Mi 4 2 137 PDF

MEDICINE INTERNATIONAL 4: 13, 2024
Immune checkpoint inhibitors in metastatic

melanoma therapy (Review)
VEDANT SHAH, VIRAJ PANCHAL, ABHI SHAH, BHAVYA VYAS,
SIDDHARTH AGRAWAL and SANKET BHARADWAJ
Department of Medicine, Smt. N.H.L. Municipal Medical College and Sardar Vallabhbhai Patel
Institute of Medical Sciences and Research (SVPISMR), Ahmedabad, Gujarat 380058, India
Received October 31, 2023; Accepted January 26, 2024
DOI: 10.3892/mi.2024.137
Abstract. An increase in the incidence of melanoma has significant breakthrough in the treatment of metastatic mela‑
been observed in recent decades, which poses a signifi‑ noma, providing improved outcomes compared to traditional
cant challenge due to its poor prognosis in the advanced therapies.
and metastatic stages. Previously, chemotherapy and
high doses of interleukin‑2 were available treatments for
melanoma; however, they offered limited survival benefits Contents
and were associated with severe toxicities. The treatment
of metastatic melanoma has been transformed by new 1. Introduction
developments in immunotherapy. Immune checkpoint 2. Immune checkpoint inhibitor drugs and their role in meta‑
inhibitors (ICIs), monoclonal antibodies that target cytotoxic static melanoma
T‑lymphocyte‑associated antigen‑4 (CTLA‑4), programmed 3. Mechanisms underlying the effectiveness of ICIs in meta‑
cell death protein 1 (PD‑1) and its ligand, PDL‑1, have static melanoma
emerged as promising therapeutic options. Commonly used 4. Combination therapy with immune checkpoint inhibitors
ICIs, such as ipilimumab, nivolumab and pembrolizumab, in melanoma
have been found to be associated with an improved median 5. Comparison between the immune checkpoint inhibitors
overall survival, recurrence‑free survival and response rates 6. Biomarkers
compared to traditional chemotherapies. Combination thera‑ 7. Factors affecting drug use
pies involving different types of ICIs, such as anti‑PD1 with 8. Adverse effects
anti‑CTLA‑4, have further enhanced the overall survival and 9. Mechanisms of resistance
response rates by targeting various phases of T‑cell activa‑ 10. Emerging newer therapeutic strategies: Targeting tumor
tion. Additionally, the development of novel biomarkers has metabolic dependencies
facilitated the assessment of responses to ICI therapy, with 11. Conclusion and future perspectives
tissue and serum‑based prognostic and predictive biomarkers
now available. The increased response observed with ICIs
also provides potential for immune‑related adverse effects 1. Introduction
on various organ systems. Further research is required to
evaluate the efficacy and safety of various combinations of The incidence of melanoma has increased over the past
ICIs, while ongoing clinical trials explore the potential of two decades (1). Each year, melanoma affects more than
newer ICIs. Concerns regarding the development of resis‑ 325,000 people. Males experience more frequent occur‑
tance to ICIs also warrant attention. The present review rences, with 174,000 yearly cases compared to females, with
summarizes and discusses the advent of ICIs with a marked 151,000 cases (2). Of note, 20% of patients with melanoma
eventually develop unresectable or distant metastatic disease
labeled as stage III/IV (3). Unfortunately, for such an
advanced‑stage disease, the prognosis remains bleak. However,
Correspondence to: Dr Viraj Panchal, Department of Medicine, understanding the advanced stages of melanoma growth and
Smt. N.H.L. Municipal Medical College and Sardar Vallabhbhai Patel progression has led to the development of promising new
Institute of Medical Sciences and Research (SVPISMR), 1, Santoor therapeutic alternatives.
Bunglows, Iscon‑Ambali Road, Ahmedabad, Gujarat 380058, India Until 2011, chemotherapy was the initial treatment for meta‑
E‑mail: virajpanchal611@gmail.com static melanoma; however, it only provided a 6‑month median
survival time and a 25% 1‑year overall survival rate. High‑dose
Key words: ipilimumab, nivolumab, pembrolizumab, melanoma, interleukin‑2 (IL‑2) was the only immunotherapy available, but
immune checkpoint inhibitors was associated with severe toxicities and only benefited a limited
number of patients (4). Currently, advances in immunotherapy
2 SHAH et al: IMMUNE CHECKPOINT INHIBITORS IN MELANOMA
and studies on cell cycle regulatory molecules have facilitated 3. Mechanisms underlying the effectiveness of ICIs in
the creation of immune checkpoint inhibitors (ICIs), a group of metastatic melanoma
monoclonal antibodies that block co‑inhibitory molecules, such
as cytotoxic T‑lymphocyte‑associated antigen‑4 (CTLA‑4), CTLA‑4 and anti‑CTLA‑4 drugs. CTLA‑4, a B7/CD28 family
programmed cell death protein 1 (PD‑1) and its ligand, member, is a coinhibitory receptor expressed on the surface
PDL1 (5‑7). Ipilimumab, nivolumab and pembrolizumab were of T‑cells that eventually inhibits T‑cells, and it is expressed
the first class of medications shown to improve the overall by regulatory T‑cells (Tregs) (14). Discovered in 1987, it was
survival of patients with metastatic melanoma (4). considered to function as a negative regulator of T‑cell activa‑
The present review provides comprehensive evidence tion until the mid‑1990s (15‑17).
regarding the role of ICIs and their utilization in advanced When CTLA‑4 is expressed on the surface of CD4+ and
melanoma cases. The outcomes of ICIs, such as ipilimumab, CD8+ T‑cells, the binding affinity increases and is higher
nivolumab and pembrolizumab are highlighted, including the to CD80 and CD86, which are the costimulatory receptors
improved survival rates and response rates associated with present on antigen‑presenting cells (APCs) compared to CD28
their use compared to traditional chemotherapies, while also which is another costimulatory receptor (18). The expression of
focusing on the mechanisms and demonstrating the potentially CTLA‑4 increases when there is an activation of T‑cell recep‑
adverse effects of these therapies. tors and the release of cytokines such as IL‑12 and interferon
Furthermore, the present review focuses on combination (IFN)‑γ. This upregulation creates a feedback inhibition loop
therapies, including anti‑PD1 with anti‑CTLA‑4, showcasing on T‑effector cells which are activated, leading to CTLA‑4
their importance compared to monotherapy. The improved acting as a natural ‘brake’ on CD4+ and CD8+ T‑cell activation
outcomes of combination therapies over traditional therapies induced by APCs, as shown in Fig. 3.
are highlighted, with an emphasis on the need for ongoing Tregs also play a key role in maintaining immune homeo‑
research, optimized treatment approaches and strategies which stasis by inhibiting excessive immune responses. One of the
can be used to overcome resistance. In addition to discussing mechanisms through which Tregs suppress effector T‑cell
