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 Trastuzumab develop resistance within one year of treatment initiation. Alteration of Antibodies Dependant Cellular Cytotoxicity (ADCC) mechanisms is one of the rational mechanisms for resistance to therapeutic Mab.
The goal of this project is to overcome this resistance by adoptive transfer using genetically engineered optimized NK cells. We thus compare efficacy of two different approaches: (i) NK cells armed with a high affinity Fc domain (FcγRIIIα/CD16) linked to its transduction chain FCϵRIγ to generate NK-CD16/γ cells that allow recognition and interaction with Mab, inducing ADCC and (ii) NK cells expressing Trastuzumab sequence fused to the transduction chain FCϵRIγ to generate NK-Her/γ that directly kill the HER2 positively cells.
In vitro, both strategies demonstrated high cytotoxic efficacy against HER2 positive cells, with direct killing systematically more efficient (reaching up to 95% with ratio E:T 5:1). Interestingly, two steps killing with NK-CD16/γ enabled a very specific cytotoxicity only in the presence of specific antibody. We demonstrated that efficacy of lysis is linked (i) to effector dose, (ii) levels of CD16/γ expression on effectors cells, (iii) HER2 expression but not level on target cells
In vivo, in Trastuzumab resistant HER2+ xenograft immunodeficient NSG mice model, complete regression was obtained only when using NK-CD16/γ in the presence of Trastuzumab. Even if the NK-Her/γ was found by IF or FACS in the tumor after IV or IP injection, they could not induce tumor regression. Analyses of NK dysfunction will be presented.
Restoration or improvement of effectors cells might be considerate as an issue in therapeutic Mab resistance treatment. Successful immune-based therapies will likely ultimately integrate strategies that combine immunotherapy approaches and immune-modulating drugs, in order to maximize their antitumor activity.
Citation Format: Sandrine Valsesia-Wittmann, Beatrice Clemenceau, Anne-Catherine Jallas, Jean-Yves Blay, Aurelien Marabelle, 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: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A14.
- ©2015 American Association for Cancer Research.