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GB1275, a first-in-class CD11b modulator: rationale for immunotherapeutic combinations in solid tumors
David G DeNardo1, Anna Galkin2, Jakob Dupont2
1Department of Medicine, ICCE Institute, Department of Pathology and Immunology, Siteman Cancer Center, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri, USA ddenardo@wustl.edu.
Journal for Immunotherapy of Cancer
|August 28, 2021
Summary
Targeting myeloid-derived suppressor cells (MDSCs) is key for overcoming resistance to cancer therapies. Activating CD11b with GB1275 shows promise in preclinical models, leading to an ongoing clinical trial for advanced solid tumors.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Immune checkpoint inhibitor (ICI) resistance is linked to myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) in the tumor microenvironment (TME).
- Targeting MDSC recruitment or function is a critical strategy for treating ICI-resistant cancers.
- CD11b/CD18 (Mac-1) integrin mediates MDSC and TAM migration, but direct inhibition has shown limited clinical success due to dosage issues.
Purpose of the Study:
- To review the therapeutic potential of targeting MDSCs in cancer therapy.
- To examine preclinical studies of GB1275, a CD11b activator, for its role in enhancing antitumor immunity and immunotherapy response.
- To provide the rationale for the ongoing phase 1/2 clinical study of GB1275 in advanced solid tumors.
Main Methods:
- Review of preclinical studies involving GB1275, a leukadherin-1 salt form, in mouse models of pancreatic adenocarcinoma, breast cancer, and lung cancer.
- Analysis of GB1275's mechanism of action, focusing on CD11b activation and its effect on immune cell migration.
- Examination of data from a phase 1/2 clinical study (NCT04060342) evaluating GB1275 in patients with advanced solid tumors resistant to immuno-oncology therapies.
Main Results:
- Preclinical studies demonstrated that GB1275 (leukadherin-1) activates CD11b, improving antitumor immune response.
- GB1275 enhanced the efficacy of immunotherapy in mouse models of various cancers.
- Activation of CD11b via leukadherin-1 has shown potential in reducing inflammatory cell migration in animal models.
Conclusions:
- Targeting MDSCs, particularly through CD11b activation with agents like GB1275, represents a promising strategy to overcome resistance to cancer therapies.
- GB1275's preclinical efficacy in improving antitumor immunity and enhancing immunotherapy response supports its clinical investigation.
- The ongoing phase 1/2 clinical trial will further evaluate the safety and efficacy of GB1275 in patients with advanced, ICI-resistant solid tumors.
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