Malignant melanoma (MM) is the most aggressive
and deadly type of skin cancer. MM is also among the most immunogenic of all
solid cancers, as supported by the presence of melanoma antigen-specific
antibodies and tumour-specific cytotoxic T cells in melanoma patients. The
ability of CD8+ T lymphocytes to prevent the melanoma formation has been shown
in preclinical and clinical studies and their presence within the tumour is
positively correlated with better prognosis in melanoma patients. Therefore,
the immunotherapy has been of interest studied in this tumour model for
decades.
The current
management of MM depends greatly on the location and depth of the primary
lesion and on its stage of presentation. Surgical resection with/out lymph node
sampling is the standard of care and if a thin MM is treated with the
appropriate surgical management, > 97% of all patients are cured. However,
prognosis is poor for patients with advanced disease, with a median survival of
6.2 months. The long-term survival for metastatic MM patients is a relatively
rare event (5) and the use of chemotherapy for advanced MM continues to be
highly unsatisfactory.
Between 1995
and 2004, 442 patients with metastatic MM were treated with more than 500
different cancer vaccines at the Surgery Branch of the National Cancer
Institute (NCI) and there was found to be a scarcely overall response rate
around 3%. In the field of immunotherapy, currently just Interleukin-2 (IL-2)
is the approved immunetherapeutic agent for treatment of patients with metastatic
MM and Interferon alpha (IFN-α) for adjuvant therapy in the treatment of
high-risk melanoma patients. Despite the fact that initial clinical results
with high-dose IL-2 was promising, subsequent trials demonstrated that it
provides a low but consistent overall response rate of 13-17%. The high-dose of
INF-α prolongs disease-free survival and recently published meta-analysis in
patients with high-risk cutaneous melanoma, showed that IFN-α is able to
significantly improve the overall survival as adjuvant therapy.
The prior
experience with immunotherapies has failed to produce significant levels of
objective responses in MM. Currently, the results of novel agents and new
immunotherapeutic approaches are renewing the optimism of the researchers. The goal
of this short communication is briefly to illustrate to the readers the latest
results of the most promising agents and newest immunological alternative
approaches against metastatic disease being tested in clinical trials.
Nonspecific
stimulation of the immune system
In the group
of novel immunotherapy agents, the Pegylated interferon alfa-2b (Pegintron,
Schering-Plough), which has a substantially longer half-life than its IFN
unconjugated molecule, has shown a significant clinical response when it is
used in combination with temozolomide in patients with advanced disease. The
efficacy and safety of Pegintron was assessed in a large European randomized
trial. In this trial 1.256 resected stage III melanoma patients, Pegintron
(N=627) arm and observational arm (N=629), were enrolled. The median
relapse-free survival was 34.8 months in the Pegintron arm vs. 25.5 months in
the observational arm (p-value 0.01). The Oncologic Drugs Advisory Committee of
the Food and Drug Administration (FDA) recently recommended for Pegintron
approval as an adjuvant treatment in patients with Stage III MM.
The results
using granulocyte-macrophage colony stimulating factor (GM-CSF) has also shown
promise. The GM-CSF also reduces the risk of melanoma recurrence in patients
with extirpated disease with a better safety profile than Pegintron. An ongoing
phase III study (ECOG E 4697) is comparing a 1-year course of GM-CSF, with or
without melanoma-antigen peptide vaccination, to placebo in patients completely
resected advanced melanoma. The preliminary data from 735 patients demonstrated
that adjuvant GM-CSF improves disease-free survival (11.8 months) as compared
with patients not receiving GM-CSF (8.8 months). The overall survival (OS) was
improved less but without achieving a statistical significance.
