Therapy for metastatic melanoma - expert opinion.

Melanoma is one of the most aggressive and dangerous tumors. It spreads early to nearby lymph nodes and metastasizes to various organs.

The prevalence of melanoma is constantly growing throughout the world, including in Russia. Until recently, the presence of metastases and the inability to remove the tumor surgically meant inevitable death for the patient.

In recent years, new effective drugs have become available that help increase the survival rate of patients with advanced melanoma. One of the most promising modern areas is immunotherapy.

Cells with damaged genes that can give rise to the growth of a malignant tumor are constantly formed in the body of any person. But the immune system finds and destroys them in time. When the number of degenerated cells reaches a certain critical value, the protective mechanisms stop working adequately. Immune cells do not react to the tumor and do not attack it.

The goal of immunotherapy is to activate the immune system, remove existing blocks, and start the process of recognizing and destroying tumor cells. Today, monoclonal antibodies are used for this - substances that perceive certain molecules as antigens and bind to them, thereby activating immune cells. The names of all such drugs end in “-mab” (from the English monoclonal antibody - “monoclonal antibody”):

• Keytruda – Pembrolizumab
• Opdivo - Nivolumab
• Yervoy – Ipilimumab
• Zelboraf – Vemurafenib
• Tafinlar – Dabrafenib

Also effective in combating melanoma in the later stages are inhibitors of BRAF, a protein that is formed as a result of a mutation in the gene of the same name and triggers the process of uncontrolled cell proliferation. Let's talk about each of these drugs in more detail.

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Keytruda

Keytruda (other names: Pembrolizumab, MK-3475) is an innovative drug that was approved by the FDA (American Food and Drug Administration) in September 2014, and is currently widely used for the treatment of late-stage melanoma . In 2014, Keytruda received Priority Review and Breakthrough Medical Designation. This means that Pembrolizumab has been included in a group of medicines that can improve the effectiveness and safety of the treatment of rare and serious diseases. That is why the drug was so quickly approved and introduced into clinical practice. This usually takes much longer.

How does Keytruda work?

Drugs for immunotherapy of melanoma and other malignant tumors have been around for quite some time. But they have always had low efficiency, and until recently scientists did not know how to deal with this problem.

The goal of immunotherapy is to activate the patient’s immune system, causing it to attack and destroy cancer cells. For a long time, the PD-1 protein became an obstacle to achieving this goal. This is an immunoglobulin, the molecules of which are embedded in cell membranes. It plays a role in the differentiation of immune cells.

The PD-1 protein blocks the immune system. It prevents T lymphocytes from recognizing and destroying cancer cells. Keytruda contains monoclonal antibodies that block PD-1. The drug helps remove the “brake”, due to which lymphocytes acquire the ability to attack tumor tissue.

When is this drug used?

Indications for use of Keytruda:

• metastatic melanoma in advanced stages;
• inoperable melanoma;
• lack of effect from treatment with other drugs.

How effective is Keytruda?

A study was conducted at the University of California, Los Angeles, which involved 173 people diagnosed with advanced melanoma. They were divided into two groups. In one of them, patients received a standard dose of the drug 2 mg per kilogram of body weight every 3 weeks. In the second group, the dose was increased 5 times (10 mg/kg). In 24% of patients receiving the drug at a dose of 2 mg/kg, the tumor decreased by more than a third. Re-growth of melanoma was not observed, and the effect of the drug lasted from 1.4 to 8.5 months (in some cases longer).

Is Keytruda safe?

The second study was conducted on 411 patients who had advanced melanoma and were taking Keytruda. However, severe side effects from the intestines, lungs and liver were rarely observed. Most often, patients experienced side effects such as increased fatigue, cough, nausea, rash, itching, loss of appetite, constipation, diarrhea, joint pain (source of research data - https://www.medicalnewstoday.com/articles/ 282101.php).

Introduction Skin cancer is a huge public health problem, with non-melanoma skin cancer (NMSC) the most common and melanoma the sixth most common in the United States. The number of aggressive skin malignancies has rapidly increased, and >90,000 cutaneous melanomas (MM) and nearly 3,000 Merkel cell carcinomas (MCC) are now diagnosed annually in the United States (1, 2) .

