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Terai et al. The liver and metastatic uveal melanoma

median OS was 6.0 months and median PFS was 3.6 associated antigens constitute an appropriate target
months. The 1-year rates of OS and PFS were 31% and for immunotherapy for metastatic disease. DCs are
11%, respectively [61] . antigen-presenting cells with the unique ability to
activate naive T cells, and hence are suitable for
Another retrospective study including 34 patients inducing immunologic antitumor responses. A group
who received 3 mg/kg ipilimumab and 5 patients who from the Netherlands treated 14 metastatic UM patients
received 10 mg/kg ipilimumab showed 1 complete with therapeutic DC vaccines loaded with gp100 and
response (CR) and 1 late partial response (PR) for an tyrosinase. Patients were required to have HLA-A*02:01
immune-related response rate of 5.1 . The OS from the phenotype or HLA-DRB*01:04 and needed to have
[62]
first dose of ipilimumab was 9.6 months (95% CI: 6.3- metastatic UM expressing gp100 and tyrosinase. All
13.4 months). Survival ranged from 1.6 to 41.6 months patients were vaccinated with autologous DCs loaded
in this study. Retrospective investigation of 56 patients with gp100 and tyrosinase in various ways (mutated
treated with anti-PD-1 or PD-L1 antibodies also showed or wild type peptides, or mRNA), 3 times, biweekly.
disappointing results [60] . Among 56 UM patients, One to 2 weeks after the last vaccination, a skin test
objective tumor responses were observed in only 2 was performed. In the absence of disease recurrence,
patients for OS of 3.6% (95% CI: 1.8-22.2%). Stable patients received a maximum of 2 maintenance cycles
disease (≥ 6 months) was observed in 5 patients. The of vaccine at 6-month intervals. T cells specific for
median PFS was 2.6 months (95% CI: 2.4-2.8 months), gp100 and tyrosinase were detected by tetramer assay
and the OS was 7.6 months (95% CI: 0.7-14.6 months). after DC vaccination in 4 (29%) of 14 patients. DC-
The result may be correlated with low expression of PD- vaccinated patients with metastatic disease showed
a median overall survival of 19.2 months. No serious
L1 in metastatic UM, compared to that of non-hepatic treatment-related adverse events (common toxicity
metastatic CM [63] . It is of note that a poor response to criteria grade 3 or 4) were observed. Clinically, no
anti-PD-1 antibody therapy has also been reported in CM regression of metastasis was observed. Ten patients
patients with hepatic metastasis [64] . This further supports showed stable disease at the first evaluation point,
the hypothesis that the liver immune microenvironment 3 months after start of vaccination, but 7 patients
itself hampers T-cell immune response against cancer subsequently progressed before the first maintenance
cells. cycle of vaccine was started at 6 months. Seven (50%)
patients survived more than 2 years after start of DC
Adoptive immunotherapy using vaccination for metastatic UM [68] . The efficacy of this
tumor-infiltrating T cells therapeutic DC vaccine remains to be investigated in
Tumor-infiltrating T cells (TIL) treatment has been a large prospective study with a more uniform antigen-
highly successful in metastatic UM with durable loading method to DC.
response and regression of bulky metastasis. In a
study at National Cancer Institute (NCT01814046), TCR and anti-CD3 antibody fusion protein
21 metastatic UM patients who were HLA-A2 IMCgp100 is a fusion protein containing gp100-specific
positive were treated with TIL therapy in phase II T cell receptor (HLA-A*02:01) and anti-CD3 scFv.
clinical trial [65,66] . Seven of 20 evaluable patients IMCgp100 binds to UM cells that express gp100 peptides
showed objective tumor regression including 6 on MHC Class I and then tags CD3 T cells to the other
+
patients with PR and one patient with CR, ongoing end via anti-CD3 antibody. Soluble TCRs have been
at 21 months post therapy. No significant difference engineered and modified to possess extremely high
was seen among responders and non-responders in affinity to gp100 peptides on HLA-A*02:01 molecules.
terms of mutation burden in tumors. On the other The early phase clinical studies showed encouraging
hand, TIL products with either less than 3% tumor- results [69,70] and a pivotal large-scale randomized phase
reactive T cells, less than 2 × 10 tumor-reactive T 2 study for metastatic UM is planned to start.
9
cells, or less than 100 pg/mL of tumor-induced IFN-γ
release yielded poor clinical responses [65] . This study Antibody target glycoprotein NMB
indicated that adoptive transfer of autologous TILs Glembatumumabvedotin (also known as CDX-011 and
can mediate objective tumor regression in patients CR011-vcMMAE) is an antibody-drug conjugate (ADC)
with metastatic UM. that targets cancer cells expressing transmembrane
glycoprotein NMB (gpNMB). It is a fusion molecule
DC vaccine containing fully-human IgG2 monoclonal antibody
Melanocyte-associated proteins including gp100, against gpNMB and the cytotoxic drug monomethyl
MART-1, tyrosinase, and TRP-1 were also expressed auristatin E (MMAE). The anti-gpNMB antibody binds to
in the majority of human UM [67] . These tumor- gpNMB expressing tumor cells and, upon internalization,

240 Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ October 31, 2017