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Intratumoral Injection of -gal Glycolipids Induces Xenograft-Like Destruction and Conversion of Lesions into Endogenous Vaccines

Uri Galili^1,*,, Kim Wigglesworth^* and Ussama M. Abdel-Motal^*

^* Department of Medicine and Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605

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 FcR. Anti-Gal constitutes 1% of immunoglobulins in humans and interacts specifically with -gal epitopes (Gal1-3Gal1-4GlcNAc-R). The binding of anti-Gal to -gal epitopes on pig cells mediates xenograft rejection. The proposed method uses glycolipid micelles with multiple -gal epitopes (-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 -gal epitopes. Efficacy of this treatment was demonstrated in 1,3-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 -gal epitopes and can produce the anti-Gal Ab. Intratumoral injection of -gal glycolipids results in local inflammation mediated by anti-Gal binding to the multiple -gal epitopes and activation of complement. These glycolipids spontaneously insert into tumor cell membranes. The binding of anti-Gal to -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 -gal glycolipids in humans is likely to induce the destruction of treated lesions and elicit a protective immune response against micrometastases.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Uri Galili, Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, Lazare Research Building, Worcester, MA 01605. E-mail address: Uri.Galili{at}umassmed.edu

² Abbreviations used in this paper: TAA, tumor-associated Ag; ADCC, Ab-dependent cell-mediated cytotoxicity; 1,3GT, 1,3-galactosyltransferase; -gal epitope, Gal1-3Gal1-4GlcNAc-R epitope; BS lectin, Bandeiraea simplicifolia IB4; CDC, complement-dependent cytolysis; DC, dendritic cell; KO, knockout mice for the 1,3GT gene; MFC, mean fluorescence channel; PKM, pig kidney membranes; Treg, regulatory T cell; WT, wild type.