Although basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) are often controlled with topical treatments, it is estimated that several thousand deaths from these diseases occur each year (3, 4).

Despite the rapid increase in the incidence of skin cancer, significant advances in the field of immunotherapy hold great promise. For example, overall 3-year survival for metastatic melanoma increased 5-fold, from 12% with dacarbazine chemotherapy (DTIC) to 58% with combination immunotherapy with the checkpoint inhibitors ipilimumab and nivolumab in 2022 (5-6).

Indeed, in 2022, James Allison (7) and Tasuku Honjo (8) were awarded the Nobel Prize in Physiology or Medicine for the discovery of CTLA4 (cytotoxic T-lymphocyte-associated antigen 4) and PD-1 (programmed-death 1), which are an important component of immunotherapy.

This review will focus on skin cancer, tumor immunotherapy, and the causes of skin cancer immunogenicity. The following will review the historical aspect of immunotherapy for melanoma, with particular emphasis on how the results of these studies have revealed the interaction of the tumor with the immune system in general. The use of immunotherapy to treat other types of skin cancer will then be discussed. Despite good results in the field of immunotherapy, at least half of patients with advanced/metastatic skin cancer are still not cured by this therapy. Significant progress in this area has been achieved over the past 5 years thanks to a large amount of research. We will therefore conclude with a detailed review of the current understanding of the mechanisms of resistance to immunotherapy, including primary and adaptive resistance.

Why is skin cancer so immunogenic for T cells?

The incidence of skin cancer is increased in patients with T-cell immunosuppression. This reflects both underlying tumor immunogenicity and the very important importance of T cells in monitoring and controlling these diseases. Both CD4+ immunosuppression (HIV/AIDS) and CD8+ immunosuppression (organ transplantation) have been associated with increased risk and worse prognosis of cSCC (9, 10), BCC (9), MCC (11–13), Kaposi's sarcoma ( KS) (14) and MM (14), with the most consistent effects observed in cSCC, MCC and KS (15).

In immunocompetent patients, emerging immunogenic skin tumors are removed unless the tumor is destroyed by immunotherapy.

The antigenicity of skin malignancies is thought to derive from tumor-associated antigens, neoepitopes, and/or viral oncoproteins. Melanomas overexpress tumor-associated antigens (eg, MAGE, MART1/MLANA, NY-ESO1 antigens), which render them susceptible to T cells. T cells recognizing these antigens escape negative selection in the thymus (16).

Sequencing methods have also established that most skin cancers, including MM (17), cSCC (18, 19), BCC (20), and virus-negative MCC (VN-MCC) (21), also have a very high tumor mutational load ( from the English tumor mutational burden, TMB). To a large extent, mutations are caused by UV, which creates new tumor epitopes (22–24). Indeed, cSCC, VN-MCC, and melanoma have the highest TMB of all solid tumors (25). TMB is a predictor of immunotherapy, supporting the finding that neoantigens make a major contribution to immunogenicity in most cancers ( 17 , 26 ).

Unlike most skin cancers, which have high levels of TMB, virus-positive skin cancers (KS and virus-positive-MCC (VP-MCC)) have extremely low levels of TMB, similar to cancers that respond poorly to immunotherapy such as ​​such as pancreatic cancer or uveal melanoma (17, 21, 27).

Despite low TMB, both KS and VP-MCC frequently respond to anti-PD-1 immunotherapy. Instead of mutations, antigenicity in these diseases is determined by the expression of viral proteins from oncoviruses (human herpes virus 8 (HHV-8) and Merkel cell polyomavirus (MCPyV), respectively) (28, 29), which are CD8 + and CD4 + T cell antigens ( 30, 31).

This clinical observation suggests that response to immunotherapy may be driven by multiple antigens and, as a consequence, that TMB-high cancers are simply more likely to produce reactive antigens than TMB-low tumors.

