ZIA SC 004020 (ZIA) | |||
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Title | Antigen-specific T-cell Activation, Application to Vaccines for Cancer and AID | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Berzofsky, Jay | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $2,592,300 | Project Dates | 00/00/0000 - 00/00/0000 |
Fiscal Year | 2017 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Childhood Cancers (2.0%) Digestive Diseases (15.0%) Interferon (10.0%) Metastasis (30.0%) |
Breast (20.0%) Cervical Cancer (5.0%) Lung (10.0%) Melanoma (15.0%) Ovarian Cancer (10.0%) Prostate (25.0%) |
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Research Type | |||
Vaccines Systemic Therapies - Discovery and Development |
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Abstract | |||
The strategies above involve 5 steps that together comprise a push-pull approach. First, we optimize the antigen to improve immunogenicity by epitope enhancement, increasing affinity for MHC. We applied this to 2 new prostate cancer antigens, TARP and POTE. We published a phase I/II TARP clinical trial in D0 prostate cancer patients using a TARP peptide epitope-enhanced to improve HLA-A2 binding and another high-affinity one we mapped. The slope of PSA rise significantly decreased among 72% of 40 patients (p = 0.0012) at 24 wks and 74% (p = 0.0004) at 48 wks, implying slowing of cancer growth. A randomized placebo-controlled phase II trial is now open, with a 2:1 randomization (44:22) of vaccine to placebo. Accrual has been substantially delayed (25 months!) by closure of the NIH Pharmacy Service that necessitated cGMP production and vialing of replacement peptides. The second step is increasing T cell avidity, needed for effective clearance of virus or cancer. We found that lowering antigen dose with a novel adjuvant allowed induction of higher avidity more protective CD4 T cells. The third step is to push the response with molecular adjuvants, such as cytokines, Toll-like receptor (TLR) ligands and NKT agonists, to improve not only the quantity but also the quality of the response. We published that IL-15 is a key mediator of CD4 T cell help for CD8 T cells and that IL-15 increased CD8 T cell avidity. We translated this to humans showing that IL-15 could substitute for CD4 help to induce a primary in vitro CD8 T cell response of naive T cells, and restored responsiveness of CD8 T cells from HIV-infected patients to normal levels. We also found that IL-1beta as adjuvant could enhance CD8 T cell responses and skew CD4 help to Th17. We found surprisingly that the Th17 CD4 cells were not good helpers for CD8 T cell responses as measured by IFN-g production, but rather skewed the CD8 response to IL-17 production through an effect on DCs dependent on IL-21 & 23. We also investigated TLR ligands as adjuvants to mature DCs and induce production of IL-12 and IL-15. We identified in mice a synergistic triple TLR ligand combination and tested this with IL-15 as vaccine adjuvants in a peptide-prime, MVA-boost mucosal vaccine for SIV in macaques, challenging intrarectally with SIVmac251. Only macaques receiving both showed partial protection. In the adaptive immune arm, only polyfunctional CD8 T cells specific for SIV antigens correlated with protection. In the innate immune arm, the adjuvants induced long-lived protection by APOBEC3G. The adjuvants also increased gut CD4 cell preservation, independent of viral load. Adjuvant alone plus a PD-1 blocker and an NKT cell agonist induced CD8-dependent protection (after intrarectal SIV challenge). Yet vaccine could induce MDSC counteracting vaccine efficacy. SIV infection also paradoxically reduced MDSC in bone marrow and increased them in the blood. We also discovered that MDSCs could be infected by SIV. The fourth step is to target the immune response to the relevant tissue, the mucosa in the case of HIV. We published a novel nanoparticle approach for vaccine delivery to the large intestine, using coated vaccine nanoparticles to allow oral delivery and release of the particles primarily in the colon, bypassing the stomach and small intestine and substituting for intrarectal delivery to protect against rectal or vaginal viral challenge. This novel approach allows selective oral delivery to the small or large intestine, enabling selective immunization in these compartments for the first time. We have recently adapted this approach to non-human primates in an AIDS vaccine. 2/7 animals so immunized were protected from acquisition of SHIVsf162P4 high dose rectal challenge (p=0.04 vs 0/29 controls). An expanded study showed 42% vaccine efficacy by an oral nanoparticle vaccine incorporating an Env-CD4D1-D2 fusion protein (FLSC) and MVA against repeated low-dose intrarectal SHIV challenge. Among nai |