Biologic and immunomodulatory events after CTLA-4 blockade with ticilimumab in patients with advanced malignant melanoma.
BACKGROUND
T-regulatory (TR) cells expressing cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) maintain peripheral immune tolerance and negatively affect host immune responses against cancer. The immunobiologic effects of ticilimumab, a human monoclonal antibody against CTLA-4, was administered to patients with metastatic melanoma who participated in a Phase I/II clinical trial.


METHODS
Thirty patients who received ticilimumab at a dose of 10 mg/kg monthly (n=20) or 15 mg/kg every 3 months (n=10) were studied at study entry and at 14-day intervals thereafter to assess lymphocyte immunophenotypes, interleukin (IL)-2 and IL-10 production, and the expression of TR-related genes in peripheral blood mononuclear cells (PBMC) from a subset of patients was studied by real-time polymerase chain reaction.


RESULTS
Four of 12 patients with immune-related adverse events (IRAE) attained objective antitumor responses (ATR), whereas only 1 of 18 patients without IRAE attained ATR (chi2=4.0; P=.0455). Patients with ATR had significant reductions in T(R) cells and constitutive IL-10 production accompanied by a significant increase in IL-2 production by activated T cells. Although IRAE+/ATR+ patients demonstrated a positive correlation between CTLA-4 and glucocorticoid-induced tumor necrosis factor receptor (GITR) transcripts (Spearman rho=.522; P=.015), IRAE-/ATR- patients had a positive correlation between the transcripts of CTLA-4 and program death-1 (PD-1) receptor (Spearman rho=.891; P=.000).


CONCLUSIONS
Antitumor responses in patients with metastatic melanoma who were treated with ticilimumab were found to be correlated with reductions in TR cells and constitutive secretion of IL-10, an increase in IL-2 production, and a positive correlation between transcripts of CTLA-4 and GITR. Conversely, a lack of ATR was found to be correlated with steady levels of TR cells and constitutive IL-10 secretion, and a positive correlation between the transcripts of CTLA-4 and PD-1.
Reuben
James M
JM
Department of Hematopathology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. jreuben@mdanderson.org
Lee
Bang-Ning
BN
Li
Changping
C
Gomez-Navarro
Jesus
J
Bozon
Viviana A
VA
Parker
Charla A
CA
Hernandez
Ingrid M
IM
Gutierrez
Carolina
C
Lopez-Berestein
Gabriel
G
Camacho
Luis H
LH
D000328:Adult; D000368:Aged; D019138:Antibodies, Blocking / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000276:immunology*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology*; D001859:Bone Neoplasms / Q000276:immunology / Q000556:secondary; D060908:CTLA-4 Antigen; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008113:Liver Neoplasms / Q000276:immunology / Q000556:secondary; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000473:pathology; D008875:Middle Aged; D012878:Skin Neoplasms / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D007376:Interleukin-2; D016753:Interleukin-10