the development of novel biomarkers for assessing ICI thera‑ activity is via CTLA‑4 signaling (19). Two anti‑CTLA‑4 drugs
peutic responses in both tissue and serum‑based prognostic have been studied in patients with melanoma: i) Ipilimumab,
and predictive markers, tumor metabolic dependencies and the first ICI evaluated and approved for the treatment of
targeting the metabolic pathways by combining ICIs are also melanoma is a fully human immunoglobulin anti‑CTLA‑4
discussed. This could provide an improved efficacy, which, to monoclonal antibody (20,21); ii) tremelimumab, a fully human
the best of our knowledge, has not been described commonly immunoglobulin anti‑CTLA‑4 monoclonal antibody which is
in the available literature focusing on ICIs used in melanoma. still under investigation (12).
There are two major mechanisms through which these
2. Immune checkpoint inhibitor drugs and their role in drugs act. First, the inhibition of CTLA‑4 signaling in cyto‑
metastatic melanoma toxic T‑cells that specifically target tumors can directly affect
these cells by enabling them to evade a state of anergy and
The surface of immune cells, such as T‑cells, assists in the enter an active proliferative effector phase. Once activated,
regulation of the immune response through various receptors. these effector T‑cells are more likely to penetrate the tumor
When activated by certain ligands, these receptors inhibit and exhibit direct cytotoxic effects on tumor cells, while also
immune cells from attacking the body's own cells. However, releasing cytokines such as IL‑2 and IFN‑γ to stimulate an
in cancer, tumor cells can take advantage by binding to these immunogenic tumor microenvironment. Thus, by blocking
checkpoint‑inhibitory receptors through their own ligands and the CTLA‑4 pathway, T‑cells that were previously inactive
suppressing the immune response, as illustrated in Fig. 1. can become activated and effectively target the tumor cells,
Commonly implicated inhibitory receptors include causing a more powerful immune response against the cancer.
(CTLA‑4, PD‑1, T‑cell immunoglobulin domain and mucin This new approach holds promise as a potential immuno‑
domain‑3 (TIM‑3), killer cell immunoglobulin‑like receptor therapy for the treatment of cancer (22).
(KIR), lymphocyte‑activation gene 3 (LAG3), glucocorti‑ The second major mechanism driving these drugs is the
coid‑induced tumor necrosis factor receptor (GITR), B‑ and blocking of CTLA‑4 signaling in Tregs, which may impair
T‑lymphocyte attenuator (BTLA) and V‑domain immuno‑ their ability to halt the activity of effector T‑cells. This inhibi‑
globulin (Ig)‑containing suppressor of T‑cell activation tion of CTLA‑4 signaling can either cause a decrease in the
(VISTA) (8‑10), as presented in Fig. 2. number of Tregs or reduce their function without affecting
Over time, several drugs have been introduced targeting their population size. Therefore, blocking CTLA‑4 on Tregs
these receptors. Ipilimumab was one of the first ICI drugs to may disrupt this suppression and lead to increased immune
be approved by the Food and Drug Administration (FDA) for activation against tumor cells (19,23,24).
the treatment of metastatic melanoma, which functions by Patients with melanoma are treated with the primary aim
blocking CTLA‑4 (11). There are numerous additional compa‑ of suppressing the molecular interplay between the melanoma
rable drugs in early phase III, phase II, or preclinical research. cells and immune effector cells. Ipilimumab, which has mainly
These include pidilizumab, atezolizumab, durvalumab and been approved for the treatment of more advanced stages, such
tremelimumab (formerly known as ticilimumab) (12,13). To as unresectable or metastatic melanoma, has been shown to be
increase the immune system's defense against cancer cells, associated with a marked overall survival rate confirmed from
these medications also work against various immunological a phase 3 clinical trial (25). The interference of ipilimumab
checkpoints (12,13). on CTLA‑4 expressed on the subset of tumor‑specific T‑cell
MEDICINE INTERNATIONAL 4: 13, 2024 3
Figure 1. Illustration demonstrating the role of immune checkpoint inhibitors in suppressing the activation of T‑cells or preventing the release of cytokines
from tumor cells.
Figure 2. Various types of immune receptors on T‑cells and their interaction with ligands present on tumor cells or immune checkpoint inhibitors in the
treatment of melanoma. APC, antigen‑presenting cell; CTLA‑4, cytotoxic T‑lymphocyte‑associated antigen‑4; PD‑1, programmed cell death protein 1;
LAG‑3, lymphocyte‑activation gene‑3; TIM‑3, T‑cell immunoglobulin domain and mucin domain‑3; BTLA, B‑ and T‑lymphocyte attenuator; KIR, killer cell
immunoglobulin‑like receptor; VISTA, V‑domain immunoglobulin (Ig)‑containing suppressor of T‑cell activation; NK cell, natural killer cell.
Figure 3. Illustration demonstrating the interaction of CTLA‑4 expression on T‑cells and CD80 and CD86 on APCs. CTLA‑4, cytotoxic T‑lymphocyte‑associated
antigen‑4; APC, antigen‑presenting cell; MHC, major histocompatibility complex.
proliferation and B7 molecules on antigen‑presenting cells is fully humanized and dostarlimab), as well as those that inhibit
expected to prevent tumor development (26). PD‑L1 (such as avelumab, atezolizumab, and durvalumab) are
being evaluated for use in melanoma cases and various other
PD‑1 pathway and anti‑PD‑1/PD‑L1 drugs. PD‑1 is a protein malignancies (NCT04020809, NCT04274816, NCT03313206,
present on the surface of T‑cells, B‑cells and natural killer NCT03842943 and NCT05928962). However, it is not yet
(NK) cells. It functions as an inhibitory molecule by binding known which inhibitor, PD‑1 or PD‑L1, is more efficient (13).
to PD‑L1 (or B7‑H1) and PD‑L2 (B7‑H2). PD‑L1 is expressed Of these, nivolumab and pembrolizumab are the two major
in numerous types of tissue, including hematopoietic cells and FDA‑approved anti‑PD‑1 monoclonal antibodies available for
certain tumors such as melanoma, where they are expressed in the treatment of advanced and metastatic melanomas.
40‑50% of cases. PD‑L2 is mainly expressed in hematopoietic Melanoma cells exhibit increased levels of PD‑L1, which
cells. The binding of PD‑1 to PD‑L1/2 inhibits the death of promotes the apoptosis of the likewise increased levels
tumor cells and promotes the conversion of T‑effector cells of T‑cells (33). It has also been found that the circulating
into Tregs, while also inducing exhaustion in peripheral melanoma antigen‑specific T‑cells and tumor‑infiltrating
T‑effector cells, as illustrated in Fig. 4 (27,28). lymphocytes express PD‑1 abnormally. It is considered that
PD‑1 and/or PD‑L1 are also expressed on cells, such as NK melanoma cells are capable of initiating, as well as sustaining
