Modulation of Lymphocyte Regulation for Cancer Therapy: A Phase II Trial of Tremelimumab in Advanced Gastric and Esophageal Adenocarcinoma

Abstract

Purpose: Cytotoxic T lymphocyte antigen 4 (CTLA4), a key negative regulator of T-cell activation, is targeted by the antibody tremelimumab to release potentially useful antitumor activity.Experimental Design: This phase II trial investigated tremelimumab as a second-line treatment for patients with metastatic gastric and esophageal adenocarcinomas. Tremelimumab was given every 3 months until symptomatic disease progression. Safety, clinical efficacy, and immunologic activity were evaluated.Results: Eighteen patients received tremelimumab. Most drug-related toxicity was mild; however, there was a single death due to bowel perforation that complicated colitis. Four patients had stable disease with clinical benefit; one patient achieved a partial response after eight cycles (25.4 months) and remains well on study at 32.7 months. Markers of regulatory phenotype, forkhead box protein 3 and CTLA4, doubled transiently in CD4 + CD25 high lymphocytes in the first month after tremelimumab before returning to baseline. In contrast, CTLA4 increased in CD4 + CD25 low/negative lymphocytes throughout the cycle of treatment. De novo proliferative responses to tumor-associated antigens 5T4 (8 of 18 patients) and carcinoembryonic antigen (5 of 13) were detected. Patients with a posttreatment carcinoembryonic antigen proliferative response had median survival of 17

Immune checkpoints programmed death 1 ligand 1 and cytotoxic T lymphocyte associated molecule 4 in gastric adenocarcinoma

“…26 Interestingly, the percentage of CTLA-4 C cells was significantly elevated in tumor samples within the CD4 C subset, potentially reflecting an increase of regulatory T cells. 30 In an additional subset-analysis, CTLA-4 as well as PD-L1 expression was elevated on CD4…”

“…Of note, this study did not report on CTLA-4 expression on primary tumor cells. 30 The aim of our study was to comprehensively analyze expression of CTLA-4, PD-1 and PD-L1 in the tumor microenvironment of gastric adenocarcinoma patients. Furthermore, mutational analysis was performed to give further insights into genomic aberrations associated with expression of these immune checkpoints.…”

CD200-CD200R signaling suppresses anti-tumor responses independently of CD200 expression on the tumor

“…As a result of this, inhibitory immune pathways have become therapeutic targets to strengthen anti-tumor responses and develop (adjuvant) therapeutic strategies in cancer treatment. Recent clinical trials with blocking antibodies against the inhibitory receptors CTLA4 and PD-1 have yielded promising results (Brahmer et al, 2010;Ralph et al, 2010). In March of this year, the blocking CTLA4 antibody Ipilimumab was approved by FDA for use in melanoma, being the first drug ever proven to prolong survival in stage IV melanoma.…”

Anti-programmed death ligand 1 (PD-L1) inhibitors in metastatic gastric cancer

“…[9,10]. Based on this finding, pembrolizumab has been approved in MSI-high tumors in U.S. Table 1 lists selected clinical trials of immune checkpoint inhibitors for metastatic GC [10][11][12][13][14][15][16].…”