Ramamoorthi et al. compared subcutaneous (s.c.) to intratumoral (i.t.) delivery of HER2 peptide-pulsed type I polarized dendritic cells (HER2-DC1), in combination with systemic anti-HER2 antibodies.The i.t. version increased intratumoral CD4+ and CD8+ T cells, B cells, NKT cells, and NK cells, induced antibody-dependent cellular cytotoxicity, generated systemic antitumor immunity, regressed primary and distant tumor growth, and improved survival in HER2pos breast cancer. CD4 and CD8 were required. HER2-DC1 delivered i.t. in combination with anti-HER2 antibodies showed better tumor control than standard-of-care paclitaxel and anti-HER2 antibodies in mice.
Contributed by Shishir Pant
BACKGROUND: Human epidermal growth factor receptor 2 (HER2) targeted antibodies in combination with chemotherapy has improved outcomes of HER2 positive (pos) breast cancer (BC) but toxicity of therapy remains a problem. High levels of tumor-infiltrating lymphocytes are associated with increased pathologic complete responses for patients treated with neoadjuvant therapy. Here we sought to investigate whether delivery of intratumoral (i.t.) multiepitope major histocompatibility complex (MHC) class II HER2 peptides-pulsed type I polarized dendritic cells (HER2-DC1) in combination with anti-HER2 antibodies without chemotherapy could enhance tumor regression by increasing anti-HER2 lymphocyte infiltration into the tumor. METHODS: BALB/c mice bearing orthotopic TUBO tumors, BALB/c mice bearing subcutaneous (s.c.) CT26 hHER2 tumors, or BALB-HER2/neu transgenic mice were all treated with i.t. or s.c. HER2-DC1, anti-HER2 antibodies, paclitaxel, T-DM1 or in combination. Immune response, host immune cells and effector function were analyzed using flow cytometry, interferon-_ ELISA and cytokine/chemokine arrays. The contributions of CD4(+) and CD8(+) T cells and antibody dependent cellular cytotoxicity (ADCC) were assessed using depleting antibodies and Fc_R KO mice. Molecular changes were evaluated by immunohistochemistry and western blot. RESULTS: HER2-DC1 combined with anti-HER2 antibodies delivered i.t. compared to s.c. induced complete tumor regression in 75-80% of treated mice, with increased tumor infiltrating CD4(+) and CD8(+) T, B, natural killer T cells (NKT) and natural killer cells, and strong anti-HER2 responses in all HER2(pos) BC models tested. The therapy caused regression of untreated distant tumors. Labeled HER2-DC1 migrated prominently into the distant tumor and induced infiltration of various DC subsets into tumors. HER2-DC1 i.t. combined with anti-HER2 antibodies displayed superior antitumor response compared to standard chemotherapy with anti-HER2 antibodies. Lasting immunity was attained which prevented secondary tumor formation. The presence of CD4(+) and CD8(+) T cells and ADCC were required for complete tumor regression. In the HER2(pos) BC models, HER2-DC1 i.t. combined with anti-HER2 antibodies effectively diminished activation of HER2-mediated oncogenic signaling pathways. CONCLUSIONS: HER2-DC1 i.t. with anti-HER2 antibodies mediates tumor regression through combined activation of T and B cell compartments and provides evidence that HER2-DC1 i.t. in combination with anti-HER2 antibodies can be tested as an effective alternative therapeutic strategy to current chemotherapy and anti-HER2 antibodies in HER2(pos) BC.
Author Info: (1) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida, USA. (2) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida, USA. (3) Cl
Author Info: (1) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida, USA. (2) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida, USA. (3) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida, USA. (4) Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. (5) Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. (6) Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. (7) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida, USA. (8) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida, USA. (9) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida, USA. (10) Department of Breast Oncology, Moffitt Cancer Center, Tampa, Florida, USA. (11) Department of Breast Oncology, Moffitt Cancer Center, Tampa, Florida, USA. (12) Biological Sciences, Kent State University, Kent, Ohio, USA. (13) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida, USA brian.czerniecki@moffitt.org. Department of Breast Oncology, Moffitt Cancer Center, Tampa, Florida, USA.
