Our Science – Berzofsky Website
Jay A. Berzofsky, M.D., Ph.D.
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Biography
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, malaria, cancer, and viruses causing cancer. He has over 460 scientific publications. Dr. Berzofsky has received a number of awards, including the U.S. Public Health Service Superior Service Award, the 31st Michael Heidelberger Award, the McLaughlin Visiting Professorship, the Australasian Society for Immunology Visiting Lectureship, and the Tadeusz J. Wiktor Memorial Lectureship. He is past President of the American Society for Clinical Investigation, 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) 2007-08. He won the NIH Director's Award and NCI Merit Award in 2008 and a Merit Award 2011.Research
T Lymphocyte Recognition of Antigens and Applications to Vaccines for AIDS and Cancer
Our research focuses on elucidating new fundamental principles governing T cell activation, regulation, and effector function, and employing these to develop more effective vaccine and immunotherapy strategies for HIV, cancer, and viruses causing cancer. This involves several steps that together comprise a push-pull approach.
First, we optimize the antigen to improve immunogenicity by epitope enhancement, changing the amino acid sequence to increase affinity for the relevant major histocompatibility (MHC) molecule. We have done this for several cancer antigens, including the prostate cancer antigen, TARP, and have now completed accrual for a phase I/II clinical trial in prostate cancer patients with rising PSA levels to determine whether the TARP peptide vaccine can reduce the rate of PSA rise. The slope of PSA rise was significantly reduced in 69-70% of patients at 24 and 48 weeks, respectively. A phase II trial is planned.
The second step is to push the response with molecular adjuvants, such as cytokines and Toll-like receptor (TLR) ligands, to improve not only the quantity but also the quality of the response. We published that IL-15 is an important mediator of CD4 T cell help for CD8 T cells, in that it is sufficient to substitute for help in animals depleted of CD4 T cells, to allow a memory CD8 response and prevent TRAIL-mediated apoptosis, and also it is necessary for help. If dendritic cells (DCs) cannot be induced by helper cells to make IL-15, then the help is not adequately delivered to CD8 T cells. We also found that IL-15 increased the avidity of the CD8 T cells, necessary for effective clearance of virus or tumor cells. We extended this research to human CD8 T cells and showed that a primary in vitro CD8 T cell response was dependent on CD4 help but that IL-15 could be substituted, but not IL-2. IL-15 also restored the in vitro responses of CD8 T cells from HIV-infected individuals. We also found that IL-15 induces a novel set of T cells expressing only the CD8α chain, not the β chain, that are distinct from conventional CD8 T cells and distinct from the CD8α-only T cells found in the gut intraepithelial compartment. These cells make substantial levels of interferon-γ and have lytic activity.
We also investigated TLR ligands as adjuvants, because these can mature DCs and induce their production of cytokines like IL-12 and IL-15. We published a study showing synergy between pairs of TLR ligands that work through different intracellular signal transducers, MyD88 or TRIF, and determined the mechanism in DCs involving unidirectional cross-talk from TRIF to enhance MyD88-dependent cytokine production. We have now found a triple TLR ligand combination that induces more effective protection against virus infection. This combination does not increase T cell quantity, but improves quality by inducing higher avidity T cells, and induces more IL-15 production, accounting for the higher avidity. We tested the triple TLR ligands, IL-15, both or neither as vaccine adjuvants in a peptide-prime, MVA-boost mucosal vaccine for SIV in macaques, challenging intrarectally with SIVmac251. Only the macaques receiving both types of adjuvants showed some protection, so we investigated correlates of protection. In the adaptive immune arm, surprisingly only polyfunctional CD8 T cells specific for SIV antigens, but not total specific T cells measured by peptide-MHC tetramer binding, correlated with protection. In the innate immune arm, we found the adjuvants induced long-lived innate protection induced by the adjuvant combination. Thus, vaccine strategies that induce both innate and adaptive immunity may be the most efficacious.
