Fowlpox‐based survivin vaccination for malignant mesothelioma therapy

Abstract

Survivin protein is an attractive candidate for cancer immunotherapy since it is abundantly expressed in most common human cancers and mostly absent in normal adult tissues. Malignant mesothelioma (MM) is a deadly cancer associated with asbestos or erionite exposure for which no successful therapies are currently available. In this study, we evaluated the therapeutic efficacy of a novel survivin-based vaccine by subcutaneous or intraperitoneum injection of BALB/c mice with murine fiber-induced MM tumor cells followed by vaccination with recombinant Fowlpox virus replicons encoding survivin. Vaccination generated significant immune responses in both models, leading to delayed tumor growth and improved animal survival. Flow cytometry and immunofluorescence analyses of tumors from vaccinated mice showed CD8+ T cell infiltration, and real-time PCR demonstrated increased mRNA and protein levels of immunostimulatory cytokines. Analyses of survivin peptide-pulsed spleen and lymph node cells from vaccinated mice using ELISPOT and intracellular cytokine staining confirmed antigen-specific, interferon-γ-producing CD8+ T cell responses. In addition pentamer-based flow cytometry showed that vaccination generated survivin-specific CD8+ T cells. Importantly, vaccination did not affect fertility or induce autoimmune abnormalities in mice. Our results demonstrate that vaccination with recombinant Fowlpox expressing survivin improves T cell responses against aggressive MM tumors and may form the basis for promising clinical applications.

Vaccination with a piggyBac plasmid with transgene integration potential leads to sustained antigen expression and CD8+ T cell responses

“…The CD8 + T cell numbers specific for eGFP followed the classic expansion/contraction pattern as expected, with three-fold more eGFP-specific CD8 + T cells at peak response in mice vaccinated with the integrating plasmid compared to those vaccinated with non-integrating plasmid. Note that a secondary boost with the integrating p mhy GENIE-3-EGFP plasmid was required for optimal immune responses similar to our previous study using viral vectors [19]. This may have been due to immune responses against the cells expressing antigen.…”

“…However, the safety of these live recombinant vectors is always a concern as uncontrolled replication can result in complications from vaccination or therapeutic use. Viral vectors that are incapable of replicating in mammalian cells such as the Fowlpox virus have been pursued as safe alternatives [19, 27], but the need for repeated boosts that may lead to neutralization of the viral vectors by circulating antibodies in these secondary inoculations is problematic.…”

Targeting the C-terminus of galectin-9 induces mesothelioma apoptosis and M2 macrophage depletion

“…Immunohistochemistry for galectin-9 (LS-B6275 mAb, LS Bio) was performed as previously described. 44 Presence of galectin-9 positive cells was evaluated on 10 fields/slide at 200× magnification with a BX43 microscope (Olympus, PA, ISA).…”

Latest developments in our understanding of the pathogenesis of mesothelioma and the design of targeted therapies

“…Survivin is an attractive candidate for cancer immunotherapy since it is abundantly expressed in most human cancers, including MM, and it is largely absent in normal adult tissues. A vaccine based on Fowlpox vector expressing survivin was found to successfully trigger an immune response in a MM mouse model [199]. The response resulted in delayed tumor growth and improved survival, indicating that the vaccine could serve as the basis for the development of clinically relevant MM immune-based treatments and/or prevention strategies [199].…”

“…A vaccine based on Fowlpox vector expressing survivin was found to successfully trigger an immune response in a MM mouse model [199]. The response resulted in delayed tumor growth and improved survival, indicating that the vaccine could serve as the basis for the development of clinically relevant MM immune-based treatments and/or prevention strategies [199]. Recently, highly immunogenic vaccines against human survivin have been developed and tested preclinically [200], confirming their potential role in human MM therapy.…”