Intratumoral
gene transfer therapy
OncoVEXGM-CSF
is a 2nd generation oncolytic herpes simplex type 1 virus vaccine encoding
human GM-CSF. OncoVEXGM-CSF represents an improvement over previous vaccine as
the virus has been genetically reprogrammed to attack cancerous cells, while
healthy cells remain undamaged. While OncoVEXGM-CSF is administered locally by
intra-tumoral injection, it provides systemic benefit by the induction of a
potent anti-tumor immune response. Primary viral infection of melanoma cells
followed by virus replication and further infection and replication by progeny
virons result in robust tumor cell lysis and the expression of GM-CSF in the
local tumor environment serves to achieve several biologic goals inducing a local
inflammation, enhancing dendritic cell activity, and increases HLA class II
expression. Interest has been generated by the 13 objective systemic (eight
complete response (CR) and five partial response (PR)) responses observed in a
recent phase II study with intratumoral injections of OncoVEXGM-CSF into 50
stage IIIc and IV melanoma patients. Injected tumours routinely responded,
often with local CR, within 2 months of therapy. A randomized Phase 3 study
began in 2009 to assess the efficacy and safety of treatment with OncoVEXGM-CSF
as compared to subcutaneously administered GM-CSF in patients with unresectable
metastatic MM.
Anti-CTLA-4
antibodies
A group of
novel monoclonal antibodies anti-cytotoxic T-lymphocyte antigen (CTLA)-4 has
been evaluated in clinical trials and has shown encouraging results. The most
promising agent is ipilumumab (also known as MDX-010 or MDX-101), which is a
human monoclonal antibody developed by Bristol-Myers Squibb. By relieving
negative regulation, this antibody effectively takes the brake off of the
immune system, allowing immune cells to attack melanoma cells more effectively.
A recent phase III, randomized double blind clinical trial evaluated the safety
and efficacy of ipilimumab in inoperable pretreated advanced stage melanoma
patients. Ipilimumab improved the median overall survival from 6.4 months to
10.1 months. After one year, 46% of patients with ipilimumab alone group and
44% of patients who received ipilimumab and gp100 vaccine were alive in
comparison to 25% of patients in the gp100 control group. After 2 years, 24%
patients treated with ipilimumab alone and 22% of patients of the
ipilimumab-combined group were alive as compared with 14% of patients treated
with gp100 vaccine alone. The ipilimumab application has been submitted for
marketing authorization approval to the FDA.
Adoptive cell
transfer (ACT)
ACT has
emerged as the most effective treatment for patients with metastatic MM.
Researchers at the NCI Surgery Branch have been working in the ATC-based
immunotherapy since 1988, but significant progress in insights and results came
in 2002 with the introduction of an inmunodepleting preparative regimen before
the ACT. In the latest NCI Surgery Branch trials multiple tumour-infiltrating
lymphocytes (TILs) were used from freshly resected metastatic melanomas. As
soon as anti-tumour activity was detected in vitro, against specific unique or
shared antigens, they underwent a rapid expansion using T-cell stimulating
antibody OKT3 and Il-2. Approximately 5×1010 cells were infused after the
myeloablative chemotherapy with cyclophosphamide with/out 2 or 12 Gy of total
body irradiation. IL-2 was administrated for 2-3 days after the ACT for in vivo
expansion of the TILs. Objective responses consisted of CR and PR were observed
in 21 of 43 patients (49%), who received no total body irradiation, in 13 of 25
patients (52%) who received 2 Gy and 18 of 25 patients (72%) who received 12
Gy. The responses were durable and were seen in all organ sites, including the
brain. The 3-year survival of patients receiving ACT with chemotherapy regimen
alone or with 2 Gy is 25% and 42% respectively, compared with 14% for the no
lymphodepletion group. The high rates of cancer regression have convinced the
researchers of the anti-tumour efficacy of ACT therapy and confirmatory studies
outside the NCI are ongoing.
Conclusion
Eliminating
both the tumour and lymphocyte-mediated immune suppressive mechanism without
adversely affecting the necessary antitumour effector cells has resulted in a
new paradigm in the immunotherapy against MM. Many novel immunotherapeutic
agents appear promising, however they still need to be tested in clinical
trials. Despite great success using the ACT-based therapy a major problem is
that personalized treatment is labour-intensive and requires strong laboratory
expertise which makes it difficult to be adopted by the cancer centers. A more
simple technique for producing large number of efficient TILs and its treatment
in combination with immunotherapeutic agents such as IL-2, anti-CTLA-4 and
other vaccines are under clinical research.
Author: Dr. L. Mendoza
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