Brain tumor immunotherapy with type-1 polarizing strategies.

Abstract

Although the safety of vaccine approaches for central nervous system (CNS) malignancies has been established in early phase clinical trials, the success of a vaccine strategy will depend critically on the ability of effector T cells to home in to CNS tumors and durably exert antitumor effects. Based on our recent studies, efficient CNS tumor homing is a characteristic of cytotoxic T lymphocytes (CTLs) with a type 1 phenotype (Tc1), and this appears to be related to the Tc1 response to the type 1 CXC chemokine ligand (CXCL) 10 [also known as interferon (IFN)-inducible protein (IP)-10] and expression of an integrin receptor very late antigen (VLA)-4 on Tc1. In addition, we have previously shown that direct intratumoral delivery of dendritic cells (DCs) ex vivo engineered to secrete IFN-alpha further enhances Tc1 homing via upregulation of CXCL10/IP-10 in the tumor microenvironment. As a means to induce IFN-alpha and CXCL10/IP-10 in the CNS tumor microenvironment in a clinically feasible manner, we used administration of polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose (poly-ICLC), a ligand for toll-like receptor 3 and melanoma differentiation-associated gene 5 (MDA5) in combination with vaccinations targeting CTL epitopes derived from glioma-associated antigens (GAAs). The combination of subcutaneous vaccination and i.m. poly-ICLC administration remarkably promoted systemic induction of antigen GAA-specific Tc1s expressing VLA-4 in the CNS tumors and improved the survival of tumor-bearing mice in the absence of detectable autoimmunity. Based on these data, we have implemented a phase I/II vaccination study using type 1 polarizing DCs loaded with GAA peptides in combination with poly-ICLC in patients with recurrent malignant glioma.

• Authors: Hideho Okada
• Journal: Annals of the New York Academy of Sciences (Ann N Y Acad Sci) Vol. 1174 Pg. 18-23 (Sep 2009) ISSN: 1749-6632 [Electronic] United States
• PMID: 19769732 (Publication Type: Journal Article, Review)

Chemical References

• Cancer Vaccines
• RNA, Double-Stranded
• RNA, Viral
• TLR3 protein, human
• Toll-Like Receptor 3
• Polylysine
• poly ICLC
• Carboxymethylcellulose Sodium
• Poly I-C

Topics

• Animals
• Brain Neoplasms (immunology)
• Cancer Vaccines (therapeutic use)
• Carboxymethylcellulose Sodium (analogs & derivatives, therapeutic use)
• Disease Models, Animal
• Glioma (immunology)
• Humans
• Immunotherapy (methods)
• Mice
• Poly I-C (therapeutic use)
• Polylysine (analogs & derivatives, therapeutic use)
• RNA, Double-Stranded (immunology)
• RNA, Viral (immunology)
• T-Lymphocytes (immunology)
• T-Lymphocytes, Cytotoxic (immunology)
• Toll-Like Receptor 3 (immunology)