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857 LAMP1 targeting of the large T antigen of merkel cell polyomavirus elicits potent CD4+ T cell responses and prevents tumor growth
  1. Claire Buchta Rosean1,
  2. Claire Buchta Rosean1,
  3. Pratima Sinha1,
  4. David Koelle2,
  5. Paul Nghiem2 and
  6. Teri Heiland1
  1. 1Immunomic Therapeutics, Inc, Rockville, MD, USA
  2. 2University of Washington, Seattle, WA, USA


Background The majority of Merkel cell carcinomas (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 a truncated form of the viral large T antigen (LT) in infected cells, and making LT an attractive target for therapeutic cancer vaccines. While induction of tumor-reactive CD8+ T cells is a major goal of cancer therapy, CD4+ T cells provide essential support to CD8+ T cells by promoting their expression of cytotoxic effector molecules and increasing their migratory capacity. Cytokines secreted by CD4+ T cells, such as IFNγ, can also exert desirable effects on the tumor microenvironment. Therefore, we set out to design a cancer vaccine that promotes potent, antigen-specific CD4+ T cell responses to MCPyV-LT.

Methods 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 a balanced T cell response. LTS220A, encoding a mutated form of MCPyV-LT that abrogates its pro-oncogenic properties, was introduced into the UNITE platform. LTS220A-UNITE, known as ITI-3000, was administered to female C57BL/6 mice intradermally in the ear with electroporation.

Results ITI-3000 promoted a potent, antigen-specific CD4+ T cell response to MCPyV-LT. Vaccination with ITI-3000 significantly delayed and slowed growth of B16F10 tumors expressing LTS220A in prophylactic and therapeutic settings, respectively. ITI-3000 induced a favorable tumor microenvironment (TME), including significantly enhanced numbers of CD4+ T cells, CD8+ T cells, NK cells, and NKT cells. Tumor-infiltrating myeloid cells were reduced in frequency in vaccinated mice and polarized towards an anti-tumor phenotype. Cytokine analysis of the TME showed significantly enhanced levels of cytokines associated with anti-tumor immune responses in ITI-3000-vaccinated mice, including IFNγ, TNFα, IL-2, and IL-1β. Additionally, ITI-3000 synergized with PD-1 blockade, further reducing tumor burden and enhancing survival in mice receiving combination therapy.

Conclusions We find that DNA vaccination with ITI-3000 using the UNITE platform enhances CD4+ T cell responses to MCPyV-LT and results in anti-tumor immune responses in a mouse model of Merkel cell carcinoma.

Ethics Approval This study was approved by Immunomic Therapeutics’ Institutional Animal Care and Use Committee, protocol number 16-11-002.

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:

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