This hypothesis is supported by the fact that the response to PD-1 immunotherapy in cutaneous melanoma with low TMB levels may be reduced (or even eliminated) by loss of one HLA antigen (32).

Also, regression of a tumor-infiltrating lymphocyte (TIL) can be mediated by a single epitope (33). Therapeutically, this implies that triggering recognition of solid tumors with a vaccine or cell therapy restricted to a few epitopes (transgenic T cell receptor (TCR) and/or transgenic chimeric antigen receptor (CAR)-T) (34) can provide an adequate immune response. especially in combination with therapies targeting the tumor microenvironment and/or resistance mechanisms.

Progress of immunotherapy for melanoma

Cutaneous melanoma results from mutations in skin melanocytes, specialized pigment cells that originate from neural crest precursors. These neural crest cells are highly motile during embryogenesis, and melanoma retains this high propensity to metastasize/spread (35).

Thus, although melanoma accounts for ~1–2% of all skin cancers (4), it is the leading cause of skin cancer mortality. Melanoma has a strong UV association ( 4 ) and is highly immunogenic due to the large number of tumor-associated mutations in the UV signature ( 25 ).

In the late 1800s, Coley developed intrapulmonary immunotherapy for melanoma. However, his injections of killed streptococci and Serratia bacteria were much less effective in melanoma than in sarcomas (36, 37), and therefore immunotherapy for melanoma was not available for many decades.

In the early 1970s, there was renewed interest in immunotherapy for melanoma. High-dose Bacillus Calmette-Guérin (BCG) was administered to patients with cutaneous melanoma metastases, resulting in local and some distant tumor regressions (38, 39).

However, toxicity and the concurrent emergence of DTIC chemotherapy have weakened the widespread use of BCG in melanoma (40), although BCG immunotherapy has been adopted for the treatment of bladder cancer. In 2017, the mechanisms of BCG response in melanoma were elucidated and involve a complex mechanism between tumor cells (increased HLA class I expression), T cells (increased CD8+ T cell infiltration and activation) and microenvironmental changes (macrophage repolarization) that increased antitumor immunity (41).

The next set of immunotherapies to be tested in melanoma included cytokine therapy. Type I interferons are multifunctional and not only activate T cells, but also enhance the presentation of tumor self-antigens and affect other cells such as macrophages, as well as inhibit T regulatory cells (Tregs) (42).

Interferons were most effective as adjuvant therapy (ie, additional treatment given after surgery), especially in patients with ulcerated tumors (43). However, low response rates and high toxicity limited the benefits. Interleukin 2 (IL-2) is a growth factor cytokine that promotes the division of T cells and other lymphocytes. At toxic dosages, IL-2 caused reactions in metastatic variants with a response rate of about 10–20% (44).

This finding was later recognized to be partly explained by the paradoxical nature of IL-2, which promotes not only the proliferation of CD8+ T effector cells but also the proliferation of Tregs. The dual nature of IL-2 was demonstrated by experiments in mice, where IL-2-deficient animals developed autoimmune reactivity (45).

A number of cell-based methods have been tested in melanoma. These include TIL-based treatments (where tumor lymphocytes are expanded in vitro), endogenous cell-based techniques (where circulating T cells recognizing specific tumor antigens are expanded), and more recently transgenic T-cell techniques (where CD8+ and CD4+ cells are transduced or TCR or CAR to create tumor specificity) (46–52).

Some impressive results have been published in the form of responses to therapy and ongoing remissions lasting more than 5 years. However, most patients treated to date have not had long-term effectiveness. Thus, there is great interest in combining cell therapy with other modalities to improve T cell recognition of tumor cells. Methods are also being sought to overcome the exhaustion of immune cellular responses and/or promote a more favorable microenvironment.

In 2015, the first intrapulmonary oncolytic virus was approved. Talimogene laherparepvec (T-vec) is a genetically engineered herpes virus that is non-pathogenic and preferentially replicates in tumor cells, leading to melanoma cell death through multiple mechanisms, including increased antigen expression.