cells, monocytes and dendritic cells (27,28). The PD‑1 pathway PD‑1 signals, T‑cell fatigue and dysfunction (33). Hence, by
operates through various mechanisms, such as reducing blocking PD‑1 in patients with melanoma, one could possibly
the activity of T‑cells during an inflammatory response, restore abnormal activation and signaling and eventually
increasing the proliferation and suppressive activity of Tregs, recover the immune effect. Pembrolizumab or lambrolizumab
and reducing the lytic activity of B‑cells and NK cells (29). were used in unresectable or metastatic melanoma in the study
The affinity between PD‑1 and PD‑L1 is 3‑fold stronger by Hamid et al (34), in an aim to elucidate the effects of PD‑1
than the affinity between PD‑1 and PD‑L2. When PD‑L1 medications in melanoma.
binds with PD‑1 on T‑cells, it results in T‑cell exhaustion, However, due to the heterogeneous nature of tumors, the
dysfunction, neutralization and the production of IL‑10 within expression of PD‑L1 is not uniform throughout. The extent of
the tumor mass. This process allows tumors that overexpress PD‑L1 expression can differ in various locations within the
PD‑L1 to protect themselves from being attacked and killed by tumor, resulting in varying levels of PD‑L1 in immunohisto‑
CD8+ cytotoxic T‑cells (30). chemical staining. Moreover, the effectiveness of PD‑L1/PD‑1
Pro‑effector cytokines, namely IL‑12 and IFN‑ γ, can inhibitors can also be influenced by several other factors,
upregulate the expression of PD‑1 and PD‑L1/L2, which helps such as the type of cancer, the patient's immune system and
to prevent excessive T‑effector cell activity. It is worth noting the genetic profile of the tumor. Thus, a more in‑depth under‑
that PD‑L1 has also been shown to inhibit CD80, indicating standing of these factors is essential for developing effective
the existence of complex interactions between CTLA‑4, PD‑1 treatment strategies that consider the heterogeneity of tumors
and other pathways (31,32). and the variability in PD‑L1 expression (35).
The PD‑1 and PD‑L1 antibody inhibitors were created The combination ICI therapy used in the treatment
with the aim of preventing the PD‑1 or PD‑L1 side from of patients with metastatic melanoma primarily involves
functioning, reactivating T‑cells and promoting an immune CTLA‑1 and PD‑1 inhibitors. This amplified the inhibitions
response against cancer cells (13). that can be simultaneously intervened during different phases
Based on promising results from clinical trials, antibodies of the interaction among melanoma cells and the immune
that inhibit PD‑1 (such as pembrolizumab, nivolumab‑IgG4 system. This, for example, includes anti‑CTLA‑4 inhibiting
Figure 4. Illustration demonstrating the interaction between PD‑1 and PD‑L1 among T‑cells and tumor cells. PD‑1, programmed cell death protein 1; PD‑L1,
programmed cell death protein ligand 1; CTLA‑4, cytotoxic T‑lymphocyte‑associated antigen‑4; MHC, major histocompatibility complex.
the priming stage at the same time anti‑PD‑1 inhibits the 4. Combination therapy with immune checkpoint inhibitors
effector stage (36,37). It has also been noted that the use of in melanoma
anti‑CTLA‑4 inhibitors results in an increased expression
of PD‑1; hence, using combination therapy results in a more The ability of anti‑CTLA‑4 and anti‑PD‑1/PD‑L1 mono‑
robust treatment response in patients with melanoma (38). clonal antibodies to target various T‑cell activation locations
and phases is the rationale for their combined use. PD‑1 is
Newer drugs. An increased understanding of immunological primarily expressed on antigen‑experienced T‑cells in periph‑
mechanisms has led to the identification of additional potential eral tissues, while CTLA‑4 is expressed by naive T‑cells in the
targets for checkpoint inhibition in the treatment of cancer. lymph nodes. According to pre‑clinical research, combining
Some of these potential targets include BTLA, VISTA, TIM‑3, ICIs is more effective than treatment with with monotherapy
CD47 and LAG‑3. i) The blockade of BTLA has been shown for managing melanoma (50‑53).
to enhance New York esophageal squamous cell carcinoma In pre‑clinical investigations, anti‑CTLA‑ 4 and
1) specific CD8+ T‑cell function and enhance the efficacy of anti‑PD‑1/PD‑L1 monoclonal antibodies have been shown to
anti‑PD‑1 (39‑41). ii) VISTA blockade has been shown to induce the infiltration of CD8+ T‑cells and the expansion of
increase T‑cell infiltration and function in tumors, thereby an inducible T‑cell co‑stimulator (ICOS)+ T helper 1‑like CD4
reducing tumor growth (10,42). iii) TIM‑3 blockade causes fraction, which in turn induces the response of CD4+ effector
T‑helper‑1 cell hyperproliferation and cytokine release, leading T‑cells. Based on this, the sequencing or combination of
to tumor shrinkage in a mouse model when combined with nivolumab with ipilimumab in metastatic cutaneous melanoma
anti‑CTLA‑4 or anti‑PD‑1 (43‑47). iv) Targeting CD47 with has been researched (50‑53). Other combination studies are on
a humanized anti‑CD47 monoclonal antibody in combination nivolumab, relatlimab and combination therapy with pembro‑
with rituximab has shown to lead to objective responses in half lizumab with low‑dose ipilimumab (54,55). The data from the
of the heavily pretreated patients with relapsed or refractory CheckMate and RELATIVITIY047 trials on the combination
non‑Hodgkin's lymphoma, including a complete response in of ICIs are presented in Table I, which demonstrate a favorable
more than one‑third of patients (48). v) An immune pathway response for such therapies (54,56,57). Table II presents data
known as LAG‑3 has been identified as a potential complement from a meta‑analysis, comparing monotherapy and combina‑
to the PD‑1/PDL1 pathway in enhancing the immune response tion therapy (47‑64).
against cancer. LAG‑3 is an immune checkpoint receptor that
regulates the function of T‑cells. BMS‑986016 is a therapy 5. Comparison between the immune checkpoint inhibitors
that targets LAG‑3 and is currently under investigation in
combination with nivolumab, which targets PD‑1, to enhance Along with the major breakthrough in melanoma treatment
the immune response against cancer cells. The combination with the use of selective BRAF inhibitors, after ~6 months of
of these two therapies has the potential to create a synergistic the median duration, resistance to therapy began to develop.
effect, leading to improved treatment outcomes for patients The BRAF mutation drives the tumor proliferation exponen‑
with cancer (49). tially by activating mitogen‑activated kinase pathway (MAP),
Table I. Summary of the results of the CheckMate and RELATIVITY047 trials performed on the combination of immune
checkpoint inhibitors for the treatment of melanoma.
Objective Median 5‑year Median 5‑Year overall

