Enhancing cytotoxic T lymphocyte (CTL) responses by directly loading CTL epitope vaccines onto MHC Class I complexes on the dendritic cell surface

University Of Utah, Salt Lake City UT

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Abstract

Project summary Cytotoxic T lymphocyte (CTL)-mediated immune responses are the primary effector mechanism in immunotherapies against cancer and virus infection. Vaccines are able to boost CTL responses, and are being intensively pursued in the laboratory and clinical settings. However, there is a large gap between the vaccine development effort and the efficacy of these vaccines. This gap motivates us to reexamine current vaccination strategies and to develop an alternative strategy to close the gap. Current strategies rely on the intra-dendritic cell (DC) processing of vaccines, which is not efficient due to multiple barriers embedded in the process. We thus aim to develop a distinct vaccination strategy that completely bypasses the intra-DC processing. To this end, and based on our preliminary research results, we propose to develop an immune-tolerant elastin-like polypeptide (iTEP)-based fusion as a vaccine carrier that is able to directly load CTL epitopes (CTL vaccines) onto the MHC class I complexes on DC surfaces. These epitopes will be subsequently used by DCs to induce CTL responses. We hypothesize that the fusion will drastically boost the effectiveness of the vaccines as compared to vaccines requiring intra-DC processing. We will engineer and characterize the fusion with the following two aims: Aim 1: Examine functionalities of the ABD-iTEP-pMMP-epitope fusion in vitro. Aim 2: Establish functionalities and effects of the ABD-iTEP-pMMP-epitope fusion in vivo. In consideration of the importance and current challenges of CTL vaccines, the main contribution of this proposed study is that it explores a novel and a direct epitope loading strategy to unprecedentedly strengthen CTL vaccine-induced responses. This novel yet straightforward strategy may bring about an unprecedented impact on these vaccines, allowing them to play a more decisive role in the immunotherapy and immune preventions of cancer, infections, and other diseases.