Determinants of efficacy of immunotherapy with tumor-derived heat shock protein gp96

Immunotherapy with gp96 was highly effective in mice bearing methylcholanthrene-induced fibrosarcomas (Meth A tumors) when treatment began 7 days or less after tumor challenge, but significantly less effective if the treatment began 9 days after challenge. Immunotherapy of pre-existing tumors showed all the hallmarks of specificity of gp96 and dose-restriction observed previously with prophylactic studies. When mice with large primary Meth A tumors were treated with surgery alone, or with surgery followed by therapy with Meth A-derived gp96, the mice that received surgery and immunotherapy did significantly better than those receiving surgery alone. The relationship between the time of initiation of immunotherapy with gp96 and its efficacy was also tested in a metastatic model of the Lewis lung carcinoma. In this model, immunotherapy with gp96 was very effective if treatment began up to 31 days after tumor challenge, but significantly less so if therapy was initiated day 33 post-tumor challenge. These observations suggest that the regulatory phenomena that interfere with immunotherapy gather momentum with surprising speed.