Study name Treatment group response rate (%) PFS PFS rate overall survival survival rate (Refs.)
CheckMate 064 Nivolumab followed 41 ‑ ‑ 76% ‑ (56)

by ipilimumab
CheckMate 064 Ipilimumab followed 20 ‑ ‑ 54% ‑ (56)
by nivolumab
Checkmate 067 Nivolumab‑ipilimumab 58 11.5 months 36% 36.9 months 52% (57)
Checkmate 067 Nivolumab 45 6.9 months 29% ‑ 44% (57)
Checkmate 067 Ipilimumab 19 2.9 months 8% 19.9 months 26% (57)
RELATIVITY‑047 Nivolumab‑relatlimab 47.7 10.1 months ‑ ‑ ‑ (54)
RELATIVITY‑047 Nivolumab 36 4.6 months ‑ ‑ ‑ (54)
PFS, progression‑free survival.
Table II. Summary of results obtained from a previous meta‑analysis of clinical trials conducted by Pradeep et al (58), which
compared the efficacy and safety of ICIs between monotherapy and combined ICI therapy in advanced melanomas.
Outcome [(Refs.); as in the Effect size in terms

meta‑analysis by Pradeep et al (58)] Comparison of HR or RR (95% CI) P‑value
Overall survival (52‑56) Nivolumab with ipilimumab vs. monotherapy HR, 0.65 (0.53‑0.79) <0.0001
Nivolumab with ipilimumab vs. nivolumab alone HR, 0.84 (0.71‑0.99) 0.04
Nivolumab with ipilimumab vs. ipilimumab alone HR, 0.54 (0.48‑0.62) <0.00001
Progression‑free survival (53,55‑58) Nivolumab with ipilimumab vs. monotherapy HR, 0.48 (0.38‑0.60) <0.0001
Nivolumab with ipilimumab vs. nivolumab alone HR, 0.68 (0.49‑0.94) 0.02
Nivolumab + ipilimumab vs. ipilimumab alone HR, 0.42 (0.37‑0.47) <0.00001
Overall response rate (52,54‑57,59) Nivolumab with ipilimumab vs. monotherapy RR, 2.15 (1.63‑2.84) <0.00001
Nivolumab with ipilimumab vs. nivolumab alone RR, 1.32 (1.22‑1.43) <0.00001
Nivolumab with ipilimumab vs. ipilimumab alone RR, 3.09 (2.74‑3.50) <0.00001
In the meta‑analysis by Pradeep et al (58), overall survival, progression‑free survival and objective response rates were the outcomes studied.
HR, hazard ratio; RR, relative risk.
and the development of resistance to BRAF inhibitors in patients who received ipilimumab plus gp100 had a longer
both MAP kinase‑dependent and MAP kinase‑independent median overall survival rate of 10 months compared to
pathways (65‑67). Resistance in MAP kinase‑dependent path‑ 6.4 months for those who received gp100 alone, with a hazard
ways includes secondary mutations in NRAS, the increased ratio (HR) for mortality of 0.68 and a statistically significant
expression of COT kinase, CRAF activation and acquired P‑value of <0.001. The median overall survival rate of patients
mutations in MEK1 (65,68‑71). MAP kinase‑independent who received ipilimumab alone was 10.1 months (HR, 0.66;
pathways include the upregulation of platelet‑derived growth P=0.003) compared to those who received gp100 alone (20).
factor receptor, additional receptor tyrosine kinases activation In the study by Robert et al (25), patients with untreated
including AXL, Erb‑B2 receptor tyrosine kinase 4) and insulin metastatic melanoma were randomly assigned to receive
like growth factor 1 receptor, the activation of PI3K/AKT either ipilimumab plus dacarbazine or dacarbazine alone. A
signaling, and the loss of phosphatase and tensin homolog significantly longer median overall survival (11.2 months) was
(PTEN) (65,69,71‑75). found in the ipilimumab plus dacarbazine group compared
to the dacarbazine alone group (9.1 months). In a follow‑up
Ipilimumab. Ipilimumab is a fully human monoclonal anti‑ maintenance study, patients who received ipilimumab
body developed to antagonize CTLA‑4. A clinical study was plus dacarbazine had a higher 5‑year survival rate (18.2%)
conducted on patients who had unresectable stage III or IV compared to those who received dacarbazine alone (8.8%).
melanoma, where they were randomly assigned in a 3:1:1 These findings suggest that ipilimumab in combination with
ratio to receive ipilimumab (3 mg/kg) plus the glycoprotein dacarbazine may be an effective treatment option for meta‑
100 (gp100) vaccine, ipilimumab alone, or gp100 alone. The static melanoma patients (76).
In a trial for ipilimumab as an adjuvant treatment performed a more effective treatment option for some patients (81).
by Eggermont et al (77), patients with stage III cutaneous mela‑ Another study was also carried out to compare the efficacy
noma who had undergone complete resection were randomly of nivolumab compared to ipilimumab as an adjuvant therapy
administered either ipilimumab (10 mg/kg) (n=475) or a in patients who had resected advanced melanoma. In patients
placebo (n=476). Following a median follow‑up of 5.3 years, with stage III or stage IV melanoma, adjuvant therapy was
the ipilimumab group had a 5‑year recurrence‑free survival administered with either nivolumab (n=453) or ipilimumab
rate of 40.8%, while the placebo group had a rate of 30.3% (n=453) and follow‑up was performed after 18 months (82).
(HR, 0.76; P<0.001). In terms of the 5‑year overall survival The 12‑month rate of recurrence‑free survival was signifi‑
rate, the ipilimumab group had a rate of 65.4% compared to cantly higher in the nivolumab group at 70.5%, vs. 60.8% in
54.4% in the placebo group (HR, 0.72; P=0.001) (77). the ipilimumab group with a HR of 0.65 (P<0.001). It was also
In the study by Ascierto et al (78), patients with unresect‑ noted that treatment‑related adverse events were 14.4% for
able stage III or IV melanoma were randomly assigned to patients treated with nivolumab and 45.9% for those treated
receive either 10 or 3 mg/kg ipilimumab. The median overall with ipilimumab. Therefore, patients who received ipilimumab
survival rate was 15.7 months for the 10 mg/kg group and therapy experienced more severe side‑effects than those who
11.5 months for the 3 mg/kg group (HR, 0.84; P=0.04). Overall, received nivolumab therapy. This suggests that nivolumab may
their study suggested that ipilimumab treatment improved the be a more effective and tolerable treatment option for patients
survival outcomes of patients with unresectable stage III or IV with stage IIIB, IIIC, or IV melanoma following surgical
melanomas, with higher doses of the drug (10 mg/kg) leading resection (82).
to an improved overall survvial compared to lower doses
(3 mg/kg) (78). Pembrolizumab. Pembrolizumab is a monoclonal antibody
which functions by blocking the PD‑1 on T‑cells and allowing
Nivolumab. Nivolumab is a monoclonal antibody that these T‑cells to identify and kill cancer cells. Similar to
