Therapeutic Vaccines for HPV-Associated Malignancies.

Human papillomavirus (HPV)-related malignancies are responsible for almost all cases of cervical cancer in women, and over 50% of all cases of head and neck carcinoma. Worldwide, HPV-positive malignancies account for 4.5% of the global cancer burden, or over 600,000 cases per year. HPV infection is a pressing public health issue, as more than 80% of all individuals have been exposed to HPV by age 50, representing an important target for vaccine development to reduce the incidence of cancer and the economic cost of HPV-related health issues. The approval of Gardasil® as a prophylactic vaccine for high-risk HPV 16 and 18 and low-risk HPV6 and 11 for people aged 11-26 in 2006, and of Cervarix® in 2009, revolutionized the field and has since reduced HPV infection in young populations. Unfortunately, prophylactic vaccination does not induce immunity in those with established HPV infections or HPV-induced neoplasms, and there are currently no therapeutic HPV vaccines approved by the US Food and Drug Administration. This comprehensive review will detail the progress made in the development of therapeutic vaccines against high-risk HPV types, and potential combinations with other immunotherapeutic agents for more efficient and rational designs of combination treatments for HPV-associated malignancies.

Examining breast cancer disparities in African Americans with suggestions for policy.

Breast cancer is a commonly diagnosed malignancy and the second leading cause of cancer-related death among American women today. The literature suggests that African American Women (AAW) are more likely to die from the disease each year compared to their White counterparts. A biological basis for this disparity exists-early age of onset, more advanced stage of the disease, more aggressive histological changes, and worse survival. Even though mechanisms underlying these disparities are poorly understood, recent studies suggest that the poorer breast cancer outcome observed in AAW may, in part, result from underlying molecular factors. The present review was undertaken to investigate if AAW do, in fact, develop a more aggressive form of breast cancer compared to other racial groups based on molecular level differences and social determinants. This review also addresses health policy changes that may be implemented to aid in eliminating this disparity.

Analyses of functions of an anti-PD-L1/TGFßR2 bispecific fusion protein (M7824).

M7824 (MSB0011359C) is a novel first-in-class bifunctional fusion protein consisting of a fully human IgG1 anti-PD-L1 monoclonal antibody (with structural similarities to avelumab) linked to the extracellular domain of two TGFß receptor 2 (TGFßR2) molecules serving as a TGFß Trap. Avelumab has demonstrated clinical activity in a range of human cancers and has been approved by the Food and Drug Administration for the therapy of Merkel cell and bladder carcinomas. Preclinical studies have shown this anti-PD-L1 is capable of mediating antibody-dependent cell-mediated cytotoxicity (ADCC). In the studies reported here, it is shown that M7824 is also capable of mediating ADCC of a wide range of human carcinoma cells in vitro, employing natural killer (NK) cells as effectors, albeit not as potent as anti-PD-L1 employing some tumor cells as targets. The addition of the IL-15 superagonist fusion protein complex ALT-803 enhanced the ADCC capacity of both anti-PD-L1 and M7824, and to levels that both agents now demonstrated similar levels of ADCC of tumor cells. TGFß is a known immunosuppressive entity. Studies reported here show TGFß1 induced reduction of several NK activation markers as well as reduction of endogenous NK lytic activity and NK-mediated ADCC of tumor cells. These phenomena could be reduced or mitigated, however, by M7824, but not by anti-PD-L1. M7824, but not anti-PD-L1, was also shown to reduce the immunosuppressive activity of regulatory T cells on human CD4+ T-cell proliferation. These studies thus demonstrate the dual functionalities of M7824 and provide the rationale for its further clinical development.

Modulatory effects of bortezomib on host immune cell functions.

Bortezomib is an inhibitor of the ubiquitin-proteasome proteolytic pathway responsible for intracellular protein turnover. Cellular proteins controlled by this pathway represent a diverse group of potential therapeutic targets, particularly in cancer cells, which exploit this proteasomal pathway to promote their growth and diminish apoptosis. Along with inhibiting the proteasome and thus sensitizing tumor cells to apoptosis, bortezomib may also have multiple effects on the host immune responses. This review summarizes the effects that bortezomib may play on immune cell subsets in various disease states in modifying lymphocyte receptors, ligands, the expression of various cytokines and chemokines and their downstream signaling. We also propose steps that can be taken to refine combinatorial strategies that include bortezomib to improve current immunotherapeutic approaches.

Increased cell surface free thiols identify effector CD8+ T cells undergoing T cell receptor stimulation.

Recognition of peptide Major Histocompatibility Complexes (MHC) by the T cell receptor causes rapid production of reactive oxygen intermediates (ROI) in naïve CD8(+) T cells. Because ROI such as H2O2 are membrane permeable, mechanisms must exist to prevent overoxidation of surface proteins. In this study we used fluorescently labeled conjugates of maleimide to measure the level of cell surface free thiols (CSFT) during the development, activation and differentiation of CD8(+) T cells. We found that during development CSFT were higher on CD8 SP compared to CD4 SP or CD4CD8 DP T cells. After activation CSFT became elevated prior to division but once proliferation started levels continued to rise. During acute viral infection CSFT levels were elevated on antigen-specific effector cells compared to memory cells. Additionally, the CSFT level was always higher on antigen-specific CD8(+) T cells in lymphoid compared to nonlymphoid organs. During chronic viral infection, CSFT levels were elevated for extended periods on antigen-specific effector CD8(+) T cells. Finally, CSFT levels on effector CD8(+) T cells, regardless of infection, identified cells undergoing TCR stimulation. Taken together these data suggest that CD8(+) T cells upregulate CSFT following receptor ligation and ROI production during infection to prevent overoxidation of surface proteins.

Development of Proteasome Inhibitors as Therapeutic Drugs.

The proteasome is a multi-unit enzyme complex found in the cytoplasm and nucleus of all eukaryotic cells and is responsible for degradation of unneeded or damaged intracellular proteins by proteolysis, a chemical reaction that breaks peptide bonds. Proteasome inhibition presents a promising approach to cancer therapy by targeting the proteasome function in tumor cells. Delineating the success of bortezomib in the treatment of multiple myeloma and mantle cell lymphoma, this review explores various proteasome inhibitors, currently in development, as molecular targeting agents in the fight against cancer. Proteasome inhibitors can be used alone or in combination with other conventional cancer therapies to sensitize tumor cells to cell death by various mechanisms and improve therapeutic benefits.