The prevailing view suggests that lung tumors may not be good targets for vaccine therapy. The reason for this belief is the fact that in lung tumor patients we do not find any indication of immune activation including a complete absence of killer cells (cytotoxic T cells) that could recognize and kill the tumors. Lung tumors are therefore classified as non-immunogenic. We suggest that this circumstance is ideal for immunotherapy of non-small cell lung carcinoma by vaccination.
We have been developing vaccines that can generate killer cells against lung tumors (non-small cell lung carcinoma) by genetic engineering lung tumor cell lines adapted to grow in cell culture. We predict that a vaccine that can generate killer cells in lung tumor patients will be effective and that the patient tumor will be defenseless against killer cell attack because the tumor cells have never before been exposed to killer cells and have not evolved protective mechanisms.
In a phase I study we found that a lung tumor vaccine, designated B7-vaccine, was able to generate killer cells and seemed to provide clinical benefit to patients. In the study proposed here we have developed a novel vaccine approach for lung tumors based on a genetically modified, secreted form of heat shock protein gp96. The vaccine is comprised of lung tumor cells that secrete hsp-gp96 and thereby provide a very strong stimulus for the immune system to generate killer cells against lung tumors.
Our initial in vitro data and data in experimental mice indicate that the gp96-vaccine is over one million-fold more efficient in the generation of killer cells than normal proteins in the absence of gp96. These properties of tumor secreted gp96 make it an ideal vaccine. In addition, these properties allow us to study how gp96 induces immunity and how it may be able to restore immunity that is suppressed in the presence of existing tumors.
In this application we plan to pursue the clinical testing of the gp96-vaccine and to conduct further research into the underlying immune response. Understanding the underlying mechanisms will allow us to develop further reagents to improve vaccine efficiency.