inhibits the interaction of PD‑1 with PD‑L1. The clinical nivolumab, pembrolizumab was also compared with ICC in
study performed by Robert et al (79) compared the efficacy ipilimumab‑refractory melanoma. A randomized controlled
of nivolumab with the standard therapy of dacarbazine. In study was conducted on patients with advanced melanoma and
their study, patients who had metastatic melanoma without a have progressed even after receiving ipilimumab and/or standard
BRAF mutation were randomly divided into two groups (1:1 BRAF therapy (83). Patients were divided into three groups as
with nivolumab at 3 mg/kg once every 2 weeks (n=210) and follows: One group (n=181) received 10 mg/kg pembrolizumab,
dacarbazine (n=208). The survival rate at 1 year was 72.9% in one group (n=180) received 2 mg/kg pembrolizumab, and
patients treated with nivolumab compared to 42.1% in patients another group (n=179) received ICC. The 6‑month progres‑
who were assigned dacarbazine (HR, 0.42, P<0.001). The sion‑free survival rate was found to be 38% in patients treated
objective response rate was 40% with nivolumab compared with pembrolizumab at 10 mg/kg (HR, 0.5 vs. ICC; P<0.0001),
to 13.9% with dacarbazine (odds ratio, 4.06; P<0.001) (79). 34% in the 2 mg/kg group (HR, 0.57 vs. ICC; P<0.0001) and
Another randomized controlled trial was carried out between 16% in the ICC group (83). Another study was conducted by
2012‑2014 on patients with advanced melanoma who Robert et al (84), this time comparing pembrolizumab with
progressed after ipilimumab therapy or a combination of ipili‑ ipilimumab. Patients with advanced melanoma were divided at
mumab and a BRAF inhibitor if they were found to be positive a 1:1:1 ratio to receive pembrolizumab at 10 mg/kg once every
for a V600E mutation (80). That study assessed the role of 2 weeks or pembrolizumab at 2 mg/kg once every 3 weeks or
nivolumab as a second‑line treatment in the management of four doses of ipilimumab at 3 mg/kg for once every 3 weeks. An
patients with advanced melanoma. Patients were divided into interim analysis was performed which revealed that the 6‑month
three groups in a 2:1 pattern where one group (n=272) received progression‑free survival of the patients treated with pembroli‑
nivolumab at 3 mg/kg once every 2 weeks and another group zumab once every 2 weeks was 47.3% (HR, 0.58 vs. ipilimumab;
(n=133) received the investigator's choice of chemotherapy P<0.001), 46.4% for those treated with pembrolizumab once
(ICC), which was either dacarbazine or paclitaxel plus carbo‑ every 3 weeks (HR, 0.58 vs. ipilimumab; P<0.001) and 26.5%
platin (80). An interim analysis of that study found that, in the for those treated with ipilimumab (84). A final analysis revealed
first 120 patients of the nivolumab group, 38 patients (31.7%) that the median overall survival rate was not reached in both
experienced confirmed objective responses, whereas only 5 out pembrolizumab groups; however, it was noted to be 16 months in
of the 47 patients (10.8%) receiving the ICC treatment exhib‑ the ipilimumab group (HR, 0.68 for pembrolizumab once every
ited similar responses. Subsequently, upon further analysis of 2 weeks vs. ipilimumab, P=0.0009; and HR, 0.68 for pembro‑
that trial, it was revealed that the median overall survival rate lizumab once every 3 weeks vs. ipilimumab, P=0.0008) (85).
of patients who received nivolumab was 16 months, while for Similarly, in the study by Robert et al (84) the 24‑month overall
those who received ICC, it was 14 months (81). The HR was survival rate was 55% in the group treated once every 2 weeks,
0.95, indicating that nivolumab did not improve the survival 55% in the group treated once every 3 weeks and 43% in the
rate of patients who had ipilimumab‑refractory metastatic ipilimumab group. Not only do nivolumab and pembrolizumab
melanoma when compared to ICC. However, nivolumab prolong overall survival, but they also maintain the quality of
had a higher overall response rate of 27% vs. 10% for ICC, life of patients with melanoma (86,87). These findings have led
and the median duration of response was also longer for to the FDA approval of pembrolizumab for ipilimumab and/or
nivolumab at 32 months compared to 13 months for ICC (77). BRAF inhibitory refractory advanced melanoma. A summary
Hence, nivolumab exhibiting a higher overall response rate of the comparison among ICIs and their outcomes in patients is
and a longer duration of response suggests that it may be presented in Table III.
Table III. Individual immune checkpoint inhibitors with the various outcomes affecting clinical decisions regarding their use.
ICI drug Compared drug Outcome (Refs.)
Ipilimumab Ipilimumab (3 mg/kg) (n=137) vs. Median overall survival (months): 10.1 vs. (20)
Gp100 (n=136) vs. ipilimumab (3 mg/kg) 6.4 vs. 10.0
with gp100 (n=403)
Ipilimumab (10 mg/kg) with dacarbazine (n=251) vs. Median overall survival (months): (76)
dacarbazine (n=251) 11.2 vs. 9.1
Ipilimumab (10 mg/kg) adjuvant (n=475) vs. Recurrence‑free survival (%): 40.8 vs. 30.3 (77)
placebo (n=476)
Ipilimumab (10 mg/kg) (n=365) vs. Median overall survival (months): (78)
ipilimumab (3 mg/kg) (n=362) 15.7 vs. 11.5
Nivolumab Nivolumab(3 mg/kg) once every 2 weeks (n=210) vs. 1‑Year survival rate (%): 72.9 vs. 42.1; (79)
dacarbazine (n=208) objective response rate (%): 40 vs. 13.9
Nivolumab (3 mg/kg) (n=272) vs. ICC (dacarbazine Median overall survival rate (months): (80)
or paclitaxel plus carboplatin) (n=133) 16 vs. 14; overall response rate (%):
27 vs. 10
Nivolumab (n=453) vs. ipilimumab (n=453) 12‑Month recurrence‑free survival (82)
rate (%): 70.5 vs. 60.8; treatment‑related
adverse events (%): 14.4 vs. 45.9
Pembrolizumab Pembrolizumab (10 mg/kg) (n=181) vs. 6‑Month progression‑free survival rate (%): (83)
pembrolizumab (2 mg/kg) (n=180) vs. ICC 38 vs. 34 vs. 16
(paclitaxel plus carboplatin, paclitaxel, carboplatin,
dacarbazine, or oral temozolomide) (n=179)
Pembrolizumab (10 mg/kg once every 2 weeks) 6‑Month progression‑free survival rate (%): (85)
(n=279) vs. pembrolizumab (2 mg/kg once every 47.3 vs. 46.4 vs. 26.5; median overall
3 weeks) (n=277) vs. four doses of ipilimumab survival rate (months): NA vs. NA vs. 16;
(3 mg/kg once every 3 weeks) (n=278) 24‑month overall survival rate (%): 55 vs.
55 vs. 43
ICC, investigator's choice of chemotherapy; NA, not available.
6. Biomarkers ii) Histotype: The majority of melanoma histotypes are not

