Tumor cell secreted gp96-Ig generates CD8 CTL against all tumor associated antigens by cross presentation of tumor-peptides via DC to CD8 T cells. In patients with cancer, the hypoxia in the tumor microenvironment generates extracellular adenosine which is highly suppressive for CTL cytotoxicity and prevents complete tumor rejection by the CTL that were generated by vaccination. Reversal of tumor hypoxia is achieved by the conceptually novel use of breathing supplemental 60% oxygen which inhibits adenosine generation and enables the vaccine-generated CTL to completely reject tumors. We want to further improve this powerful combination, using complete tumor rejection as readout, by (AIM 1) studying molecular and cellular details required for generation of the most powerful CTL response; by (Aim2) studying pharmacological inhibitors of adenosine production in the tumor as substitute for 60% oxygen; by (Aim 3) investigating the combination therapy in spontaneous tumor systems resembling human tumors; and by (Aim 4) evaluating the method for multiple other tumors; measuring memory; analyzing recurrence rate over time and evaluate repeat therapy. Together the studies will provide the foundation for translating the protocol into effective clinical studies that are already beginning.