Abstract A22: Overcoming therapeutic MAb resistance in agressive HER2-positive breast carcinomas by adoptive immunotherapy using optizimed effectors cells.
Authors: Valsesia-Wittmann Sandrine , Clemenceau Beatrice , Jallas Anne-Catherine , Blay Jean-Yves , Caux Christophe , Vie Henri 
Published: August 2014

The HER2 receptor is overexpressed in 25% of breast cancers and is associated with poor prognosis. Herceptin (Trastuzumab), a monoclonal antibody targeting HER2 has been demonstrated to improve survival of HER2 overexpressing metastatic breast cancer. However, half of patients who initially respond to Herceptin develop resistance within one year of treatment initiation, and in the adjuvant setting 15% of patients still relapse after one year of treatment despite Herceptin-based therapy.

The goal of this project is to compare efficacy of two adoptive immunotherapies approaches by genetically engineered NK cells to overcome this resistance. For the first approach, we developed NK cells armed with an high affinity Fc domain (FcγRIIIα, CD16) linked to its transduction chain FCϵRIγ (CD16/γ) to allow recognition and interaction with Mab, inducing Antibodies Dependant Cellular Cytotoxicity (ADCC). For the second approaches, we developed NK cells expressing Herceptin sequence fused to the transduction chain FCϵRIγ (CD16/γ) to directly kill the HER2 positively cells.

Results obtained in vitro demonstrated higher direct killing efficacy of NK expressing Herceptin/γ against HER2 amplified breast carcinoma cells BT474 or SKBR3. However, abnormal reactivity against cells with low or undetectable HER2 expression by FACS analysis was observed (15 to 30% of lysis). This might represent an important limitation point for clinical use.

On the other hand, “two step killing by ADCC” with NK-CD16/γ 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 (i) to effector dose, (ii) levels of CD16/γ expression on effectors cells, (iii) HER2 expression on target cells but not HER2 level of expression.

We then compared in vivo efficacy of both approaches (“one step” vs “two step”ADCC) in HER2+ xenograft model using immunodeficient NOD-SCID mβ2-/- mice. Complete regression of herceptin resistant HER2+ xenograft was obtained only with NK- CD16γ in the presence of herceptin. Our last results will be presented.

Because the alteration of ADCC mechanisms during Herceptin treatment is one rational explanation for the acquired resistance, restoring or improving effectors cells might represent next step in therapeutic humanized Mab resistance treatment. Successful immune-based therapies will likely ultimately integrate strategies that combine immunotherapy approaches and immune-modulating drugs (including toll-like receptor modulators, antibodies specific for the PD-1, the OX-40 ore the CD40 pathways, in order to maximize their antitumor activity.

Citation Format: Sandrine Valsesia-Wittmann, Beatrice Clemenceau, Anne-Catherine Jallas, Jean-Yves Blay, Christophe Caux, Henri Vie. Overcoming therapeutic MAb resistance in agressive HER2-positive breast carcinomas by adoptive immunotherapy using optizimed effectors cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A22.