considered prognostic when looked at individually from tumor
The prognostic marker for melanoma traditionally used is thickness, and are therefore not included in the American Joint
the depth of invasion and the associated mitotic count of the Committee on Cancer staging system (90,109,110). However,
affected cells. With advancements being made, newer prog‑ a nodular melanoma is an independent predictor which can
nostic markers have been found and used. Prognostic and be used for the measurement of recurrence and its association
predictive biomarkers have gained importance, particularly in with mortality due to melanoma (111).
the treatment of melanoma. iii) Digital images trained from AI: New advancements
have allowed for the development of deep learning‑based
Serum biomarkers. The role of serum biomarkers in the early biomarkers, which can help to stratify the stages of melanoma
detection of melanoma is described in Table IV (88‑106). into risk groups, and thus associate disease‑specific survival
with two independent validating cohorts to accurately predict
Tissue markers the prognosis of patients with early‑stage melanoma (112).
Prognostic markers. i) Tumor infiltrating lymphocyte (TIL) iv) Melanoma cell adhesion molecule (MCAM): Expressed
patterns are often divided into grades, such as ‘absent’, in 80% of metastatic tumors, MCAM is a cell adhesion
which is no presence of any lymphocytes within the tumor, marker (113). Those who are positive for MCAM have signifi‑
‘non‑brisk’, which suggest few foci of lymphocytes within cantly worse 5‑year survival rates than those who are negative
the tumor, or ‘brisk’, which is a large diffuse infiltration of for MCAM, and there is an inverse association between the
lymphocytes within the tumor (107). As demonstrated by amount of marker expressed and survival (114,115).
Clark et al (107) in 1989, as well as by others, the presence of v) Ki‑67: Ki‑67 is a unique nuclear antigen that can function
brisk TILs in a vertical growth pattern is often associated with as a marker for cellular proliferation during the active phase
a favorable disease‑specific survival and overall survival rate of the cell cycle (116). For melanomas who have a thickness
after non‑brisk and absent patterns of TILs (107,108). <1 mm, the risk of metastasis increases with the expression of
Table IV. Role of serum biomarkers in melanoma.
Biomarker Use Type Information (Refs.)
LDH Prognostic and predictive Protein‑based The AJCC staging scheme includes blood LDH as an independent prognostic biomarker for metastatic
melanoma. A univariate analysis revealed that an increased amount of LDH was associated with a lesser
response to anti‑PD‑1 medications in patients who received anti‑PD‑1 monotherapy (88).
It was previously found that patients with elevated LDH and NLR levels, despite receiving ICIs, had poor
a OS and PFS (89).
Elevated serum LDH levels increased the disease stage of patients with metastasis to stage IV M1c (1)
metastatic disease, which included individuals with metastases to the lungs, as well as to other visceral
sites apart from the central nervous system (90,91).
S100 Prognostic Protein‑based S100B levels in serum are affected by the tumor load, and higher values of S100B may be used as a
prognostic biomarker and a sign of disease progression (92‑94).
It was previously found that the discriminative ability with serum S100B levels for detecting disease
relapse was much higher than that of serum LDH (95).
miRNA Prognostic Genomic The role of miRNAs as post‑transcriptional inhibitors of translation has been substantially
investigated (96‑100). It has been discovered that these small non‑coding RNAs are detectable in exosomes
in serum (101). It has been demonstrated that aberrant levels of expression of certain miRNAs are
associated with the stage and recurrence of disease (102,103).
miRNAs are crucial in the deregulation of a number of oncogenic pathways in uveal melanoma, which can
facilitate the metastatic spread of disease. The study by Wróblewska et al (104) found that it may be
beneficial to use differentially expressed miRNAs as a biomarker for the evaluation of the risk of
metastasis in patients with uveal melanoma.
MEDICINE INTERNATIONAL 4: 13, 2024
ctDNA Prognostic Genetic It has been demonstrated that circulating tumor DNA testing may detect BRAF V600e mutations, which is
helpful for determining how effectively the BRAF/MEK inhibitor therapy works. Imaging scan
measurements of disease progression and treatment effectiveness have been found to be associated with
the amount of circulating tumor DNA (105,106).
Both univariate and multivariate analyses have revealed an association between ctDNA detectability and a
shorter OS. Patients with distant metastases (79%) were more likely to have ctDNA detected than those
with no distant metastases or only intracranial tumors (32%). Elevated protein S100 and CRP levels were
more closely linked to detectable ctDNA than LDH (104).
AJCC, American Joint Committee on Cancer; LDH, lactate dehydrogenase; PD‑1, programmed cell death protein 1; NLR, neutrophil‑lymphocyte ratio; ICI, immune checkpoint inhibitor; OS, overall
survival; PFS, progression‑free survival; miRNA, microRNA; ctDNA, circulating tumor DNA.
9
Ki‑67 and an increased mitotic rate (117). However, with the among women of reproductive age. As opposed to this, post‑
increasing thickness of melanomas, Ki‑67 can serve as a more menopausal women have a relatively low incidence of the
effective prognostic marker than the mitotic rate, and is often disease, thus raising the possibility that sex hormones such as
associated with ulceration within the tumor, necrosis, higher estrogen may be involved in the growth of the disease (158).
level Clark's level of invasion, and even vascular invasion (118). As a result, estrogen levels should be considered an important
In addition, with recurrent melanomas, higher values of Ki‑67 biomarker in advanced melanoma. Elderly patients aged ≥65
exhibit an independent association with a decreased overall treated with combination therapy comprising of ipilimumab
survival (119). and nivolumab have not exhibited a considerable difference
vi) Lymphatic invasion: In research on primary mela‑ in overall mortality. When prior exposure to ipilimumab is
nomas with a thickness >1 mm, D2‑40 staining was assessed considered, women have a 2.82‑fold increased risk of mortality
for lymphatic invasion, which is an antibody against sialo‑ as compared to prior‑exposed males with ipilimumab (158).
glycoprotein that selectively attaches on endothelial cells of Moderate colitis which does not require the use of intrave‑
lymphatic vessels and helps detect sentinel lymph node metas‑ nous steroids is consistent with an improved overall survival
tasis (120‑122). of patients with stage IV melanoma when treated with a single
vii) Osteopontin: Overexpressed in numerous visceral anti‑CTLA‑4 drug, but not with combination drugs. This
malignancies, osteopontin is known as an integrin‑binding holds true even after the completion of therapy (159). Multiple
protein and used as a biomarker to measure tumor progress nonrandomized studies have shown excellent results in patients
and metastasis (123‑125). It functions as an independent who discontinue treatment after being treated for 1‑2 years
predictor for the prognosis of melanoma and was found to be and disease progression is also uncommon in the following
associated with increased sentinel lymph node positivity in a 2‑5 years of treatment termination (160‑162). This is in contrast
cohort of 345 patients who had primary melanoma detected to the progression of disease of patients with non‑small cell
using immunohistochemical analysis (126). lung cancer, for whom treatment continuation led to improved
viii) Driver mutations: It has been found that BRAF results compared to treatment termination (163).
and NRAS are associated with a significantly lower
melanoma‑specific survival in high‑risk tumors, such as 8. Adverse effects
a stage >2 (127). NF1 mutations has also been found to be
associated with a lower disease‑specific survival and overall The use of PD‑1 inhibitors, namely nivolumab and pembro‑
survival (128). However, further research is required to iden‑ lizumab, and the anti‑CTLA‑4 drug, ipilimumab, has been
tify patients with BRAF mutations and uncover the role of shown to be associated with a steady regression in malignan‑
BRAF mutations in directing the treatment strategy. cies, including metastatic melanoma (164).
Predictive markers. The role of predictive markers in PD‑1 inhibitors function in the tumor setting, while
melanoma and its clinical importance is summarized in CTLA‑4 inhibitors act on lymphoid tissue, resulting in a
Table V (61,129‑151). wide and different set of adverse events (165). Combination
therapies with nivolumab and ipilimumab have been proven
7. Factors affecting drug use to be more effective with a response rate of 59% as compared
to when used alone, with response rate of 43% for nivolumab
Therapy with nivolumab affects the frequencies of innate and 15‑20% for ipilimumab. Moreover, an increased response
lymphoid cells (ILCs) in peripheral blood in patients with mela‑ rate is associated with an increase in adverse events, resulting
noma. The frequency, as well as the secretory activity of ILC in an overall increase in adverse events with the combination
subsets, particularly ILC2s, are affected by treatment. Albeit of nivolumab with ipilimumab, as compared to nivolumab or
nivolumab was found to not effectively alter serum cytokine ipilimumab monotherapy (36,62).
