Browsing by keyword "Lymphocytes, Tumor-Infiltrating"
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Concerted potent humoral immune responses to autoantigens are associated with tumor destruction and favorable clinical outcomes without autoimmunityPURPOSE: The therapeutic importance of immune responses against single versus multiple antigens is poorly understood. There also remains insufficient understanding whether responses to one subset of antigens are more significant than another. Autoantibodies are frequent in cancer patients. They can pose no biological significance or lead to debilitating paraneoplastic syndromes. Autoreactivity has been associated with clinical benefits, but the magnitude necessary for meaningful results is unknown. Autologous tumor cells engineered to secrete granulocyte macrophage colony-stimulating factor generate immune infiltrates in preexisting metastases with associated tumor destruction. We sought to identify targets of responses from this vaccination strategy. EXPERIMENTAL DESIGN: Postvaccination sera used in screening a cDNA expression library prepared from a densely infiltrated metastasis of a long-term surviving melanoma patient identified several autoantigens. Additional autoantigens were identified through similar screenings in non-small cell lung cancer and murine models, and proteins implicated in cancer propagation. ELISAs for several targets were established using recombinant proteins, whereas others were evaluated by petit serologies. RESULTS: Eleven gene products were identified through serologic screening from two patients showing highly favorable clinical outcomes. A subset of antigens revealed significant changes in antibody titers compared with weak responses to other proteins. Time course analyses showed coordinated enhanced titers against several targets as a function of vaccination in responding patients. CONCLUSIONS: This study shows the range of biologically significant antigens resulting from a whole-cell vaccine. Targets include autoantigens that are components of cell cycle regulation. Potent antibody responses against multiple autoantigens are associated with effective tumor destruction without clinical autoimmunity.
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Intratumoral injection of alpha-gal glycolipids induces xenograft-like destruction and conversion of lesions into endogenous vaccinesThis 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.