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Published on: June 25, 2015
A Chimeric Antibody against ACKR3/CXCR7 in Combination with TMZ Activates Immune Responses and Extends Survival in
Nicole Salazar1, Jeffrey C Carlson2, Kexin Huang3
1Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Palo Alto Veterans Institute for Research (PAVIR), Veterans Affairs Palo Alto Health Care System (VAPAHCS), Palo Alto, CA, USA.
Abstract:
Glioblastoma (GBM) is the least treatable type of brain tumor, afflicting over 15,000 people per year in the United States. Patients have a median survival of 16 months, and over 95% die within 5 years. The chemokine receptor ACKR3 is selectively expressed on both GBM cells and tumor-associated blood vessels. High tumor expression of ACKR3 correlates with poor prognosis and potential treatment resistance, making it an attractive therapeutic target. We engineered a single chain FV-human FC-immunoglobulin G1 (IgG1) antibody, X7Ab, to target ACKR3 in human and mouse GBM cells. We used hydrodynamic gene transfer to overexpress the antibody, with efficacy in vivo. X7Ab kills GBM tumor cells and ACKR3-expressing vascular endothelial cells by engaging the cytotoxic activity of natural killer (NK) cells and complement and the phagocytic activity of macrophages. Combining X7Ab with TMZ allows the TMZ dosage to be lowered, without compromising therapeutic efficacy. Mice treated with X7Ab and in combination with TMZ showed significant tumor reduction by MRI and longer survival overall. Brain-tumor-infiltrating leukocyte analysis revealed that X7Ab enhances the activation of M1 macrophages to support anti-tumor immune response in vivo. Targeting ACKR3 with immunotherapeutic monoclonal antibodies (mAbs) in combination with standard of care therapies may prove effective in treating GBM.
Insights
A novel antibody targeting ACKR3 shows promise for treating glioblastoma (GBM). This immunotherapy, X7Ab, effectively reduces GBM tumors and enhances anti-tumor immunity, offering new hope for patients with this aggressive brain cancer.
Area of Science:
- Oncology
- Immunology
- Neuroscience
Background:
- Glioblastoma (GBM) is an aggressive brain tumor with poor prognosis and limited treatment options.
- The chemokine receptor ACKR3 is highly expressed in GBM and associated with treatment resistance, making it a potential therapeutic target.
Purpose of the Study:
- To engineer and evaluate the efficacy of a novel antibody, X7Ab, targeting ACKR3 in GBM.
- To assess the therapeutic potential of X7Ab, alone and in combination with temozolomide (TMZ), in preclinical GBM models.
Main Methods:
- Development of a single chain FV-human FC-immunoglobulin G1 (IgG1) antibody (X7Ab) targeting ACKR3.
- Hydrodynamic gene transfer for in vivo antibody overexpression.
- Assessment of therapeutic efficacy using MRI, survival studies, and analysis of brain-tumor-infiltrating leukocytes.
Main Results:
- X7Ab demonstrated efficacy in killing GBM cells and ACKR3-expressing vascular endothelial cells by activating NK cells, complement, and macrophages.
- Combination therapy with X7Ab and a reduced dose of TMZ significantly reduced tumor size and improved survival in mice.
- X7Ab treatment enhanced M1 macrophage activation, promoting an anti-tumor immune response.
Conclusions:
- Targeting ACKR3 with the immunotherapeutic antibody X7Ab is a promising strategy for GBM treatment.
- Combining X7Ab with standard therapies like TMZ may improve therapeutic outcomes and reduce treatment toxicity.
- Further investigation into ACKR3-targeted immunotherapies holds potential for advancing GBM treatment.
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