CTLA4 blockade increases Th17 cells in patients with metastatic melanoma

Euw, Erika von; Chodon, Thinle; Attar, Narsis; Jalil, Jason; Koya, Richard C.; Comin-Anduix, Begoñya; Ribas, Antoni

doi:10.1186/1479-5876-7-35

Cited by 162 publications

(108 citation statements)

References 32 publications

Supporting

Mentioning

106

Contrasting

Order By: Relevance

“…Recent evidence suggests that the numbers of T reg and T H 17 cells are inversely correlated in the same tumor and that considerable functional plasticity exists between T reg and T H 17 cells (35). CTLA-4 induces T H 17 cells in peripheral blood of patients with metastatic melanoma and T H 17 cells have been shown to promote antigen-specific antitumor immunity (36). Hence, the combination of chemotherapy and CTLA-4 blockade could skew the T reg /T H 17 balance toward a T H 17 phenotype.…”

Section: Discussionmentioning

confidence: 99%

CTLA-4 Blockade Expands Infiltrating T Cells and Inhibits Cancer Cell Repopulation during the Intervals of Chemotherapy in Murine Mesothelioma

Yun

Tagawa

et al. 2012

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Cancer immunotherapy has shown promising results when combined with chemotherapy. Blocking CTLA-4 signaling by monoclonal antibody between cycles of chemotherapy may inhibit cancer cell repopulation and enhance the antitumoral immune reaction, thus improve the efficacy of chemotherapy in mesothelioma. The impact of CTLA-4 blockade on the early stage of tumor development was evaluated in a subcutaneous murine mesothelioma model. CTLA-4 blocking antibody was administered following each cycle of chemotherapy, and monotherapy was included as controls. Antitumor effect was evaluated by tumor growth delay and survival of the animals. Tumor cell repopulation was quantified by bromodeoxyuridine incorporation and Ki67 by immunohistochemistry and/or flow cytometry. In vitro cell killing was determined by classic chromium-released assay, and reverse transcription PCR (RT-PCR) was carried out to determine the gene expression of associated cytokines. Anti-CTLA-4 monoclonal antibody was able to inhibit tumor growth at early stage of tumor development. Antitumor effect was achieved by administration of CTLA-4 blockade between cycles of chemotherapy. Tumor cell repopulation during the intervals of cisplatin was inhibited by CTLA-4 blockade. Anti-CTLA-4 therapy gave rise to an increased number of CD4 and CD8 T cells infiltrating the tumor. RT-PCR showed that the gene expression of interleukin IL-2, IFN-g, granzyme B, and perforin increased in the tumor milieu. Blockade of CTLA-4 signaling showed effective anticancer effect, correlating with inhibiting cancer cell repopulation between cycles of chemotherapy and upregulating tumor-infiltrating T lymphocytes, cytokines, and cytolytic enzymes in a murine mesothelioma model.

show abstract

Section: Discussionmentioning

confidence: 99%

CTLA-4 Blockade Expands Infiltrating T Cells and Inhibits Cancer Cell Repopulation during the Intervals of Chemotherapy in Murine Mesothelioma

Yun

Tagawa

et al. 2012

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…Recently, ICOS expression was associated with interleukin-17-secreting CD4+ T cells in a murine model of autoimmune colitis (21). Interleukin-17-secreting CD4+ T cells, or Th17 T cells, have also been implicated in mediating tumor immunity (22), and in a cohort of melanoma patients receiving single-agent tremelimumab, treatment was associated with an increase in interleukin-17-secreting T cells (23). A previous study of six bladder cancer patients receiving neoadjuvant ipilimumab also noted an increase in ICOS+ T cells in blood and tumor following therapy (15).…”

Section: Discussionmentioning

confidence: 99%

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

Vonderheide

LoRusso

Khalil

et al. 2010

Clinical Cancer Research

263

163

View full text Add to dashboard Cite

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.

show abstract

“…Several genes of interest including IL-17, CTLA-4, CD70, and CD27 have been extensively studied for immunotherapy development [18][19][20][21]. IL-17E and IL-17A were found to be higher in cell supernatants and blood serum of patients who have oral epithelial squamous cell carcinoma when compared to healthy people [22].…”

Section: Discussionmentioning

confidence: 99%

Collision Tumor of Primary Laryngeal Mucosal Melanoma and Invasive Squamous Cell Carcinoma with IL-17A and CD70 Gene Over-Expression

Sirikanjanapong

Lanson

Amin

et al. 2010

Head and Neck Pathol

View full text Add to dashboard Cite

The most common primary malignancy of the larynx is the squamous cell carcinoma (SCC). The primary malignant melanoma is quite rare in this location. Less than 60 cases of laryngeal melanomas have been reported to date. To our knowledge, collision primary malignant melanoma and invasive squamous cell carcinoma in the vocal cords has not been reported. We report a 53-year-old male patient who was diagnosed with a collision tumor of laryngeal melanoma and invasive SCC. Multiple Th17 pathway related genes including CTLA-4, IL-17A-F, PLZF, FoxP3, RorγT, CD27, and CD70 were analyzed by reverse transcriptase-polymerase chain reaction (Rt-PCR) in this case. Both IL-17A and CD70 genes were detected in this case of collision tumor. The results may define useful biomarkers for early diagnosis of mucosal melanoma and open an immunotherapeutic field for clinical management with the potential benefit from the immunomodulators that enhance both genes.

show abstract

CTLA4 blockade increases Th17 cells in patients with metastatic melanoma

Cited by 162 publications

References 32 publications

CTLA-4 Blockade Expands Infiltrating T Cells and Inhibits Cancer Cell Repopulation during the Intervals of Chemotherapy in Murine Mesothelioma

CTLA-4 Blockade Expands Infiltrating T Cells and Inhibits Cancer Cell Repopulation during the Intervals of Chemotherapy in Murine Mesothelioma

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

Collision Tumor of Primary Laryngeal Mucosal Melanoma and Invasive Squamous Cell Carcinoma with IL-17A and CD70 Gene Over-Expression

Contact Info

Product

Resources

About