Primary Immunoprevention of Triple-Negative Breast Cancer
Abstract
Background: We believe that primary immune prevention represents the greatest unmet need for controlling breast cancer. Despite an outstanding childhood vaccination program that prevents diseases caused by numerous pathogens, we have no comparable adult vaccination program capable of providing similar protection against the development of diseases we confront with age like breast cancer. This deficiency in our health care is due at least in part to the widely held belief that cancer preventive vaccines must target disease-inducing pathogens. In the absence of a definitive pathogen implicated in the development of breast cancer, we propose that the breast-specific lactation protein, alpha-lactalbumin, may substitute for an unavailable pathogen as an immune target for developing safe and effective primary immune prevention of triple-negative breast cancer (TNBC), the most aggressive and lethal form of breast cancer and the predominant form of this disease occurring in women at high genetic risk due to mutations in their BRCA1 genes. Alpha-lactalbumin is a breast-specific protein expressed at high levels in the majority of TNBC tumors, but its expression in normal human tissues is confined exclusively to breast tissues only during late pregnancy and lactation. Thus, we reasoned that as long as lactation is avoided, pre-emptive immunity directed against alpha-lactalbumin would not cause any immune damage to normal tissues but would destroy the vast majority of emerging TNBC tumors. In our preclinical studies in mice, we found that vaccine-induced immunity against alpha-lactalbumin provided significant protection and therapy against the growth of a variety of spontaneously growing breast tumors as well as against commonly used transplantable models of breast cancer. Most importantly, we found that this immunity occurred without inducing any damage to normal tissues. Overarching Challenge: Our application directly addresses the development of primary immune prevention of breast cancer, a major unmet need for gaining optimized control over this disease. Hypothesis: We hypothesize that alpha-lactalbumin vaccination may provide safe and effective prophylaxis against TNBC that may be of particular benefit to women with BRCA1 mutations who are at very high risk for developing this most lethal and aggressive form of breast cancer and who have the greatest need for a preventive vaccine. Specific Aims: We propose two aims. In Aim 1, we will complete a Phase Ia clinical trial designed to determine dosage and safety of alpha-lactalbumin vaccination in subjects who have been recently diagnosed with high-risk TNBC that has not metastasized and have recovered from current standard of care therapy. Initiating our vaccination in these subjects is ethically mandated before attempting to vaccinate healthy, cancer-free subjects. In Aim 2, we will complete a Phase Ib clinical trial designed primarily to determine safety of alpha-lactalbumin vaccination in healthy, cancer-free subjects who have voluntarily elected to undergo mastectomy as prophylaxis for their high genetic and/or familial risk for breast cancer. Study Design: Our clinical studies will involve vaccination of subjects with an emulsion containing highly purified human alpha-lactalbumin and an adjuvant capable of inducing an immune response consistent with the development of effective tumor immunity. In Aim 1, our objectives will be to define the toxicity, the maximum tolerated dose, and the lowest immunologic dose of the alpha-lactalbumin vaccine. In Aim 2, our objective will be to determine whether alpha-lactalbumin vaccination induces immune damage to normal breast tissues. Impact: Our proposal provides two important measurable biologic endpoints focused on the development of effective tumor immunity and the absence of detectable immune-mediated damage to normal tissues. Our studies will form the basis for initiating advanced Phase II/III trials to de
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710593
Entities
People
- George Budd
Organizations
- Cleveland Clinic
- United States Army