profiles, pro‑inflammatory and angiogenic substances such as A CTLA‑4 blockade with or without anti‑PD‑1 antibody
IL‑1, IL‑6, CCL2, CXCL8 and VEGF had levels outside the produces adverse events in a dose‑dependent manner (166,167).
normal range in 7 of the 18 cytokines. In addition, the produc‑ Considering that older patients are more inclined to develop
tion of IL‑5 and IL‑13 was affected, which are released during rheumatologic events and female patients are also at an
parasite infections and allergic reactions (152). In malignant increased risk, the toxicity profile may vary according to age
melanoma, type 3 ILC is suspected in tumor suppression (153). and sex (168,169).
Serum levels of IL‑6, CXCL8 and CCL2 in particular, surge However, as these molecules are targeted, due to the
during melanoma progression, while mature NKp44+ ILC3s resulting immune response, an increase in the incidence of
protect against melanoma (154). autoimmune conditions is observed; these adverse events are
As previously demonstrated, the advancement of melanoma known as immune‑related adverse events (irAE). If severe
was comparable with aging, although the treatment outcome irAEs occur with one of the drugs, then it is a safe practice
did not differ significantly, and there was no significant change to re‑challenge the patient with a different class of drug (165).
in the survival outcomes of elderly patients as compared to These drugs have the following on the following systems.
young ones. Moreover, it was recommended that both age
groups should be treated in similar manner (155). Primary Gastrointestinal tract. Diarrhea is the most frequent irAE
and secondary resistance are also a key factor affecting drug with incidences between 10 and 13% (164).
use (84,156). Combination therapy with ipilimumab and
nivolumab, as approved by the FDA, has been proven to be Endocrine disorders. In decreasing order, the first endocrine
efficient (157). There is an increased incidence of melanoma system that is most affected by ICIs is the thyroid gland
Table V. Role of predictive biomarkers and their clinical relevance.
Type Biomarker Clinical relevance (Refs.)
Tumor intrinsic TMB/neoantigen Tumors with a higher TMB are potentially more responsive to ICIs; a reason for this
profile may be the fact that these tumors express more neoantigen and hence, may be
recognized easily as a target by T‑cells (129). With the increasing evidence of the
ability of TMBs to predict the response to immunotherapy in melanoma, various
studies have been conducted (130,131). In a previous study, 321 patients with
melanoma were treated with ICIs and it was found that with a higher TMB, one could
predict an increased survival following treatment (132).
Driver mutations Immunotherapy was found to be more effective in patients with activating NRAS genes
than in those without such mutations. According to the CheckMate 067 study, those
patients with BRAF‑mutation in melanoma had a 4‑year overall survival rate of 62%
with combination therapy with ipilimumab and nivolumab, when compared to only
50% with nivolumab alone and 33% with ipilimumab alone (61,133).
Tumor MHC Longer overall survival, a greater response rate, and an increased infiltration of CD4+
microenvironment and CD8+ T‑cells in the tumor microenvironment were all associated with elevated
levels of MHC‑II expression. Conversely, ipilimumab treatment was found to be
associated with a higher risk of disease progression when MHC‑I expression was
lower (<30%), with a 100% negative predictive value (134‑136).
HLA supertypes Two HLA supertypes were identified and linked to CTLA‑4 inhibition therapeutic
outcomes: HLA‑B44 was associated with a longer survival, while HLA‑B62 was
associated with a shorter survival (137).
PD‑L1 PD‑L1 is a complex biomarker to study since it is regulated by several pathways, which
is vulnerable to high sampling error, and expressed on numerous immune cells in the
microenvironment (138). Treatment with PD‑1 inhibitors has been demonstrated to be
successful in both patients with and without PD‑L expression; however, the quality
of immunohistochemical staining for PD‑L1 is not dependable for clinical use (139,141).
Immune ICI‑sensitive melanomas exhibited more oxidative phosphorylation and lipid
metabolism metabolism than ICI‑resistant tumors using high resolution mass spectrometry. In
addition, elevated lipid metabolism increases antigen presentation, which may be the
reason why ICI‑sensitive cancers have a better response to therapy (142).
TIL/TCF‑7 It has been demonstrated that TCF‑7, a transcription factor, promotes a central memory
stem‑like state, and that TCF7‑expressing CD8+ cells have the ability to self‑renew
and differentiate into effector cells (143,144). TCF‑7‑positive cells appear to be the
ones that multiply following anti‑PD1 therapy (145). According to this finding, TCF‑7
expression has been linked to successful clinical results in patients with melanoma
receiving ICIs (146). In light of this, further research is required to establish the role of
TCF7 expression as a predictive biomarker in patients with melanoma who are being
treated with ICIs and its role as a therapeutic target.
GEP Research has been performed to identify a gene expression profile (GEP) that can
predict the response to pembrolizumab. It was discovered that the 18‑gene profile
could identify aspects of the tumor microenvironment that are pertinent to predicting
the clinical outcome of pembrolizumab that are independent of tumor type. This
indicates that GEPs, such as the 18‑gene profile, can be utilized to predict how different
types of cancer will respond to PD‑1/PD‑L1 inhibitors (147‑149).
IPRES The IPRES transcriptional signature is a peculiar pattern of gene expression that is
present in tumors which are resistant to anti‑PD‑1 medications. Increased activity in
genes is related to an increase in transition through the mesenchyme, helping in cell
adhesion, extracellular matrix remodeling, increase in angiogenesis, and wound
repair which are the hallmark of this pattern. The response rate to anti‑PD‑1 therapy can
be enhanced with the identification of transcriptomic features that are associated with
anti‑PD‑1 resistance, which may suggest the mitigation of IPRES‑related biological
process and eventually, an enhance response rate to treatment (147)
Table V. Continued.
Type Biomarker Clinical relevance (Refs.)
Host factors Gut microbiome Patients with high‑fiber diets were 5‑fold more likely than those with low‑fiber diets
to respond to anti‑PD‑1 therapy. In addition, regardless of the type of antibiotic, indi
viduals who had received antibiotics for >30 days prior to commencing ICI treatment
suffered worse outcomes. A past but not concurrent antibiotic treatment has an impact
on the gut microbiome's ‘activating’ response to ICIs (150).
Stress A solid tumor line was grafted into mice, and they were then treated with an anti‑PD‑1
monoclonal antibody. Subsequently, they were made to experience social defeat stress,
and compared to the mice who did not experience this type of stress; the mice who were
socially defeated with stress responded to PD‑1 inhibition less effectively (151).
Others AI According to recent research, pre‑treatment computerized H&E slides can be used to
artificially predict the probability of a response to ICIs (112).
TMB, tumor mutational burden; ICI, immune checkpoint inhibitor; MHC, major histocompatibility complex; HLA, human leukocyte antigen;
CTLA‑4, cytotoxic T‑lymphocyte‑associated antigen‑4; PD‑L1, programmed cell death protein ligand 1; TCF‑7, transcription factor 7; IPRES,
innate anti‑PD1 resistance; AI, artificial intelligence; H&E, hematoxylin and eosin.
(typically hypothyroidism observed following a transient proteins (such as tyrosinase and TRP‑2), the interference of
thyroiditis‑induced thyrotoxicosis) followed by the rest of the PD‑1 signaling may result in autoimmune vitiligo (180). This
endocrine organs. The median time frame from the start of offers a reasonable explanation for the onset and durability of
the treatment to the development of thyroid symptoms, most depigmentation in patients receiving immunotherapy.
commonly hypothyroidism, is 6 weeks, followed by pituitary
(hypophysitis), adrenals (primary adrenal insufficiency) and Lungs. Case series studies have demonstrated that patients
β‑cells of the pancreas (insulin deficient diabetes, analogous to develop organizing pneumonia, diffuse alveolar damage,
type 1 diabetes) (170). These are different from the side‑effects acute respiratory distress syndrome (ARDS) and non‑specific
brought on by conventional cytotoxic chemotherapy or even interstitial pneumonia, which is then managed by intravenous
more recent molecular‑targeted medicines, which infrequently and oral steroids (181‑185).
result in endocrine dysfunction (171).
Liver and kidneys. A previous meta‑analysis revealed adverse
Skin disorders. Non‑specific adverse events such as macu‑ effects associated with the use of anti‑PD‑1/PD‑L1 mono‑
lopapular rash, pruritus, psoriasiform, eczematous and clonal antibodies for malignancies with an increased incidence
lichenoid dermatosis are among the most prevalent (172,173). of pancreatitis, and increased levels of liver enzymes, such as
Compared to anti‑PD‑1 monotherapy, the maculopapular aspartate aminotransferase and alanine transaminase, elevated
rash phenotype is more prevalent when CTLA‑4 inhibition creatinine levels, nephritis and renal failure (164).
is implemented (21). Bullous pemphigoid, vitiligo‑like skin
hypopigmentation/depigmentation and alopecia are other 9. Mechanisms of resistance
