LAMP1 targeting of the large T antigen of Merkel cell polyomavirus results in potent CD4 T cell responses and tumor inhibition

Frontiers in Immunology

Immunology

David M. Koelle¹  Paul Nghiem²  Joseph J. Carter³  Denise A. Galloway³  Claire Buchta Rosean⁴  Jeneice Hamilton⁴  Teri Heiland⁴  Erica C. Leyder⁴ 

[1] Department of Medicine, University of Washington, Seattle, WA, United States;Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Center, Seattle, WA, United States;Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, United States;Department of Global Health, University of Washington, Seattle, WA, United States;Department of Translational Research, Benaroya Research Institute, Seattle, WA, United States;Division of Dermatology, Department of Medicine, University of Washington, Seattle, WA, United States;Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, United States;Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States;Immunomic Therapeutics Inc., Rockville, MD, United States;

关键词: immunotherapy;    cancer vaccine;    Merkel cell polyomavirus;    Merkel cell carcinoma;    tumor microenvironment;   

DOI  :  10.3389/fimmu.2023.1253568

 received in 2023-07-05, accepted in 2023-08-14,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionMost cases of Merkel cell carcinoma (MCC), a rare and highly aggressive type of neuroendocrine skin cancer, are associated with Merkel cell polyomavirus (MCPyV) infection. MCPyV integrates into the host genome, resulting in expression of oncoproteins including a truncated form of the viral large T antigen (LT) in infected cells. These oncoproteins are an attractive target for a therapeutic cancer vaccine.MethodsWe designed a cancer vaccine that promotes potent, antigen-specific CD4 T cell responses to MCPyV-LT. To activate antigen-specific CD4 T cells in vivo, we utilized our nucleic acid platform, UNITE™ (UNiversal Intracellular Targeted Expression), which fuses a tumor-associated antigen with lysosomal-associated membrane protein 1 (LAMP1). This lysosomal targeting technology results in enhanced antigen presentation and potent antigen-specific T cell responses. LTS220A, encoding a mutated form of MCPyV-LT that diminishes its pro-oncogenic properties, was introduced into the UNITE™ platform.ResultsVaccination with LTS220A-UNITE™ DNA vaccine (ITI-3000) induced antigen-specific CD4 T cell responses and a strong humoral response that were sufficient to delay tumor growth of a B16F10 melanoma line expressing LTS220A. This effect was dependent on the CD4 T cells’ ability to produce IFNγ. Moreover, ITI-3000 induced a favorable tumor microenvironment (TME), including Th1-type cytokines and significantly enhanced numbers of CD4 and CD8 T cells as well as NK and NKT cells. Additionally, ITI-3000 synergized with an α-PD-1 immune checkpoint inhibitor to further slow tumor growth and enhance survival.ConclusionsThese findings strongly suggest that in pre-clinical studies, DNA vaccination with ITI-3000, using the UNITE™ platform, enhances CD4 T cell responses to MCPyV-LT that result in significant anti-tumor immune responses. These data support the initiation of a first-in-human (FIH) Phase 1 open-label study to evaluate the safety, tolerability, and immunogenicity of ITI-3000 in patients with polyomavirus-positive MCC (NCT05422781).

【 授权许可】

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Copyright © 2023 Buchta Rosean, Leyder, Hamilton, Carter, Galloway, Koelle, Nghiem and Heiland