Detailed analysis of immunologic effects of the cytotoxic T lymphocyte-associated antigen 4-blocking monoclonal antibody tremelimumab in peripheral blood of patients with melanoma

Begoña Comin-Anduix¹ , Yohan Lee² , Jason Jalil¹ , Alain Algazi¹ , Pilar de la Rocha¹ , Luis H Camacho³ , Viviana A Bozon⁴ , Cecile A Bulanhagui⁴ , Elisabeth Seja⁵ , Arturo Villanueva⁵ , Bradley R Straatsma⁶ , Antonio Gualberto⁴ , James S Economou¹^,7^,8 , John A Glaspy⁵^,8 , Jesus Gomez-Navarro⁴ and Antoni Ribas¹^,5^,8

¹Department of Surgery, Division of Surgical Oncology, University of California Los Angeles (UCLA), Los Angeles, CA, USA

²Department of Human Genetics, UCLA, Los Angeles, CA, USA

³Oncology Consultants PA, Houston, TX, USA

⁴Pfizer Global Research and Development (PGRD), New London, CT, USA

⁵Department of Medicine, Division of Hematology/Oncology, UCLA; Los Angeles, CA, USA

⁶Department of Ophthalmology, Jules Stein Eye Institute, UCLA Los Angeles, CA, USA

⁷Department of Microbiology, Immunology and Molecular Genetics

⁸Jonsson Comprehensive Cancer Center, UCLA Los Angeles, CA, USA

author email corresponding author email

Journal of Translational Medicine 2008, 6:22doi:10.1186/1479-5876-6-22


Published:	1 May 2008

Abstract

Background

CTLA4-blocking antibodies induce tumor regression in a subset of patients with melanoma. Analysis of immune parameters in peripheral blood may help define how responses are mediated.

Methods

Peripheral blood from HLA-A*0201-positive patients with advanced melanoma receiving tremelimumab (formerly CP-675,206) at 10 mg/kg monthly was repeatedly sampled during the first 4 cycles. Samples were analyzed by 1) tetramer and ELISPOT assays for reactivity to CMV, EBV, MART1, gp100, and tyrosinase; 2) activation HLA-DR and memory CD45RO markers on CD4⁺/CD8⁺cells; and 3) real-time quantitative PCR of mRNA for FoxP3 transcription factor, preferentially expressed by T regulatory cells. The primary endpoint was difference in MART1-specific T cells by tetramer assay. Immunological data were explored for significant trends using clustering analysis.

Results

Three of 12 patients eligible for immune monitoring had tumor regression lasting > 2 years without relapse. There was no significant change in percent of MART1-specific T cells by tetramer assay. Additionally, there was no generalized trend toward postdosing changes in other antigen-specific CD8⁺cell populations, FoxP3 transcripts, or overall changes in surface expression of T-cell activation or memory markers. Unsupervised hierarchical clustering based on immune monitoring data segregated patients randomly. However, clustering according to T-cell activation or memory markers separated patients with clinical response and most patients with inflammatory toxicity into a common subgroup.

Conclusion

Administration of CTLA4-blocking antibody tremelimumab to patients with advanced melanoma results in a subset of patients with long-lived tumor responses. T-cell activation and memory markers served as the only readout of the pharmacodynamic effects of this antibody in peripheral blood.

Clinical trial registration number

NCT00086489