less‑common irCAEs (174,175). Although severe reactions,
such as Stevens‑Johnson syndrome, toxic epidermal necrolysis A myriad of ongoing clinical trials and practices have discov‑
and drug reaction with eosinophilia and systemic symp‑ ered multiple mechanisms leading to resistance to ICIs. More
toms are uncommon, cutaneous consequences are typically precisely, these include changes in the tumor microenviron‑
self‑limiting (174‑176). Early diagnosis and the administration ment prohibiting T‑cell interaction, tumor invasion and tumor
of corticosteroids or antitumor necrosis factor‑agents are the cell destruction by effector mechanisms. The key to tumor
foundation of treatment algorithms for irCAEs (176,177). cell destruction via effector T‑cells is through the processing
However, the use of corticosteroids before or after ICI initiation of tumor antigens to antigen‑presenting cells. The failure of
may result in a diminished antitumor efficacy. Anti‑CTLA‑4 antigen‑presenting components in this pathway is a major
and anti‑PD1 therapy have both been associated with reports cause of resistance in melanoma (186). β2 microglobulin is
of vitiligo (178). The occurrence of skin hypopigmentation or an key molecule responsible for the folding and transporta‑
depigmentation such as vitiligo has been linked to an extensive tion of major histocompatibility complex‑1 to the surface of
anticancer benefit from drug treatment in patients with mela‑ cells. Mutations in these molecules have been noted in patients
noma. Vitiligo has been proven as a positive predictive factor in with melanoma at the time of anti‑PD1 treatment failure (187).
measuring the tumor response to treatment. In comparison with Other mechanisms responsible for limiting T‑cell trafficking in
the general population, patients with melanoma have a 10‑fold the tumor microenvironment include mutations in BRAF, and
increased incidence of drug‑related cutaneous hypopigmenta‑ the inhibition of PTEN. This leads to the increased expression
tion and depigmentation (179). Since the PD‑L1:PD1 pathway of immunosuppressive molecules, such as VEGF (188). It also
mostly regulates the peripheral tolerance of melanosomal inhibits the migration and trafficking of effector T‑cells (189).
In addition to these tumor‑intrinsic mechanisms, various it was combined with an anti‑PD1 antibody, it markedly
tumor‑extrinsic mechanisms also play a role in the develop‑ improved the survival and increased immune response with
ment of resistance to ICIs. These include the development of reduced tumor cell mass (199). With such promising results, a
new inhibitory checkpoints, immunosuppressive cytokines number of newer anti‑PI3K medicines are being developed and
and molecules in the tumor microenvironment suppressing tested to increase efficacy (NCT01390818). Despite this, more
immune cell function. One such example is the production of novel promising approaches are needed to prove the success
transforming growth factor β (TGF‑β) by tumor cells. TGF‑β is of combining anti‑PI3K drugs with ICIs in the treatment of
an immunosuppressive cytokine that functions by stimulating melanoma (200).
Tregs and inhibiting the cytotoxicity of effector T‑cells (190).
To summarize, understanding and investigating the 11. Conclusion and future perspectives
potential mechanisms that lead to resistance to ICIs is crucial
in developing effective strategies to guide therapy. Further The development of ICIs and targeted therapies has played a
studies are required to identify new mechanisms and develop crucial role in revolutionizing the management of melanomas
targeted therapies to improve the clinical outcome of patients by improving the overall and progression‑free survival.
undertaking immunotherapy. Although both of these therapies have advantages and disad‑
vantages, combination therapy (ICI + ICI, or ICI + targeted
10. Emerging newer therapeutic strategies: Targeting therapies) has been found to be more effective in improving
tumor metabolic dependencies patient outcomes. However, there is limited literature avail‑
able regarding combination therapies and different types of
Tumor cells sustain themselves by utilizing altered metabolic potential combinations. There are also insufficient data on
pathways by using nutrients, such as glucose, tryptophan and patients and their responses to draw sufficient conclusions. The
arginine to produce toxic metabolites such as adenosine, lactate development of drug‑related adverse effects with the use of
and kynurenine (191,192). Such toxic metabolites produce an combination therapies is also a debatable question. However,
unfavorable environment for the antitumor cells to function when developing newer ICIs to achieve a more effective
resulting in increased expression of immune checkpoints and response, a focus should certainly be placed on the integration
expansion of Tregs (193). of nanotechnology or antibody engineering. Through these,
The mechanism that tumor cells use is the mutation in the one can increase drug delivery to a specific target and thus
myelocytomatosis oncogene (MYC) and PI3K/AKT/mamma‑ increase overall response. In addition, focusing on epigenetic
lian target of rapamycin (mTOR) signaling pathways. The modulation and developing ICIs that target those changes can
increased expression of hypoxia‑inducible factor‑1‑ α leads enhance the responsiveness of ICIs.
to the overexpression of the PI3K/AKT/mTOR pathway, as There may be concerns regarding resistance to ICIs in
well as glucose transporters such as glucose transporter 1, patients with melanoma. Some patients may have resistance
leading to increased glucose consumption and acidification of to certain ICIs from the beginning or may develop them
the tumor microenvironment (194,195). As hypoxia is gener‑ as an acquired resistance with subsequent treatment after
ated, glucose depletion occurs and increased toxic waste is progression of a tumor with clinical benefit. Further treat‑
produced within the tumor microenvironment, resulting in the ment decisions shall be made on the basis of evaluation of
inhibition of tumor antigen presentation by APCs (196). Thus, the tumor and factors related to the patient, focusing on
there is an overall decrease in the antitumor immune response targeted therapeutic drugs, other immunotherapy drugs,
by T‑effector, macrophages or NK cells, while pro‑tumor cellular therapies, intralesional therapies, or chemotherapy. It
immune cells such as Tregs proliferate to increase the expres‑ is important to tailor ICI treatment based on an individual's
sion of inhibitory checkpoint ligand PD‑1 on immune cells, genetic makeup and tumor characteristics to decrease the
inhibiting the antitumor immunity (197). With the advance‑ resistance. The early identification of tumor biomarkers can
ment of technologies, newer therapeutic strategies that target predict future responses to particular ICIs and may help to
the immunosuppressive tumor microenvironment generated select a personalized treatment strategy. Furthermore, with
by tumor cells may be developed to reprogram the behavior of the use of tumor metabolic pathway inhibitors in combina‑
immune cells, leading to an improved efficacy in terms of the tion with ICIs, targeting signaling pathways and immune
treatment response. responses can be better used to overcome potential resistance
One of the important T‑cellular processes is the activation to ICIs than when used alone.
of the PI3K pathway, which plays a vital role in proliferation Trials are being conducted on newer inhibitory immune
and differentiation. Monotherapy, which inhibits the PI3K checkpoint targets, as well as certain inhibitory targets beyond
pathway, has not yielded any significant results in the treat‑ immune checkpoints. These include LAF‑3, TIM‑3, B7‑H3
ment of cancer; however, combining PI3K inhibitors and the and B7‑H4, CD73, etc. which are immune checkpoints, and
PD‑1‑PDL1 blockade has shown some notable results (198). CEACAM1, CEACAM5/6, CCL2/CCR2, etc. which are other
The loss of PTEN, which is a PI3K‑inhibiting tumor suppressor inhibitory targets (201). It is essential to maintain enrollment
often mutated in tumor cells, results in the uncontrolled growth in clinical trials so that newer ICIs, additional inhibitory treat‑
of tumor cells and escapes the immune destruction imposed ments, combination therapy, and mechanisms of resistance
on it. As previously demonstrated, when mice with PTEN‑null and methods of overcoming the resistance can all be further
melanoma were treated in vivo with the PI3K β inhibitor, investigated.
GSK2636771, this resulted in a decreased AKT phosphoryla‑ In conclusion, with the increasing incidence of mela‑
tion and the activation of mTOR targets. Additionally, when noma over the past two decades, managing it with different
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MEDICINE INTERNATIONAL 4: 13, 2024

Immune checkpoint inhibitors in metastatic

Received October 31, 2023; Accepted January 26, 2024

Objective Median 5‑year Median 5‑Year overall

CheckMate 064 Nivolumab followed 41 ‑ ‑ 76% ‑ (56)

PFS, progression‑free survival.

Outcome [(Refs.); as in the Effect size in terms

ICI drug Compared drug Outcome (Refs.)

ICC, investigator's choice of chemotherapy; NA, not available.

6. Biomarkers ii) Histotype: The majority of melanoma histotypes are not

Biomarker Use Type Information (Refs.)

Table V. Role of predictive biomarkers and their clinical relevance.

Type Biomarker Clinical relevance (Refs.)

Type Biomarker Clinical relevance (Refs.)

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