Cancer immunotherapy: moving beyond current vaccines
Review of: Rosenberg SA, Yang JC, Restifo NP. Nature Med 2004; 10:909- 915
What are the reasons for the low total objective response rate (less than 3%) in cancer vaccine trials? Perspectives on this important question and future strategies were reported in Nature Medicine, September 2004 issue, by Rosenberg and colleagues.
Identification of a substantial number of tumorassociated antigens lead to a fast growing enthusiasm directed toward the use of cancer vaccines-active immunizations designed to treat growing tumors. Beside a clear overview of the large number of reported or on-going trials, Rosenberg et al also point out that there is a need for standard oncological criteria for evaluating and reporting objective clinical responses to treatment. A recently proposed set of criteria is Response Evaluation Criteria in Solid Tumors (RECIST) which assume a 30% reduction in the sum of the maximum diameters of lesions to indicate a response, along with the appearance of no new or progressive lesions. However, the most commonly used definition of objective clinical response, is reduction of at least 50% in the sum of the products of the perpendicular diameters of all lesions without a 25% growth of any lesion or the appearance of new lesions. The latter definition was used in studies between February 1995 and April 2004, comprising 440 individuals with metastatic cancer, treated with 541 different cancer vaccines at the Surgery Branch, NCI. The objective response rate was only 2.6%, which is similar to the overall response rate of cancer vaccine trials performed by others. Of the 440 patients treated, 422 had metastatic melanoma, and ten suffered from renal cancer. No other urological malignancies were included in these studies. Altogether. only four patients showed a complete response and nine were classified as partial responders. Overall objective response rate was 2.9% (11/381) in patients receiving peptide vaccine immunization and 1.9% (3/160) for patients treated with viral vaccine.
The authors also summarized the results from 35 other trials including 765 patients with other cancer types, and concluded that a reevaluation of future directions for cancer immunotherapy trials would be valuable. The less encouraging results from clinical trials so far, Rosenberg et al claim, should not be interpreted to mean that cancer vaccine approaches are at an investigational dead end. The authors support this view by providing descriptions of central mechanisms that hold promise and can be used to develop more successful treatment modalities in the future. Cell transfer immunotherapy must be further explored. T-cells can destroy established tumors, and lymphoid tumors are easier to treat than solid tumors, because they express co-stimulatory molecules which are necessary to convert quiescent precursor lymphocytes into activated cells with the effector functions required for tumor eradication.
In conclusion, the future looks bright if the following criteria can be met: (1) in vivo generation of sufficient numbers of immune cells to recognize tumor antigens (2) successful trafficking of these cells to infiltrate the tumor stroma, and (3) local activation of the immune system to manifest appropriate effector mechanisms causing tumor destruction.
