Chief, Vaccine Branch
Center for Cancer Research, National Cancer Institute
Hosted by Chad Mirkin
We have developed nanoparticle vaccines to induce mucosal immunity against viral infections, and a TARP epitope-enhanced peptide vaccine against prostate cancer that has been translated to a promising clinical trial, and it may be possible to combine these approaches in a nanoparticle vaccine for cancer. First, regarding the nanoparticle mucosal vaccine, we had earlier discovered that one of the most effective routes for inducing GI mucosal immunity in mice was the intrarectal route. To develop a more practical route of delivery mimicking that, we developed nanoparticle vaccines coated with Eudragit for oral delivery that could be formulated to release the nanoparticles after reaching the large intestine. Indeed, these mimicked the intrarectal vaccination, inducing both T and B cell immunity and protecting against an intrarectal or intravaginal challenge with a vaccinia recombinant expressing the HIV envelope protein. We translated this approach to rhesus macaques in which we could similarly deliver antigen selectively to the large intestine and, in preliminary studies, could achieve some protection against intrarectal challenge with SHIV, a chimeric SIV expressing the HIV envelope protein. Thus, oral nanoparticle vaccines may provide a practical effective approach to inducing mucosal immunity.
Second, we have developed an enhanced peptide vaccine against prostate cancer. We mapped epitopes in the TARP prostate cancer antigen binding to HLA-A2, the most common human class I HLA molecule, and then modified the sequence to improve binding, and demonstrated that these could induce human T cells that killed human tumor cells expressing TARP and HLA-A2, proving that TARP is naturally processed and presented in these tumors. We have now carried out a clinical trial in stage D0 prostate cancer, the stage in which the primary tumor was removed but rising PSA indicates microscopic recurrence. In this setting, the slope of PSA rise has been found to predict clinical outcome. The epitope-enhanced peptide vaccine was able to reduce the PSA slope in 74% of patients at one year compared to baseline slope before treatment (p = 0.0004), and in 15% the absolute level of PSA also fell. An improved version of this vaccine, not limited to HLA-A2, is now in a phase II placebo-controlled trial.
Finally, we have developed a nanoFACS technology that can analyze and sort 100 nm diameter extracellular vesicles such as exosomes, 100-fold smaller in diameter and 1 million-fold smaller in volume than an average cell. These are normally lost in the noise of conventional flow cytometers. The ability to study and isolate subsets of exosomes could open the door to new biomarkers for cancer and response to therapy, and well as markers of immune responses.
Dr. Jay Berzofsky was appointed Chief of the new Vaccine Branch, Center for Cancer Research, National Cancer Institute, in 2003, after being Chief of the Molecular Immunogenetics and Vaccine Research Section, Metabolism Branch, National Cancer Institute, NIH, since 1987. He graduated Summa cum Laude from Harvard (1967), and received a Ph.D. and M.D. from Albert Einstein College of Medicine. After interning at Massachusetts General Hospital, he joined NIH in 1974. Dr. Berzofsky's research has focused on antigen processing and presentation by MHC molecules, the structure of antigenic determinants, cytokine and regulatory cell control of T cell function and avidity, and translation to the design of vaccines for AIDS, cancer, and viruses causing cancer. He has 492 scientific publications and a number of awards. He was elected as President of the American Society for Clinical Investigation (1993-94), a member of the Association of American Physicians, and a Fellow of the American Association for the Advancement of Science, and was elected Distinguished Alumnus of the Year for 2007 by the Albert Einstein College of Medicine. He was also elected Chair of the Medical Sciences Section of the American Association for the Advancement of Science (AAAS) for 2007-2008. In 2008, he received the NIH Director’s Award and the NCI Merit Award, and in 2011 he received another NCI Director’s Merit Award.