Systemic delivery of neutralizing antibody targeting CCL2 for glioma therapy.
Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) inhibit anti-tumor immune responses and facilitate tumor growth. Precursors for these immune cell populations migrate to the tumor site in response to tumor secretion of chemokines, such as monocyte chemoattractant protein-1 (MCP-1/CCL2), which was originally purified and identified from human gliomas. In syngeneic mouse GL261 glioma and human U87 glioma xenograft models, we evaluated the efficacy of systemic CCL2 blockade by monoclonal antibodies (mAb) targeting mouse and/or human CCL2. Intraperitoneal (i.p.) administration of anti-mouse CCL2 mAb as monotherapy (2 mg/kg/dose, twice a week) significantly, albeit modestly, prolonged the survival of C57BL/6 mice bearing intracranial GL261 glioma (P = 0.0033), which was concomitant with a decrease in TAMs and MDSCs in the tumor microenvironment. Similarly, survival was modestly prolonged in severe combined immunodeficiency mice bearing intracranial human U87 glioma xenografts treated with both anti-human CCL2 mAb and anti-mouse CCL2 antibodies (2 mg/kg/dose for each, twice a week) compared to mice treated with control IgG (P = 0.0159). Furthermore, i.p. administration of anti-mouse CCL2 antibody in combination with temozolomide (TMZ) significantly prolonged the survival of C57BL/6 mice bearing GL261 glioma with 8 of 10 treated mice surviving longer than 70 days, while only 3 of 10 mice treated with TMZ and isotype IgG survived longer than 70 days (P = 0.0359). These observations provide support for development of mAb-based CCL2 blockade strategies in combination with the current standard TMZ-based chemotherapy for treatment of malignant gliomas.
Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Xinmei
X
Zhu
Mitsugu
M
Fujita
Linda A
LA
Snyder
Hideho
H
Okada
D000818:Animals; D057134:Antibodies, Neutralizing / Q000627:therapeutic use*; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000276:immunology*; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D004334:Drug Administration Schedule; D016503:Drug Delivery Systems; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D016233:Immunotherapy, Active; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D022423:Myeloid Cells / Q000187:drug effects; D009368:Neoplasm Transplantation; D011070:Poly I-C / Q000627:therapeutic use; D018709:Statistics, Nonparametric; D000077204:Temozolomide
D057134:Antibodies, Neutralizing; D018906:Antineoplastic Agents, Alkylating; D018932:Chemokine CCL2; D003606:Dacarbazine; D011070:Poly I-C; D000077204:Temozolomide