Exploitation of costimulatory SA-4-1BBL in the development of therapeutic cancer vaccines.

SA-4-1BBL;Adjuvant;Cancer;SA-OX40L;Therapeutic vaccine;MPLA

Abhishek K. Srivastava

University:University of Louisville

Department:Microbiology and Immunology

关键词: SA-4-1BBL;    Adjuvant;    Cancer;    SA-OX40L;    Therapeutic vaccine;    MPLA;   

Others  :  https://ir.library.louisville.edu/cgi/viewcontent.cgi?article=2366&context=etd

美国|英语

来源: The Universite of Louisville's Institutional Repository

【 摘 要 】

Cancer accounts for nearly one-quarter of deaths in the United States, exceeded only by heart diseases. Despite the development of various strategies to treat cancer, it remains one of the most deadly diseases worldwide due to the limited effects of treatments available. The limited efficacy of these current treatment modalities, such as surgery, radiotherapy, and chemotherapy, are often due to their association with adverse side effects arising from lack of specificity for tumors, and most importantly their failure of eliminating residual and micro-metastatic tumors, which can lead to recurrences. Therefore, there is a dire need to develop tumor-specific therapies that not only eliminate primary tumors, but also micro-metastasis and prevent recurrences. In this regard, therapeutic cancer vaccines based on tumor-associated antigens (TAAs) has evolved as a promising approach due to their safety profile, ease of production, storage, transportation, administration to a broad patient population and most importantly establishment and/or maintenance of long-term immunological memory critical for the control of recurrences, a major cause of cancer death. However, despite theoretical promise, development of therapeutic cancer vaccines has been facing numerous set-backs mostly due to the weak immunogenicity of T AAs, tolerance to self-T AAs and various immune evasion mechanisms employed by progressing tumors. Therefore, we hypothesized that use of natural costimulatory ligands of TNF family as adjuvant may overcome these limitations due to their effect on cells of innate, adaptive, and regulatory immunity without any sign of toxicity. The tumor necrosis factor receptor (TNFR)/TNF superfamily represents a crucial group of costimulatory receptor/ligands as most of the receptors of this family are inducibly expressed on various immune cells. Costimulatory receptors that are inducibly expressed or upregulated on activated T cells may serve as preferred targets for immunomodulation due to their potential to selectively target antigen-experienced T cells for expansion, survival, and establishment of long-term immunological memory. Among these family members, 4-1BB/4-1BBL signaling has recently been much appreciated as its signaling provides the essential survival signals, particularly in CD8+ T cells. 4-1BB signaling into T cells allows CD8+ T cell expansion, cytokine production, development of CTL effector function, and prevention of apoptotic cell death by up-regulating anti-apoptotic Bcl-xL and Bcl-2 molecules. As the aim of tumor immunotherapy is to generate long-lasting immune response, particularly CD8+ T cell specific response, for the destruction of tumor cells, in this project, we focused on the utilization of 4-1 BBL either alone or in combination with other