Imagine calling T-cells, macrophages, and antibodies into action by taking a simple pill that instantaneously programs both adaptive and innate arms of the immune system to attack a tumor or virus, preventing infection and halting disease. Such an approach could meet major unmet challenges in biomedical research and therapy. My goal is to develop novel approaches that allow innate and acquired immunity to be purposefully targeted to pathogens of interest. These studies build on recently revealed mechanisms of Toll-like receptor signaling, ideas concerning approaches of targeting their sensing abilities to pathogens of defined interest and insights gained from our own invention of chemically programmed antibodies. Ultimately, these studies will allow scientists to program a variety of immune cells and responses to attack pathogens of interest using a variety of mechanisms. We will apply these results to studies in cancer therapy. Furthermore, we will explore novel approaches that should allow for circulating immunoglobulins induced with covalent vaccines to be programmed to inhibit HIV-1 and flu virus entry. The vaccines that result from these studies may be of both prophylactic and therapeutics utility. I will develop novel chemical approaches aimed at learning how to purposefully target innate immunity, T- cells, and macrophages to defined pathogens. I will apply these developments to create new cancer therapies. I will develop a novel approach to orally available chemically programmed immunity. I will apply developments in orally available chemically programmed immunity towards new vaccine strategies for HIV-1 and flu.

Public Health Relevance

This research will explore new approaches towards directing immune responses to fight cancers and viruses. If successful, new therapies for cancer and HIV-1 will result. Additionally, a new approach to vaccines against HIV-1 and swine flu will be created.

National Institute of Health (NIH)
National Cancer Institute (NCI)
NIH Director’s Pioneer Award (NDPA) (DP1)
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Special Emphasis Panel (ZGM1-NDPA-B (01))
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Bhatia, Kishor
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Scripps Research Institute
La Jolla
United States
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Perdigão, Pedro; Gaj, Thomas; Santa-Marta, Mariana et al. (2016) Reactivation of Latent HIV-1 Expression by Engineered TALE Transcription Factors. PLoS One 11:e0150037
Inokuma, Tsubasa; Fuller, Roberta P; Barbas 3rd, Carlos F (2015) N-Sulfonyl-β-lactam hapten as an effective labeling reagent for aldolase mAb. Bioorg Med Chem Lett 25:1684-7
Liu, Jia; Gaj, Thomas; Yang, Yifeng et al. (2015) Efficient delivery of nuclease proteins for genome editing in human stem cells and primary cells. Nat Protoc 10:1842-59
Gaj, Thomas; Liu, Jia (2015) Direct protein delivery to mammalian cells using cell-permeable Cys2-His2 zinc-finger domains. J Vis Exp :
Wallen, Mark C; Gaj, Thomas; Barbas 3rd, Carlos F (2015) Redesigning Recombinase Specificity for Safe Harbor Sites in the Human Genome. PLoS One 10:e0139123
Gaj, Thomas; Sirk, Shannon J; Tingle, Ryan D et al. (2014) Enhancing the specificity of recombinase-mediated genome engineering through dimer interface redesign. J Am Chem Soc 136:5047-56
Gaj, Thomas; Liu, Jia; Anderson, Kimberly E et al. (2014) Protein delivery using Cys2-His2 zinc-finger domains. ACS Chem Biol 9:1662-7
Patterson, James T; Asano, Shigehiro; Li, Xiuling et al. (2014) Improving the serum stability of site-specific antibody conjugates with sulfone linkers. Bioconjug Chem 25:1402-7
Gaj, Thomas; Sirk, Shannon J; Barbas 3rd, Carlos F (2014) Expanding the scope of site-specific recombinases for genetic and metabolic engineering. Biotechnol Bioeng 111:1-15
Gaj, Thomas; Barbas 3rd, Carlos F (2014) Genome engineering with custom recombinases. Methods Enzymol 546:79-91

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