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7. Restoration of DAP Kinase Tumor Suppressor Function: A Therapeutic Strategy to Selectively Induce Apoptosis in Cancer Cells Using Immunokinase Fusion Proteins

Author

Tur, Mehmet Kemal, Daramola, Adebukola K., Gattenloehner, Stefan, Herling, Marco, Chetty, Shivan, Barth, Stefan, Tur, Mehmet Kemal, Daramola, Adebukola K., Gattenloehner, Stefan, Herling, Marco, Chetty, Shivan, and Barth, Stefan

Abstract

Targeted cancer immunotherapy is designed to selectively eliminate tumor cells without harming the surrounding healthy tissues. The death-associated protein kinases (DAPk) are a family of proapoptotic proteins that play a vital role in the regulation of cellular process and have been identified as positive mediators of apoptosis via extrinsic and intrinsic death-regulating signaling pathways. Tumor suppressor activities have been shown for DAPk1 and DAPk2 and they are downregulated in e.g., Hodgkin's (HL) and B cell lymphoma (CLL), respectively. Here, we review a targeted therapeutic approach which involves reconstitution of DAPks by the generation of immunokinase fusion proteins. These recombinant proteins consist of a disease-specific ligand fused to a modified version of DAPk1 or DAPk2. HL was targeted via CD30 and B-CLL via CD22 cell surface antigens.

Published
2017

8. The development of novel HIV-1 vaccines using modified recombinant BCG

Author

Chetty, Shivan, Williamson, Anna-Lise, and Chapman, Rosamund

Subjects
Medical Virology, complex mixtures
Abstract

Vaccination continues to represent the most effective means of providing immunological protection against infectious disease in human populations. With the World Health Organisation (WHO) reporting over 1.2 million AIDS related deaths in 2014, an efficacious HIV1 vaccine is urgently needed. The UCT Human Immunodeficiency Virus (HIV) Vaccine Development Group has focussed on understanding novel HIV-1 vaccine vectors, such as modified BCG, combined with modified vaccinia Ankara in the context of heterologous prime boost regimes. The tuberculosis vaccine Bacillus Calmette–Guérin (BCG) has a wellestablished safety profile as well as notable adjuvant activity with an estimated 3 billion doses administered globally since 1921. The development of modern molecular biology techniques in recent times has led to the creation of modified strains of BCG which have been shown in many cases to be safer and/or more immunogenic than the wild type strains in terms of delivering heterologous antigen. This study focuses on exploiting and combining two particular strategies of rBCG modification. The first is the development of auxotrophic strains that contain deletions geared towards preventing the bacteria from synthesising essential growth compounds or amino acids. An example of this is the ΔpanCD auxotroph of rBCG which does not synthesise pantothenic acid and thus has limited intracellular replication leading to less pathology. The UCT group has previously reported that HIV vaccines vectored by the Pasteur strain of rBCG ΔpanCD induced less pathology but improved immunogenicity as compared to Pasteur WT in the murine model (when used a prime in conjunction with an MVA boost). A second notable BCG modification strategy is the inclusion of exogenous genes to improve the immunogenicity of rBCG as a vaccine vector. An example of this is the insertion of the detoxified Clostridium perfringens toxin, perfringolysin O (pfo), into the rBCG genome. Upon expression, pfo forms pores in the endosome which facilitates translocation of vaccine derived antigen into the cytoplasm. This modification has been shown to lead to cross priming of T cells and improve the induction of vaccine specific CD8+ T cell as compared to controls.

Published
2016

17. A Molecular Assay for Sensitive Detection of Pathogen-Specific T-Cells

Author

Kasprowicz, Victoria O., primary, Mitchell, Jessica E., additional, Chetty, Shivan, additional, Govender, Pamla, additional, Huang, Kuan-Hsiang Gary, additional, Fletcher, Helen A., additional, Webster, Daniel P., additional, Brown, Sebastian, additional, Kasmar, Anne, additional, Millington, Kerry, additional, Day, Cheryl L., additional, Mkhwanazi, Nompumelelo, additional, McClurg, Cheryl, additional, Chonco, Fundisiwe, additional, Lalvani, Ajit, additional, Walker, Bruce D., additional, Ndung'u, Thumbi, additional, and Klenerman, Paul, additional

Published
2011
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18. Prospective Monitoring Reveals Dynamic Levels of T Cell Immunity to Mycobacterium Tuberculosis in HIV Infected Individuals

Author

Chetty, Shivan, Govender, Pamla, Pillay, Mona, Jaggernath, Manjeetha, Ndung’u, Thumbi, Klenerman, Paul, Mitchell, Jessica E., Kasmar, Anne G., Walker, Bruce David, and Kasprowicz, Victoria Olivia

Subjects
Biology, Immunology, Immune Cells, Immune Response, Immunologic Techniques, Microbiology, Virology, Co-Infections, Medicine, Clinical Immunology, Diagnostic Medicine, Infectious Diseases, Bacterial Diseases, Mycobacterium, Tuberculosis, Viral Diseases, HIV, Infectious Disease Control
Abstract

Monitoring of latent Mycobacterium tuberculosis infection may prevent disease. We tested an ESAT-6 and CFP-10-specific IFN-\(\gamma\) Elispot assay (RD1-Elispot) on 163 HIV-infected individuals living in a TB-endemic setting. An RD1-Elispot was performed every 3 months for a period of 3–21 months. 62% of RD1-Elispot negative individuals were positive by cultured Elispot. Fluctuations in T cell response were observed with rates of change ranging from −150 to +153 spot-forming cells (SFC)/200,000 PBMC in a 3-month period. To validate these responses we used an RD1-specific real time quantitative PCR assay for monokine-induced by IFN-\(\gamma\) (MIG) and IFN-\(\gamma\) inducible protein-10 (IP10) (MIG: r = 0.6527, p = 0.0114; IP-10: r = 0.6967, p = 0.0056; IP-10+MIG: r = 0.7055, p = 0.0048). During follow-up 30 individuals were placed on ARVs and 4 progressed to active TB. Fluctuations in SFC did not correlate with CD4 count, viral load, treatment initiation, or progression to active TB. The RD1-Elispot appears to have limited value in this setting.

Published
2012
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