Therapeutic cancer vaccines in prostate cancer: the paradox of improved survival without changes in time to progression

Abstract

Therapeutic cancer vaccines represent a new class of agents in the treatment of cancer. Sipuleucel-T is an antigen-presenting cell-based vaccine that recently demonstrated a significant 4.8-month improvement in overall survival in advanced prostate cancer patients and was well tolerated. The findings of that study have been met with skepticism, primarily because the agent did not change initial disease progression and yet led to longer survival. Although the commonly accepted treatment paradigm suggests that treatments should initially decrease tumor volume, perhaps vaccines work differently. Vaccines may induce delayed responses not seen in the first few months of therapy or they may initiate a dynamic immune response that ultimately slows the tumor growth rate, resulting in longer survival. Subsequent therapies may also combine with the induced immune response, resulting in a combination that is more effective than conventional treatments alone. Also, other treatments may alter tumor-associated antigen expression, enhancing the immune response. Future trials are currently planned to investigate these hypotheses; however, the results of the sipuleucel-T vaccine in prostate cancer should not be dismissed. Results with another vaccine in prostate cancer are similar, perhaps suggesting a class effect. In a broader context, clinicians may need to reconsider how they measure success. Several agents have been approved that produce superior disease progression results, but do not affect overall survival. Given the toxicity and costs of cancer therapies, perhaps studies should put more weight on long-term survival endpoints than on short-term endpoints that may be less consequential.

Figure 1.

Tumor growth is a dynamic biologic process that is the combined result of cells dividing and other cells dying. Intrinsic tumor biology, as well as extrinsic factors such as therapies, affect the tumor's growth rate. However, chemotherapy (red line) only affects the tumor growth rate while it is being administered, which may result in a dramatic but transient response. Following discontinuation of chemotherapy, the growth rate returns to its pretreatment slope, driven by the underlying biology of the tumor. Immunotherapy (blue line), on the other hand, can alter the biology of the host by inducing an active antitumor immune response including a memory response. This may not cause an immediate or dramatic change in tumor burden, but continued cumulative slowing pressure on tumor growth rate, especially if started early in the disease course, may lead to substantially longer overall survival. The arrow indicates the initiation of treatment; cross indicates time of death from cancer.