Purpose: The mammalian target of rapamycin (mTOR) functions within the PI3K/Akt signaling pathway as a critical modulator of cell survival. Methods: The mTOR inhibitor temsirolimus (CCI-779) was combined with chemo-radiotherapy in GBM patients in a dose-escalation Phase I trial. The first 12 patients were treated with CCI-779 combined with RT/TMZ and adjuvant TMZ. A second cohort of 13 patients was treated with concurrent CCI-779/RT/TMZ followed by adjuvant TMZ monotherapy. Results: Concomitant and adjuvant CCI-779 was associated with a high rate (3 of 12 patients) of Grade 4/5 infections. By limiting CCI-779 treatment to the RT/TMZ phase and using antibiotic prophylaxis, the rate of infections was reduced, although 2 of 13 patients developed exacerbation of pre-existing fungal or viral infections. DLTs were observed in 2 of 13 patients with this modified schedule. Weekly CCI-779 (50 mg/week) combined with RT/TMZ is the recommended Phase II dose and schedule. The immune profile of patients in the second cohort was assessed before, during, and after CCI-779 therapy. There was robust suppression of helper and cytotoxic T-cells, B-cells, natural killer (NK) cells and elevation of regulatory T (Tregs) cells during CCI-779/RT/TMZ therapy with recovery to baseline levels during adjuvant TMZ of cytotoxic T-cells, NK cells and Tregs. Conclusions: The increased infection rate observed with CCI-779 combined with chemo-radiotherapy in GBM was reduced with antibiotic prophylaxis and limiting the duration of CCI-779 therapy. The combined suppressive effects of CCI-779 and TMZ therapy on discrete immune compartments likely contributed to the increased infectious risks observed.
- Received June 1, 2010.
- Revision received August 16, 2010.
- Accepted September 5, 2010.