T-vec also expresses granulocyte/macrophage colony-stimulating factor (GM-CSF) to promote the maturation and function of specialized antigen-presenting cells (APCs), including dendritic cells in the microenvironment. T-vec is associated with an overall response rate of 26%, with higher response in invasive versus noninvasive lesions (53). Various other oncolytic viruses are being studied, as well as combinations of T-vec with other immunotherapies.

Numerous therapeutic approaches have been taken in the form of vaccination against melanoma. Recently, tumor-specific neoantigens in vaccines have been tested in early phases (54, 55).

These studies demonstrated the generation of tumor-specific T-cell immune responses and early clinical activity. The effectiveness and optimal timing of vaccine treatment are currently being studied. The HLA ligand for melanoma has recently been identified, i.e. tumor-specific peptides (neoantigens and/or overexpressed tumor antigens) that are present on melanoma offer significant promise for further vaccine improvement (56).

By far, the greatest success in immunotherapy for melanoma has been achieved with the use of immune checkpoint inhibitors. The first to reach the clinic was ipilimumab, an anti-CTLA4 monoclonal antibody that targets the interaction between APCs (antigen-presenting cells) and T cells. During antigen-specific activation of lymphocytes, one of the B7 proteins (also called CD80 and CD86) on the APC binds to CD28 on the T cell, which stimulates activation and induces CTLA4 expression. CTLA4 on T cells then competes with CD28 for binding to B7 and thus inhibits T cell activation (7, 57, 58).

Although ipilimumab monotherapy in metastatic cancer has a response rate of <20%, the potential for long-term responses and improved overall survival led to FDA approval of the drug. in 2011 (6, 59, 60).

In 2014, the FDA approved two PD-1 inhibitors that target PD-1/PD-L1 (PD-1 ligand 1) signaling between T cell and tumor cell or T cell and APC (8). Both pembrolizumab and nivolumab as monotherapy are associated with response rates of ~40–45% (6, 61). The addition of ipilimumab to pembrolizumab or nivolumab improves response rates by ~10% but results in a significant increase in toxicity, including a markedly increased incidence of immune-mediated adverse events (6).

In addition to immune checkpoint inhibitors, BRAF inhibitors (BRAFi) and MEK inhibitors have recently been approved for the treatment of cutaneous melanoma with BRAF V600 mutations ( 62 ). Consistent with results obtained with the use of tyrosine kinase inhibitors (TKIs) in other indications, melanoma typically develops resistance to BRAF/MEK inhibition.

Interestingly, there is some suggestion that these inhibitors have immunological effects in addition to direct antitumor effects (63), also exhibit specific efficacy in the presentation of tumor-specific antigens (64) and enhance the function of cytolytic T cells, as well as polarize microenvironment (65, 66).

The introduction of immunoreactive inhibitors and TCIs has changed the history of treatment of advanced melanoma. In the DTIC era, from 1974 to 2011, the overall 3-year survival rate of clinical trial participants with metastatic melanoma from initiation of first-line treatment was ~13% (5). In 2022, overall survival at 3 years had improved to >50% (Figure 1).

Potential of the immune system in the treatment of metastatic solid tumors.

With rare exceptions (eg, testicular cancer), chemotherapy as single agents or combination regimens has proven insufficient for the treatment of metastatic solid tumors. Targeted therapy is often effective for months or years, but does not lead to a complete cure. This is due to the large number of cancer cells in metastatic cancers at the time of diagnosis (~1 billion per gram) and therefore the statistical likelihood that a treatment-resistant subclone already exists at the time of treatment.

However, the adaptive immune system can interact with various tumors and mediate their elimination. Indeed, this has been demonstrated in melanoma with high-dose IL-2 therapy, where 5–10% of patients were cured without further need for treatment, and the longest-lasting responses currently span decades (67).

Although the exact duration of response to anti-CTLA4 and anti-PD-1 therapy in melanoma remains to be studied, recent evidence suggests that survival plateaus at 2–3 years, with continued response at >8 years and >3.5 years after cessation of therapy, thereby maintaining the therapeutic potential of these approaches (68, 69). Thus, experience in the treatment of melanoma shows the ability of the immune system to properly treat metastatic solid tumors with the right approach.

