Tremelimumab in Combination with Exemestane in Patients with Advanced Breast Cancer and Treatment-Associated Modulation of Inducible Costimulator Expression on Patient T Cells

Abstract

Purpose: Tremelimumab is a fully human monoclonal antibody specific for CTL-associated antigen 4 (CTLA4) with single-agent activity in certain tumors but has not been evaluated in patients with breast cancer.Experimental Design: In a phase 1 study, 26 patients with advanced, hormone-responsive breast cancer received tremelimumab (3-10 mg/kg) every 28 days or every 90 days plus exemestane 25 mg daily. The objectives were to determine safety and the maximum tolerated dose (MTD) of tremelimumab with exemestane and, secondarily, to assess tumor response, pharmacokinetics, and immune pharmacodynamics.Results: Most treatment-related adverse events were mild to moderate with the most common being diarrhea (46% of patients), pruritus (42%), constipation (23%), and fatigue (23%). Dose-limiting toxicities were transient serum transaminase elevations (one patient) and diarrhea (four patients). The MTD of tremelimumab with exemestane was 6 mg/kg every 90 days. Among 13 patients treated at the MTD, none developed grade 3 or 4 treatment-related diarrhea. No pharmacokinetic interaction was observed between tremelimumab and exemestane. The best overall response was stable disease for ≥12 weeks in 11 patients (42%). Treatment was associated in most patients with increased peripheral CD4+ and CD8+ T cells expressing inducible costimulator (ICOS) and a marked increase in the ratio of ICOS+ T cells to FoxP3+ regulatory T cells.Conclusions: Tremelimumab plus exemestane is tolerable in patients with hormone-responsive advanced breast cancer. Treatment is associated with increased ICOS+ T cells, which likely signals immune activation secondary to CTL-associated antigen 4 blockade. Clin Cancer Res; 16(13); 3485-94. ©2010 AACR.

Targeted cancer immunotherapy with oncolytic adenovirus coding for a fully human monoclonal antibody specific for CTLA-4

“…With regard to safety, it may be promising that plasma mAb was lower than what has been tolerated in humans trials. 33,34,49,50 Emphasizing the utility of local versus systemic CTLA4 blockage, it has been reported that combination of tumor-localized anti-CTLA4 scFv expression with systemic T-Reg depletion has a synergistic effect. 51 Further, the authors did not observe autoimmune reactions in a murine model when anti-CTLA-4 scFv Ab was expressed by the tumors and anti-CD25 Abs were administered intraperitoneally.…”

Harnessing the Immune System to Fight Cancer: The Promise of Genetic Cancer Vaccines

“…Also, inducible costimulator (ICOS) a member of the immunoglobulin gene family, seems to be involved. In some studies a correlation between increased frequency of circulating CD4 + ICOShigh T cells and Overall Survival has been shown (Chen et al, 2009;Vonderheide et al, 2010;Charton et al, 2010). Promising biomarkers also appear to be increases in CD54RO and HLA-DR on circulating CD4 + and CD8 + T cells (Comin-Anduix et al, 2008), poly-epitope antigen specific immune responses (Yuan et al, 2008) and degree of intratumoural Treg infiltration (Ribas et al, 2009).…”

Immune Regulation in Breast Cancer Metastasis and Immunotherapy

“…No signiicant clinical response was observed by treatment although 42% of patients achieved stable disease for more than 3 months [55]. The anti-CTLA4 mAb ipilimumab is now being tested in patients with earlier stage or lower tumor burden.…”