Intratumoral injection of alpha-gal glycolipids induces xenograft-like destruction and conversion of lesions into endogenous vaccines.
This study describes a novel cancer immunotherapy treatment that exploits the natural anti-Gal Ab to destroy tumor lesions and convert them into an endogenous vaccine targeted to APC via FcgammaR. Anti-Gal constitutes 1% of immunoglobulins in humans and interacts specifically with alpha-gal epitopes (Galalpha1-3Galbeta1-4GlcNAc-R). The binding of anti-Gal to alpha-gal epitopes on pig cells mediates xenograft rejection. The proposed method uses glycolipid micelles with multiple alpha-gal epitopes (alpha-gal glycolipids). These glycolipids are extracted from rabbit red cell membranes and are comprised of ceramides with carbohydrate chains containing 5-25 carbohydrates, all capped with alpha-gal epitopes. Efficacy of this treatment was demonstrated in alpha1,3-galactosyltransferase knockout mice producing anti-Gal and bearing B16 melanoma or B16/OVA producing OVA as a surrogate tumor Ag. These mice are unique among nonprimate mammals in that, similar to humans, they lack alpha-gal epitopes and can produce the anti-Gal Ab. Intratumoral injection of alpha-gal glycolipids results in local inflammation mediated by anti-Gal binding to the multiple alpha-gal epitopes and activation of complement. These glycolipids spontaneously insert into tumor cell membranes. The binding of anti-Gal to alpha-gal expressing tumor cells induces the destruction of treated lesions as in anti-Gal-mediated xenograft rejection. Anti-Gal further opsonizes tumor cells within the lesion and, thus, targets them for effective uptake by APC that transport the tumor Ags to draining lymph nodes. APC further cross-present immunogenic tumor Ag peptides and elicit a systemic anti-tumor immune response. Similar intratumoral injection of alpha-gal glycolipids in humans is likely to induce the destruction of treated lesions and elicit a protective immune response against micrometastases.
Galili
Uri
U
Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA. Uri.Galili@umassmed.edu
Wigglesworth
Kim
K
Abdel-Motal
Ussama M
UM
D000818:Animals; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology; D002240:Carbohydrate Sequence; D003713:Dendritic Cells / Q000276:immunology; D004910:Erythrocyte Membrane / Q000737:chemistry / Q000276:immunology; D005700:Galactosyltransferases / Q000235:genetics; D006017:Glycolipids / Q000008:administration & dosage* / Q000276:immunology / Q000302:isolation & purification; D007167:Immunotherapy / Q000379:methods*; D007267:Injections; D008198:Lymph Nodes / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010047:Ovalbumin / Q000276:immunology; D011817:Rabbits; D012878:Skin Neoplasms / Q000276:immunology / Q000628:therapy*; D014183:Transplantation, Heterologous / Q000276:immunology; D014312:Trisaccharides / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D006017:Glycolipids; D014312:Trisaccharides; C076569:alpha-galactosyl epitope; D010047:Ovalbumin; D005700:Galactosyltransferases; C047006:N-acetyllactosaminide alpha-1,3-galactosyltransferase