Nventa Biopharmaceuticals Corp.

Infection with human papillomavirus type 16 (HPV16) is strongly associated with a number of disease states, of which cervical and anal cancers represent the most drastic endpoints. Induction of T-cell-mediated immunity, particularly cytotoxic T lymphocytes (CTL), is important in eradication of HPV-induced lesions. Studies have shown that heat shock protein fusion proteins are capable of inducing potent antigen-specific CTL activity in experimental animal models. In addition, E7-expressing tumors in C57BL/6 mice can be eradicated by treatment with HspE7, an Hsp fusion protein composed of Mycobacterium bovis BCG Hsp65 linked to E7 protein of HPV16. More importantly, HspE7 has also displayed significant clinical benefit in phase II clinical trials for the immunotherapy of HPV-related diseases. To delineate the mechanisms underlying the therapeutic effects of HspE7, we investigated the capability of HspE7 to induce antigen-specific protective immunity. Here, we demonstrate that HspE7 primes potent E7-specific CD8 + T cells with cytolytic and cytokine secretion activities. These CD8 + T cells can differentiate into memory T cells with effector functions in the absence of CD4 + T-cell help. The HspE7-induced memory CD8 + T cells persist for at least 17 weeks and confer protection against E7-positive murine tumor cell challenge. These results indicate that HspE7 is a promising immunotherapeutic agent for treating HPV-related disease. Moreover, the ability of HspE7 to induce memory CD8 + T cells in the absence of CD4 + help indicates that HspE7 fusion protein may have activity in individuals with compromised CD4 + functions, such as those with invasive cancer and/or human immunodeficiency virus infection.

There is a high prevalence of diseases caused by human papillomavirus (HPV) infection. Unfortunately, current treatments are inadequate. However, because there is evidence to support a role for the immune system in host defence against this virus, an immunotherapeutic approach is warranted. The existing immunotherapies are not completely effective, nor are they durable. In addition, natural history studies associated with spontaneous regression have provided little guidance to the design of successful interventions. This state of knowledge has encouraged efforts towards the development of novel immunotherapeutic strategies. Successful preclinical studies of therapeutic vaccine candidates have led to clinical studies for a variety of HPV-associated indications, such as anogenital warts and cervical and anal intraepithelial neoplasia. Immunisation approaches such as adjuvanted peptides, virus-like particles and fusion constructs are discussed. Specifically, chimaeric molecules comprised of mycobacterial heat-shock proteins (Hsps) and HPV16 E7 appear promising.

A number of recent findings have highlighted the similarities between neurogenesis during development and neurodegeneration during Alzheimer disease. In fact, neuronal populations that are known to degenerate in Alzheimer disease exhibit phenotypic changes characteristic of cells re‐entering the cell division cycle. In this study, we extended these findings by investigating components of the cell cycle, known to trigger progression through G1 through activation of signal transduction cascades. Specifically, we found that proteins implicated in G1 transition, namely Cdc42/Rac, are upregulated in select neuronal populations in cases of Alzheimer disease in comparison to age‐matched controls. Importantly, Cdc42/Rac shows considerable overlap with early cytoskeletal abnormalities suggesting that these changes are an extremely proximal event in the pathogenesis of the disease. Given the functional role of Cdc42/Rac in various cellular processes known to be perturbed in Alzheimer disease, namely cytoskeletal organization, oxidative balance, and oncogenic signaling, it is likely that increased neuronal Cdc42/Rac is highly significant in relation to the pathogenic process and contributes to neuronal degeneration. In fact, these findings suggest that Alzheimer disease is an oncogenic process.