Page 1074 - Clinical Immunology_ Principles and Practice ( PDFDrive )

ChaPTEr 77 Immunotherapy of Cancer 1039

Several early-phase clinical trials have evaluated different doses, costimulatory signal for T-cell proliferation and survival. We
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schedules, and combinations of immune checkpoint inhibitors have shown that ICOS effector T cells increase in patients after
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in patients with mCRPC. A phase I/II trial (CA184–107) of anti-CTLA-4 (ipilimumab) treatment. An increased frequency
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ipilimumab as a single agent or in combination with radiotherapy of ICOS CD4 T cells was also identified as a pharmacodynamic
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in patients with previously treated mCRPC demonstrated a biomarker of anti-CTLA-4 therapy. Another study with a
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decline in prostate-specific antigen (PSA) in 15% of patients. different anti-CTLA-4 antibody (tremelimumab) also reported
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However, a phase III clinical trial (CA184–043) of bone-directed an increase in ICOS CD4 T cells in blood samples obtained
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radiotherapy followed by either ipilimumab or placebo in patients from patients with breast cancer. Collectively, these findings
with mCRPC failed to demonstrate an improvement in OS. 43 indicated a biologically relevant role for ICOS in antitumor
Further studies are warranted to investigate the potential immune responses elicited by anti-CTLA-4 therapy.
effects of combining immune checkpoint therapy with other Furthermore, preclinical studies demonstrated that combina-
treatment strategies, including other immunotherapies, chemo- tion therapy with anti-CTLA-4 plus an agonist to target the
therapy, radiotherapy, and hormonal agents, in patients with ICOS/ICOSL pathway led to a significant improvement in T-cell
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prostate cancer in different treatment settings (metastatic hor- responses and tumor rejection. These data led multiple phar-
mone-naïve or metastatic castration-resistant disease). maceutical companies to pursue the development of an anti-ICOS
antibody, including a recent trial with GSK3359609, an anti-ICOS
IMMUNE COSTIMULATORY MOLECULES antibody for treating patients with advanced solid tumors
(NCT02723955; ClinicalTrials.gov).
Multiple ligand-receptor interactions play a pivotal role in shaping ICOS previously was shown to be expressed on T-follicular
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T-cell responses, including those that positively regulate T-cell helper cells (Tfh cells). A clinical trial is ongoing with administra-
function, thus making them potential targets for cancer immu- tion of an anti-ICOS antibody as treatment for patients with
notherapy. Many such costimulatory molecules are being relapsed or refractory peripheral T-cell lymphoma follicular
investigated in preclinical or early-phase clinical studies. The variant or angioimmunoblastic T-cell lymphoma (ClinicalTrials.
two major families of costimulatory receptors expressed by T gov).
cells are the immunoglobulin-like (Ig) superfamily (including
inducible T-cell costimulator [ICOS]) and the tumor necrosis 4-1BB (CD137)
factor receptor (TNFR) superfamily (including OX40 and 4-1BB (CD137) is an activation-induced costimulatory molecule
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4–1BB). These costimulatory molecules are suitable candidates that is expressed on activated T cells, NK cells, dendritic cells,
for the development of targeted therapeutics. A schematic eosinophils, mast cells, endothelial cells, and some tumor
overview of the costimulatory and coinhibitory ligand-receptor cells. Anti-4-1BB mAs have demonstrated improved antitumor
interactions is illustrated in Fig. 77.4. T-cell responses, with rejection of established syngeneic tumor
cell lines in preclinical models. Several early-phase trials with
Inducible T-Cell Costimulator anti-4-1BB antibodies have been initiated, and they have dem-
ICOS is another member of the CD28/CTLA-4 immunoglobulin onstrated antitumor responses, including partial remission and
superfamily, whose expression is increased upon T-cell activation. stabilization of disease in a subset of patients with advanced
ICOS can be expressed on activated effector T cells as well as malignancies; however, immune-related adverse events (irAEs)
on activated T regulatory cells (Tregs). ICOS interacts with its have led to reevaluation of the dose and schedule of treatment
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ligand, ICOSL, which is expressed on APCs, and provides a key with anti-4-1BB agonists. Two separate phase I clinical studies

Macrophage
PD-L1/
MHC-II VISTA PD-L2

Coinhibitory VISTA
interactions Dendrictic cell LAG-3 receptor PD-1 PD-L1/
PD-L2

PD-1/PD-L1 PD-1 TIM-3 Galectin 9 or
B7 CTLA-4 other receptor
B7 CD28
MHC-peptide complex TCR Tumor cell
OX40 L OX40 T cell
Costimulatory 4-1BB L 4-1BB
ICOS
ICOS L
interactions
Fig 77.4 Costimulatory and coinhibitory ligand–receptor interactions: A schematic overview
of the costimulatory and coinhibitory interactions between a T cell and dendritic cell; T cell and
a macrophage and a T cell and a tumor cell in the tumor microenvironment.