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


CONCLUSIONS
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.


BACKGROUND
NCT00086489.
Comin-Anduix
Begoña
B
Department of Surgery, Division of Surgical Oncology, University of California Los Angeles, Los Angeles, CA, USA. bcomin@mednet.ucla.edu
Lee
Yohan
Y
Jalil
Jason
J
Algazi
Alain
A
de la Rocha
Pilar
P
Camacho
Luis H
LH
Bozon
Viviana A
VA
Bulanhagui
Cecile A
CA
Seja
Elisabeth
E
Villanueva
Arturo
A
Straatsma
Bradley R
BR
Gualberto
Antonio
A
Economou
James S
JS
Glaspy
John A
JA
Gomez-Navarro
Jesus
J
Ribas
Antoni
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD / Q000096:biosynthesis* / Q000276:immunology*; D060908:CTLA-4 Antigen; D016000:Cluster Analysis; D005260:Female; D015234:HLA-A Antigens / Q000378:metabolism; D015789:HLA-A2 Antigen; D006801:Humans; D007107:Immune System; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D008875:Middle Aged; D013601:T-Lymphocytes / Q000378:metabolism
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; C520704:tremelimumab