune response biomarkers in head and neck squamous cell carcinoma (HNSCC) in irradiated area
Presenter: Carole Pflumio
Session: Poster Display session 3
Resources:
Abstract
4030 - HLA-Ligandome analysis reveals target antigens of oropharyngeal squamous cell carcinoma
Presenter: Simon Laban
Session: Poster Display session 3
Resources:
Abstract
2979 - Topographical distribution of sentinel lymph nodes in early tongue squamous cell carcinomas
Presenter: Hiroyuki Goda
Session: Poster Display session 3
Resources:
Abstract
3517 - Role of follow-up (FU) FDG-PET/CT (FU-FDG-PET/CT) in patients with locoregionally advanced squamous cell carcinoma of the head and neck (LA-HNSCC) treated with chemotherapy and radiotherapy (RT), either concurrent (CRT) or sequential (ST).
Presenter: Bert Van Den Heuvel
Session: Poster Display session 3
Resources:
Abstract