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Response to Comment on "Analysis of the Cellular Mechanism of Antitumor Responses and Autoimmunity in Patients Treated with CTLA-4 Blockade"

Surgery Branch, National Cancer Institute, Bethesda, MD 20892

In our article analyzing the cellular mechanisms of antitumor and autoimmune effects of CTLA-4 blockade (1), the cells that were tested were obtained 3 wk after the last dose of anti-CTLA-4 mAb. All patients had received many doses of anti-CTLA-4 Ab administered every 3 wk, and because the half-life of this Ab is 2–3 wk, it would be expected that any depletion of T regulatory cells would be seen at the 3-wk time point. It is possible, however, as Drs. O’Mahony and Janik point out, that we could have missed a decrease in T regulatory cells at earlier time points. In fact, Drs. O’Mahony and Janik point out that at 1–4 days after administration of anti-CTLA-4 Ab they did see a significant decrease in the number of T regulatory cells.

As a result of their letter, we have performed additional experiments testing the presence of T regulatory cells obtained before and 4 days after administration of anti-CTLA-4 mAb in a patient in our protocol. This patient had received 5 mg/kg anti-CTLA-4 Ab twice and 9 mg/kg twice every 3 wk. Before and 4 days after the fifth dose at 9 mg/kg, blood was obtained and cell analysis was performed simultaneously on these cryopreserved specimens. As in our prior results, there was no evidence of decrease in T regulatory cells. Comparing pre- and post-4-day treatment samples, the CD4⁺Foxp3⁺ cells increased from 14.6 to 18.2%, and the percentage of Foxp3⁺CD25⁺ cells increased from 23.0 to 34.4%. In addition, we purified CD4⁺ cells and performed semiquantitative RT-PCR analysis of Foxp3 levels in these cells. Following immunomagnetic bead purification, the CD4 cells isolated by negative selection were 90–94% pure. In samples obtained 4 days after administration of anti-CTLA-4 Ab, the number of Foxp3 mRNA copies per 10⁶ -actin copies increased from 1419 to 1862.

Thus, the results we obtained in this patient studied 4 days after administration of anti-CTLA-4 Ab were similar to those obtained in samples obtained 3 wk following administration of the Ab. Although further studies on samples taken at short times after administration of anti-CTLA-4 Ab are warranted, it seems unlikely to us that the mechanism of action of anti-CTLA-4 Ab administration is due to a decrease of T regulatory cells.

References

1. Maker, A. V., P. Attia, S. A. Rosenberg. 2005. Analysis of the cellular mechanism of antitumor responses and autoimmunity in patients treated with CTLA-4 blockade. J. Immunol. 175: 7746-7754. [Abstract/Free Full Text]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Rosenberg, S. A. Search for Related Content PubMed Articles by Rosenberg, S. A.