Editors' ChoiceCancer Vaccines

Surrogates of Survival

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Science Translational Medicine  18 Apr 2012:
Vol. 4, Issue 130, pp. 130ec69
DOI: 10.1126/scitranslmed.3004168

Past, present, and future may indeed be, to quote Albert Einstein, “only a stubbornly persistent illusion.” But as creatures tied to time, human beings look to the future, and scientists try to predict it. In particular, cancer biologists seek ways of assessing, in a timely manner, whether a cancer therapy has succeeded. Now, Fong et al. show how measuring the expression of selected molecules on the surface of a specialized subset of lymphocytes [regulatory T cells (Treg cells)] permits prediction of survival in patients with glioblastoma—the most common and aggressive type of primary brain tumor—before and after immunotherapy.

Tumors that display rapid progression in the appearance of symptoms require aggressive multipronged therapeutic regimens that can include chemotherapy, surgery, radiotherapy, and immunotherapy. In the past decade, promising results have been obtained with tumor vaccines that consist of immune cells that have been engineered to express tumor antigens. However, the lack of easily measurable immunological parameters with which to evaluate the association of such treatments with eventual clinical outcome remains an important unresolved problem.

In the new work, the authors used in vitro–treated peripheral blood mononuclear cells from each patient to obtain autologous antigen-presenting dendritic cells (DCs) and cultured the cells with patient-specific glioblastoma lysates or tumor peptides to create a vaccine for immunotherapy. Patients were injected with their specifically engineered vaccines three times over the course of 8 weeks. Although no significant changes were observed in the expression of lymphocyte activation markers, the authors noted that every single unit increase in the Treg ratio was associated with an increased risk of death (~2.6-fold; P = 0.0228). The authors also noted that a reduction in helper and cytotoxic T cell expression of the inhibitory lymphocyte molecule CTLA-4 was associated with survival of glioblastoma patients after DC vaccination. Furthermore, the authors were able to suggest pre- and post-treatment cut-off point ratio values for monitoring of the expression of these markers and the design of future prospective studies to evaluate therapeutic success.

This study supports previous observations suggesting an association between the presence of Treg cells in tissues and the suppression of antitumor immune responses. The authors showed that Treg numbers can be measured in blood to evaluate the performance of DC vaccines in a noninvasive manner. Further studies are required to validate these results in additional groups of patients with glioblastomas or other types of tumors and who are undergoing distinct therapeutic regimes. Although the data do not provide a mechanistic explanation to explain the relationship between the effect of the vaccine and variations in Treg numbers, the work of Fong et al. predicts a brighter future for immunotherapy evaluation.

B. Fong et al., Monitoring of regulatory T cell frequencies and expression of CTLA-4 on T cells, before and after DC vaccination, can predict survival in GBM patients. PLoS One 7, e32614 (2012). [Abstract]

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