Abstract P4-11-04: Targeted vaccination against human a-lactalbumin may provide immunotherapy and immunoprevention of triple negative breast cancer

We have previously shown that a-lactalbumin vaccination mediates protection against the development of murine breast cancer in the absence of any detectable inflammatory changes in all normal non-lactating tissues examined. Based on these results, we have proposed that α-lactalbumin vaccination of healthy, cancer-free, adult women may provide safe and effective immunoprevention of breast cancer. Several issues have been raised over the past several years questioning the feasibility of applying this autoimmune strategy for breast cancer immunoprevention in the normal, healthy, cancer-free adult female population. These concerns have focused on whether adult women would be immunologically responsive to human α-lactalbumin, whether a history of lactation would create an insurmountable tolerance that would preclude generating effective immunity against α-lactalbumin, whether α-lactalbumin is immunologically available in human breast tumors, and whether expression of α-lactalbumin in normal non-breast tissues would predispose to systemic autoimmune complications. Here we provide an accumulation of several new findings that directly address these issues: 1) In vitro priming of peripheral blood mononuclear cells (PBMC) from normal healthy adult women results in frequencies of α-lactalbumin-specific interferon-gamma (IFNγ) producing T cells that are consistent with those mediating protection against breast tumor formation in mice; 2) Frequencies of IFNγ-producing T cells and the level of protection from the development of breast tumors are virtually identical whether vaccination occurs in parous mice with a history of lactation and breastfeeding or whether vaccination occurs in non-parous mice with no history of lactation; 3) ONCOMINE data base searches repeatedly show highly significant overexpression of α-lactalbumin in triple negative breast cancer (TNBC). This expression was confirmed experimentally using several methods including RT-PCR, Western blot analysis, and longitudinal visualization of α-lactalbumin gene expression during in vivo growth of human TNBC in immunodeficient mice. This in vivo visualization of α-lactalbumin gene expression was facilitated by measuring bioluminescence from growing human HCC1937 TNBC cells stably transfected with a lentivirus designed to regulate firefly luciferase expression under control of the human α-lactalbumin promoter; and 4) Evidence from the Human Protein Atlas indicates negative immunohistochemical staining for α-lactalbumin in 78 normal human tissues examined, thereby confirming the widely held view that α-lactalbumin expression in normal human tissues is confined exclusively to the lactating breast. Collectively, these findings indicate that normal, healthy, adult women are capable of mounting an immune response to human α-lactalbumin, that a history of lactation and breastfeeding has no impact on the induced immunity and the protection it provides against the development of breast cancer, and that α-lactalbumin vaccination may be most effective in providing therapy and immmunoprevention of TNBC, the most aggressive form of breast cancer and the most common variant occurring in women with BRCA1 mutations (supported by NIH R01 CA140350). Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-11-04.