Abstract 1784: Comparing genetically engineered T cells for chimeric TCR versus CD16 + Herceptin for adoptive immunotherapy against HER2 positive breast carcinomas

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL The HER2 receptor is overexpressed in 25% of breast cancers and is associated with poor prognosis. Herceptin, a monoclonal antibody targeting HER2 has been demonstrated to improve survival of HER2 overexpressing metastatic breast cancer. However, majority of patients who initially respond to Herceptin develop resistance within one year of treatment initiation, and in the adjuvant setting 15% of patients relapse after 5 years despite Herceptin-based therapy. The goal of this project is to develop and compare efficiency of two adoptive immunotherapy approaches by genetically engineered T cells to overcome this resistance. For the first approach, we developed T lymphocytes armed with an anti-HER2 chimaeric TCR (CAR-CTL) to directly kill the HER2 positively cells. For the second approach, we developed T lymphocytes armed with a high affinity IgG FcR (FcγRIIIα, CD16) linked to its transduction chain FC∈RIγ (CD16/γ). In this latter case, the HER2 antigen is pre-targeted by Herceptin Ab to induce a “two step killing” through Antibodies Dependant Cellular Cytotoxicity (ADCC). Results obtained in vitro demonstrated the high direct killing efficiency of anti-HER2 chimaeric TCR CTL against HER2 amplified breast carcinoma cells BT474 or SKBR3 (>75%). However, abnormal reactivity of these CTL against cells with low to undetectable HER2 expression was observed (15 to 30% of lysis). This constitutive non specific activation of chimaeric TCR might represent an important limitation point for clinical use. On the other hand, “two step killing” with CD16/γ-CTL demonstrated a very specific cytotoxicity against HER2 positive cells through ADCC only in the presence of Herceptin. We demonstrated that efficacy of specific lysis is linked to levels of CD16/γ expression and appeared independent of HER2 targeted antigen level. We are comparing in vivo efficacy of both approaches (“one step” TCR vs “two step”ADCC) to induce regression of HER2 + or – breast carcinoma xenograft in immunodeficient mice model NOD-SCID mβ2-/-. Our last results will be presented. Because the alteration of ADCC mechanisms during Herceptin treatment is one rational explanation for the acquired resistance, improving effectors might represent a safe adjuvant treatment to prevent resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1784. doi:10.1158/1538-7445.AM2011-1784