The third step is to target the immune response to the relevant tissue, the mucosa in the case of HIV. We have studied mucosal T cell trafficking and discovered a lack of equilibrium between the intraepithelial compartment and the lamina propria in the small intestine, leading to a distinct founder effect in the narrower repertoire of intraepithelial T cells. We also found that one can prime mucosally with a DNA vaccine and direct a response to mucosa that after boosting systemically with a viral vector vaccine and vice versa, allowing for new combinations of vaccines to induce both systemic and mucosal immunity. We have previously compared mucosal versus subcutaneous delivery of a peptide AIDS vaccine in macaques and found that only the mucosal route induced CD8 T cells in the gut mucosa and was more effective at reducing virus load even in the blood because it more effectively cleared virus from the major reservoir for SIV replication in the gut mucosa that was seeding the bloodstream. We further found that induction of such CD8 T cells in the gut mucosa before intrarectal challenge with an AIDS virus could significantly delay dissemination of virus from the initial site of infection in the mucosa to the bloodstream. We conclude that the local CD8 T cell response was able to reduce the initial nidus of infection at the site of transmission, and that if we could more completely eradicate the virus at the initial nidus of infection, we might nip it in the bud and abort the infection before it disseminated and became established. We showed that this protective effect was correlated with induction of high avidity CD8 T cells in the gut mucosa, and not with CD8 T cells in the blood or peripheral lymph nodes. Development of a mucosal vaccine for HIV is most important because 85-90% of transmission is through a mucosal route, either genital or gastrointestinal, and because the major site of replication is in the gut mucosa, regardless of the route of transmission. We then devised a nanoparticle vaccine coated in a way to allow release in either the small or large intestine after oral delivery. Delivery to the large intestine mimicked intrarectal immunization by a more practical route, and achieved protective T and B cell immunity against both rectal and vaginal viral challenge, whereas delivery to the small intestine did not. These findings are being extended in further non-human primate studies as the preclinical basis for a human clinical trial. We have also investigated the mechanisms of homing to the colorectal mucosa, and shown that colonic DCs program T cells to preferentially return to the colon, and have investigated the chemokines involved.
The fourth step is to pull the response by removing the brakes, i.e., blocking the negative regulatory mechanisms that inhibit the immune response. We previously discovered a new immunoregulatory pathway involving NKT cells that suppresses tumor immunity. The NKT cells make IL-13 that induces myeloid cells to make TGF-β, which suppresses the CD8 T cell response. However, as we and others have also seen that NKT cells can protect against tumors, we needed to resolve this paradox. We found that type I NKT cells (using an invariant TCRα chain) protected, whereas type II NKT cells (using diverse T cell receptors) suppressed immunity. Moreover, selective activation of type I or type II NKT cells showed they cross-regulated each other, defining a new immunoregulatory axis, analogous to the axis between Th1 and Th2 cells that has profoundly affected immunology. The NKT cells are among the first responders, so the balance along the NKT axis could influence subsequent adaptive immune responses. We found that type II NKT cells also suppress conventional CD4 and CD8 antigen-specific T cells, so they are broadly suppressive. We are examining the mechanisms of suppression and also investigating the relationship between suppressive NKT cells and CD25+ Foxp3+ T regulatory cells. In one tumor model we find that both Treg cells and type II NKT cells can suppress tumor immunity, but that the effect of the latter is counterbalanced by type I NKT cells unless the latter are absent. In trying to tip the balance along the NKT regulatory axis, we find that blocking IL-13 can delay growth of spontaneous, autochthonous tumors even in HER-2 transgenic mice that develop aggressive independent tumors in all 10 mammary glands. Conversely, stimulating with a type I NKT cell agonist can protect against tumors. We discovered a new class of NKT cell agonist represented by beta-mannosylceramide, that protects against tumors by a novel mechanism dependent on TNF and nitric oxide synthase (NOS) but not on interferon-gamma, distinct from that of alpha-galactosylceramide which is dependent on interferon-gamma and not on TNF or NOS. We are exploring the mechanism of this protection, but because this new agonist avoids natural alpha-gal antibodies and induces less anergy than alpha-GalCer, and because it synergizes with alpha-GalCer and also stimulates human iNKT cells, we are pursuing it as an immunomodulator to improve immunity against human cancer. We are comparing different NKT agonists, so that we may be able to tailor the protective response to fit different conditions and to achieve synergy between different mechanisms of protection.
A key mediator of the NKT regulatory pathway and an important regulator of T regulatory cells is TGF-β. We have found that blockade of TGF-β can protect against certain tumors in mice, and can synergize with anti-cancer vaccines in two mouse models. The protection is dependent on CD8 T cells, and when used in combination with a vaccine, the anti-TGF-β increases the number of both total and high avidity CD8 T cells. We have translated this into a human clinical trial of a human anti-TGF-β monoclonal antibody in a CRADA with Genzyme, in melanoma and renal cell cancer. The phase I study showed some activity including one 89% partial remission. We are now developing phase II clinical trials in melanoma and prostate cancer, and would like to combine the antibody with a vaccine to induce anti-cancer immunity.
Finally, we published that an adenovirus vaccine expressing the extracellular and transmembrane domains of HER-2 can cure large established mammary cancers and lung metastases in mice. The mechanism surprisingly involves antibodies that inhibit HER-2 function, rather than T cells. We have now made a similar recombinant adenovirus expressing the human HER-2 domains to carry out a clinical trial in human cancer patients that we hope to open in mid-2012.
This page was last updated on 3/12/2013.
