Advances in immunotherapy for melanoma
Redman et al. BMC Medicine
Advances in immunotherapy for melanoma
Jason M. Redman 0 1
Geoffrey T. Gibney 0 1
Michael B. Atkins 0 1
0 Department of Medicine, Georgetown University Medical Center , Washington DC , USA
1 Georgetown Lombardi Comprehensive Cancer Center 3970 Reservoir Road, NW Research Building, Room E501, 20007 Washington DC , USA
In recent years, the introduction and Federal Drug Administration approval of immune checkpoint inhibitor antibodies has dramatically improved the clinical outcomes for patients with advanced melanoma. These antagonist monoclonal antibodies are capable of unleashing dormant or exhausted antitumor immunity, which has led to durable complete and partial responses in a large number of patients. Ipilimumab targets the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) receptor. Nivolumab and pembrolizumab target programmed cell death protein 1 (PD-1) receptors and have proven to be superior to ipilimumab alone. The combination of ipilimumab and nivolumab has yielded higher response rates, greater tumor shrinkage, and longer progression-free survival than either monotherapy alone. As other promising immunotherapies for melanoma proceed through clinical trials, future goals include defining the role of immune checkpoint inhibitors as adjuvant therapy, identifying optimal combination strategies, and developing reliable predictive biomarkers to guide treatment selection for individual patients.
Anti-PD-1; Immunotherapy; Ipilimumab; Melanoma; Nivolumab; Pembrolizumab
Background
Advanced melanoma has historically been associated with
a poor prognosis, with a median overall survival (OS) of
8–10 months and a 5-year survival rate of 10 % [
1
].
Chemotherapy clinical trials produced modest benefit to
patients, with short-lived objective responses typically seen
in less than 15 % of patients [
2
]. Initial studies in the
1980s demonstrated the ability of interleukin-2 (IL-2) to
mediate tumor regression in melanoma and other
malignancies [
3
]. In addition, it was recognized that patients
with melanoma tumors infiltrated with T cells had better
long-term survival, potentially as a result of an active
antitumor response by the immune system, which led to
therapeutic approaches using recombinant high-dose IL-2
to induce immune-mediated tumor cell lysis in patients
with metastatic melanoma [
4, 5
]. Pooled data from
patients treated at the National Cancer Institute and within
the Extramural IL-2 Working Group demonstrated
objective responses in 16 % of patients treated with high-dose
IL-2 [6], of which, nearly half were durable or permanent,
suggesting that long-term survival or ‘cure’ is possible.
However, IL-2 is associated with a number of serious
toxicities, largely related to vascular leak syndrome, requiring
inpatient management at experienced centers. While these
factors have limited its generalized use, high-dose IL-2
serves as proof of principle that immunotherapies can
eliminate tumor cells in some patients, encouraging efforts
to develop better tolerated and more effective
immunotherapy regimens.
In order to achieve antitumor effects, cytotoxic T
lymphocytes (CTL) must not only migrate to the tumor,
but must also be capable of tumor cell lysis. While the
presence of tumor infiltrating lymphocytes (TIL) is
frequently seen in melanoma tumors, TILs often have a
diminished capacity for proliferation, cytokine production,
and tumor lysis [
7
]. However, when TILs are removed
from the tumor microenvironment (TME) and grown
ex vivo, they can exhibit potent and specific antitumor
activity, implying that the immune climate within the
TME can dampen CTL activity. Evidence suggests that
inflammation caused by immune infiltration can induce
immune escape mechanisms, including interferon
(IFN)gamma-mediated upregulation of programmed
deathligand 1 (PD-L1) in the TME and increased numbers of
regulatory T cells (Tregs) [
8
]. The engagement of PD-L1
(and PD-L2) with the programmed cell death protein 1
(PD-1) receptor on CTL leads to T cell exhaustion.
Antibodies to PD-1 or PD-L1 have been shown to block the
interaction between these molecules and restore antitumor
immunity within the TME [
9, 10
].
Another mechanism of dampened immune response
that is thought to predominately exert its effects in
secondary lymphoid organs, as opposed to within the
TME, involves cytotoxic T lymphocyte-associated protein
4 (CTLA-4) expression on T cells. CTLA-4 is a receptor
exclusively expressed on T cells that binds to CD80 (B7.1)
and CD86 (B7.2) on antigen-presenting cells [
11
]. T cell
inhibition via this receptor occurs through multiple
mechanisms. By outcompeting CD28 for binding to B7.1 and
B7.2, CTLA-4 can prevent the co-stimulation necessary to
generate and maintain T cell activation. Additionally,
evidence suggests that expression of CTLA-4 on Tregs
is important in T cell inhibition [
12
]. Antibodies to
CTLA-4 have been shown to block the interaction
between CTLA-4 and (...truncated)