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Abstract
Abstract Human epidermal growth factor receptor 2 (HER2) overexpression accounts for 30% of invasive breast cancer (BC) and is critically associated with aggressive disease, recurrence and metastasis. Adoptive cell therapy approaches using cytotoxic CD8 T cells and natural killer cells have been shown to trigger anti-tumor immunity in BC. However, the immunosuppressive tumor microenvironment (TME) can inhibit response to these therapies and diminish the presence and function of tumor-infiltrating lymphocytes. Recently, we have shown a critical role for anti-tumor CD4 Th1 cells in dendritic cells (DC) intratumoral (i.t.) delivery in combination with anti-HER2 therapy. This combination therapy enhanced systemic and local anti-tumor immunity and eradicated tumors in HER2 positive BC with a requirement for CD4 Th1 cells. Here we investigated the efficacy of i.t. delivery of both autologous anti-tumor CD4 Th1 cells and tumor antigen pulsed type 1 polarized dendritic cells (HER2-DC1) in a HER2 mammary carcinoma model. CD4 T cells were isolated from BALB/c mice that had completely regressed (pCR) from orthotopic TUBO tumors following HER2-DC1 i.t. or combination therapy with anti-HER2 antibody. CD4 Th1 cells were then expanded by co-culturing with HER2-DC1 in the presence of interleukin (IL)-2 and IL-7 cytokines. BALB/c mice bearing orthotopic TUBO tumors were treated weekly for six weeks with anti-tumor CD4 Th1 cells i.t., non-specific CD4 Th1 cells i.t., HER2-DC1 i.t. or combination therapy. The i.t. delivery of anti-tumor CD4 Th1 cells combined with HER2-DC1 induced a strong anti-tumor response with survival benefit and complete tumor eradication in 50% of treated mice. Importantly, the i.t. delivery of anti-tumor CD4 Th1 cells were critical for providing priming signals to HER2-DC1 within the TME via CD40/CD40L engagement (licensing). This was supported by a strong anti-tumor response and complete tumor regression in 60% of orthotopic TUBO tumor bearing mice treated with CD40/CD40L licensed HER2-DC1 i.t. therapy compared to un-licensed HER2-DC1 i.t. therapy. Additionally, enhanced survival and functionality of human and mouse HER2-DC1 was observed following activation of CD40/CD40L signaling using anti-CD40 agonistic antibody in vitro. Collectively, these results suggest a new promising therapeutic strategy using DC1-anti-tumor CD4 Th1 adoptive cell therapy intratumoral delivery to induce DC1 priming and create robust anti-tumor immunity within the TME in BC. Citation Format: Ganesan Ramamoorthi, Amy Aldrich, Colin Snyder, Brian Czerniecki. Intratumoral delivery of autologous tumor antigen specific CD4 Th1 cells combined with dendritic cells eradicates HER2 mammary carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4056.
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