Yiping Yang, MD, PhD
Duke University Medical Center
Leukemia / Lymphoma
The role of innate immunity in active immunotherapy for lymphoma.
An ultimate goal of cancer immunotherapy is to activate tumor-specific T cells through therapeutic vaccinations to eradicate pre-established tumor. However, tumor-specific T cell tolerance remains one of the major barriers in cancer immunotherapy. Thus, to elicit effective anti-tumor immunity, it is necessary to develop vaccine strategies capable of overcoming T cell tolerance.
In the previous application funded by Alliance for Cancer Gene Therapy, we have demonstrated an essential role of the innate immune system in shaping adaptive immune responses. In a series of 10 peer-reviewed publications, we have identified several parameters that are critical for the potency of a vaccine in overcoming T cell tolerance: 1) the ability of the vaccine to activate multiple innate immune pathways, leading to production of both type I interferons (IFNs) and pro-inflammatory cytokines; 2) the ability to activate both plasmacytoid dendritic cells (pDCs) and conventional DCs (cDCs); and 3) the ability to activate other innate immune cells such as NK cells, which further enhances adaptive immune responses.
Based on these important parameters, we have demonstrated in a murine model of pre-established lymphoma that DC vaccines co-administered with the TLR9 ligand, CpG in vivo are effective in activating tumor-specific T cell response and treating pre-established lymphoma. This is probably related to the ability of CpG to activate both cDCs and pDCs and to produce pro-inflammatory cytokines and type I IFNs, respectively. In addition, CpG can also activate NK cells.
In this application, we will test the central hypothesis that DC vaccines co-administered with CpG in vivo are effective in activating tumor-specific CD8+ T cell response in patients with lymphoma through the following three specific aims: 1) To perform and analyze FDA required bio-distribution and toxicology studies in mice; 2) To obtain full regulatory approval and GMP manufacturing of DC vaccines to support the trial; and 3) To conduct a pilot phase I to study the safety and immunological efficacy of Epstein-Barr virus (EBV)-derived tumor antigen (LMP2) loaded DC vaccines in patients with EBV-associated lymphoma. We plan to administer LMP2-loaded DC vaccines twice intravenously.
The boost vaccination will be administered 4 weeks after the first vaccination. GMP-grade CpG will be given intramuscularly with each vaccination. We will determine the safety and feasibility of the treatment by determining 1) clinical toxicology; 2) tumor antigen-specific immune responses; 3) although a secondary goal, anti-tumor effect will also be measured. In summary, this will be the first clinical trial designed to enhance anti-tumor immunity using a combined strategy of tumor.
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Yiping Yang, MD
School of Medicine
2019 Msrb-Ii, 106 Research Drive
Durham, NC 27710