METHODS AND COMPOSITIONS FOR ADOPTIVE IMMUNOTHERAPY

摘要

In a first aspect the present invention provides a method for producing an adoptive immune response to a target cell in a subject, said method including the steps of engineering a CD4+ T cell and engineering a CD8+ T cell to express a molecule capable of binding to an antigen on the target cell, and administering an effective number of the engineered CD4+ and CD8+ T cells to the subject. According to this method the CD4+ T cell and the CD8+ T cell are obtained from the subject, engineered, and re-administered to the subject to produce the adoptive immune response Applicants have found that in adoptive transfer experiments in vivo, administration of sufficient numbers of antigen engineered CD4+ in combination with engineered CD8+ cells leads to a significantly enhanced immune response to a target cell. It is demonstrated herein that the injection of CD4+ and CD8+ T cells engineered to express a molecule capable of binding to a tumor associated antigen led to significant improvement in survival of subjects having established lung metastases, compared with transfer of unfractionated spleen-derived (largely CD8+) engineered T cells. Importantly, anti-tumor responses in the subjects correlated with persistence and localization of engineered T cells at the tumor site and in the blood and spleen. Applicants have further demonstrated herein that subjects treated with engineered CD4+ and CD8+ T cells that survived primary tumor challenge could reject a subsequent rechallenge with the same tumor. The studies disclosed herein demonstrate the therapeutic advantage in the combined transfer of antigen-specific gene-modified CD4+ and CD8+ T cells to significantly enhance T cell adoptive strategies for the treatment conditions such as cancer and infectious diseases.