Immunization against antigens expressed in pre-invasive or proliferative breast lesions has been shown to offer a unique approach to breast cancer prevention. Vaccines can elicit memory Tcellsthat remain in lymph nodes until exposed to the target antigen. Upon stimulation, T-cells migrate to the site of antigen expressing lesions and will proliferate and destroy those lesions.HER-2/neu (HER2), insulin like growth factor binding protein 2 (IGFBP2), and insulin like growth factor receptor-1 (IGF1R) are overexpressed across all subtypes of DCIS, involved in itsinitiation and progression to invasive breast cancer, and are associated with poor prognosis. These proteins have also been shown to be immunogenic, i.e. elicit both humoral and cellularimmune responses in breast cancer patients. A multi-antigen multi-peptide vaccine targeting these proteins was shown to be effective in suppressing the development of palpable lesions and slowing tumor growth in preclinical models of HER2+ and HER2- breast cancers, TgMMTV-neu and TgC3(I)-Tag, respectively. Interestingly, concurrent vaccination and oral administration of a retinoic X receptor (RXR) agonist, bexarotene, significantly improved disease-free survival in TgMMTV-neu mice, suggesting that the RXR agonist bexarotene enhanced protective immunity in vaccinated mice. Subsequently, the multi-antigen multipoeptide vaccine targeting the three antigens, HER2-IGFBP2-IGF1R, has been reformulated to a DNA vaccine platform termed WOKVAC. A clinical trial is currently underway to evaluate the safety and immunogenicity of the WOKVAC in women with locally advanced non-metastatic HER2 negative breast (ClinicalTrials.gov NCT02780401). Retinoids comprise a group of compounds related to vitamin A, including its natural and synthetic analogues. These are biochemically converted to retinoic acid (RA) that binds to its cognate nuclear receptors, RAR (retinoic acid receptor) and RXR (retinoic X receptor) to regulate gene transcription. RARs and RXRs are nuclear receptors that function as transcription factors, regulating cell growth, cell differentiation, cell survival and death pathways. RXR-selective agonists, Rexinoids bind to RXR but not to RAR. The ability of these agents to activate multiple cellular pathways, and the ubiquitous expression of RXR make them interesting therapeutic molecules. There has been significant interest in this class of compounds in cancer therapy as evidenced by anticancer activity of the RXR agonist bexarotene (Targretin), which is approved for the treatment of cutaneous T-cell lymphoma. These agents have shown anti-tumor efficacy in a variety of rodent models of mammary and lung cancers. However, the elevation of triglyceride levels associated with bexarotene and other analogs such as 9-cis-retinoic acid, UAB76 and UAB11 is a major concern particularly in the cancer prevention setting, where high-risk but relatively healthy individuals may have to be treated for a prolonged period of time. Significant efforts have been made to develop RXR agonists that promote beneficial effects in pre-neoplastic tissues with little or no lipid toxicity. One suchcompound is 9-cis-UAB30 (UAB30). In preclinical studies, oral dosing of UAB30 was shown not to induce triglyceride accumulation in sera of female rodents, while oral administration of bexarotene substantially enhanced serum lipid levels, suggesting that UAB30 avoids the major dose-limiting toxicity of bexarotene and be useful in long-term chronic dosing. Extensive preclinical studies have also been conducted, demonstrating that UAB30 is not mutagenic. A Phase 0 dose escalation study conducted in healthy volunteers demonstrated that UAB30 has favorable pharmacology as an oral agent. A double-blind, placebo controlled Phase 1 study designed to determine the maximum tolerated dose of UAB30 in human after 28days of chronic dosing is underway (ClinicalTrials.gov NCT01935960).As noted above, a recent study by Disis et al has demonstrated that the combination of the RXR agonist bexarotene with the multi-antigen multi-peptide vaccine targeting HER2, IGFBP-2 and IGF-1R is more effective than either agent alone in preventing the development of invasive breast cancer in a transgenic mouse mammary tumor model. Bexarotene on its own increased tumor infiltrating CD8+ T cells to a level comparable to what was seen in animals receiving vaccine alone. These data suggest that the immune stimulation may be a significant contributor to the efficacy of bexarotene observed in breast cancer model, and may synergize with the vaccine to enhance the anti-tumor efficacy. There is also evidence to indicate that treatment with Rexinoids have important immunomodulating effects on T cells, e.g. augmenting interleukin-2 receptor expression by activated T cells and preventing activation-induced cell death, a process T cells undergo when exposed to chronic amounts of cancer associated antigens. Furthermore, retinoic acid has been shown to play a key role in immune homeostasis, has a role in balancing Th17 and regulatory T cells, and is also essential for proper T helper cell responses. Interestingly, vitamin A has been recognized as an essential nutrient for the proper function of the immune system for nearly 100 years. Therefore, chemo-immunoprevention strategies such as combination of RXR agonists and cancer vaccines may be a rational approach to breast cancer prevention when the vaccine is administrated in the presence of subclinical disease. Considering the low toxicity profile and tolerability, UAB30 may be more desirable than bexarotene in the combination study with WOKVAC to gain well-tolerated and long lasting anti-tumor response in treating DCIS and preventing invasive breast cancer.
Public Health Relevance Statement: Project Terms: <3-methyl TTNEB><9-cRA><9-cis-Retinoic Acid> 