Concerted Potent Humoral Immune Responses to Autoantigens Are Associated with Tumor Destruction and Favorable Clinical Outcomes without Autoimmunity

Abstract

Purpose: 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.

Autologous Melanoma Vaccine Induces Antitumor and Self-Reactive Immune Responses That Affect Patient Survival and Depend on MHC Class II Expression on Vaccine Cells

“…Gogas and colleagues (44) showed that the preventive efficacy of IFN-α in high-risk melanoma patients was significantly correlated with an increase in serum levels of antithyroid, antinuclear, anti-DNA, and anticardiolipin autoantibodies. Although those authors regard the humoral response as a prognostic marker, it is possible that the survival benefit was gained by immune targeting of biologically significant antigens shared by normal and tumor cells (45). This is possibly the case for the significant correlation we found between survival and the increase in the antibody level against livin.…”

CD20+ B Cells: The Other Tumor-Infiltrating Lymphocytes

“…Furthermore, cell-based cancer vaccines can be used to elicit broader Ab responses that closely resemble those associated with naturally occurring TIL-Bs. For example, in melanoma and prostate cancer patients receiving cell-based vaccines expressing GM-CSF, the development of autoantibodies to self-antigens was associated with favorable clinical responses (91)(92)(93). It is less clear how best to enhance the immunoregulatory and Ag presentation functions of TILBs.…”

Induction of Abscopal Anti-Tumor Immunity and Immunogenic Tumor Cell Death by Ionizing Irradiation - Implications for Cancer Therapies

“…Combined treatment with lower doses of CT plus GM-CSF secreting whole cancer cell vaccines might therefore overcome immune tolerance and induce anti-tumor immune responses [180]. It is important to note that immune responses against multiple antigens are associated with efficient tumor destruction [181].…”