Adjuvant immunotherapy with ipilimumab was associated with better melanoma survival compared with placebo control in patients with resected stage III (nodular) melanoma (43).

More recently, adjuvant immunotherapy with nivolumab or pembrolizumab has been associated with better survival and freedom from progression after resected stage III melanoma (or for nivolumab III/IV). This confirms the likely effectiveness of immunotherapy in the initial stages, with a small tumor size (70, 71).

Among patients whose metastatic melanoma was treated with anti-PD-1, pretreatment is associated with lower response rates and worse overall survival, supporting the potential for improved response if treatment is initiated in the context of low burden (72).

There are several hypotheses as to why immunotherapy may be more effective in terms of both response to treatment and cure in mild forms of cancer. The first hypothesis is based on the fact of mutations: a higher number of tumors means a higher chance of having a subclone that is resistant to immunotherapy, such as a β-2-microglobulin mutation that abolishes tumor-specific antigen presentation ( 73 ). The second hypothesis is based on facts about the microenvironment: larger tumors are more likely to have a microenvironment that is more suppressive of CD8 + T cells, contains less oxygen, more lactate (74, 75), and more fibroblasts and M2-like macrophages (76) , which represent biochemical and physical (77) barriers to T cell function.

Although patient treatment has low efficacy rates for poorly differentiated tumors, the optimal timing of initiation of anti-PD-1 has yet to be established. One school of thought suggests that for resectable cancer, neoadjuvant (ie, given before surgery) initiation of immunotherapy may be more effective.

Neoadjuvant checkpoint inhibition may have a greater ability to induce epitope spread with the tumor serving as its own “vaccine” with intact draining lymph nodes to potentiate responses to anti-PD-1 antibody therapy. However, clinical data supporting this hypothesis are limited to small case series (78, 79).

It remains unclear whether these benefits outweigh the risk to the patient of complications from immunotherapy and increased delay in surgical treatment. The current standard of care is surgical resection before immunotherapy. However, this may change following research in this area.

Use of anti-PD-1 in other tumors.

Given the good outcomes in many melanoma patients treated with immune checkpoint inhibitors, as well as the established immunogenicity of other skin cancers, immune checkpoint inhibition with PD-1 and/or PD-L1 inhibitors has been attempted for many other skin cancers. These studies show high response rates in skin cancer that are superior to experience with other solid tumors, as shown in Fig. 2.

Phase II trials have been conducted on NMSC in cSCC and MCC. For cSCC, the response was 47% to the anti-PD-1 drug Cemiplimab (80). This led to its recent FDA approval. Regarding MCC, responses to pembrolizumab (56%) (81, 82) and avelumab (anti-PD-L1; 62%) (83) both exceed 40% as first-line treatment. In addition, overall survival is significantly improved with these agents compared with data obtained with chemotherapy (82, 84). The response to pembrolizumab is independent of whether MCC is induced by virus or ultraviolet light (82).

Data are emerging on the effects of anti-PD-1 monotherapy on metastatic BCC, CS, and cutaneous angiosarcoma. For BCC, a prospective study included nine patients, of whom four (44%) responded to treatment (20).

For KS, a retrospective review included nine consecutive patients with HIV-associated KS (six objective responders; 67%) (27), and there was a second case series with two responding KS patients. For cutaneous angiosarcoma, a positive response was described in one case (85). Also, other data from studies confirm a high response rate for these nosologies, comparable to other types of skin cancer.

Skin toxicity of checkpoint inhibitors

The toxicity of immune checkpoint inhibitors is largely due to a wide range of immune-related adverse events (iRAEs) as well as an autoimmune response to healthy tissue. iRAE rates for immune checkpoint inhibitors prescribed for the treatment of skin cancer appear similar to those for other malignancies, with the exception of increased skin toxicity. The National Comprehensive Cancer Network (NCCN) recently published guidelines for iRAEs and their management (86).

Because iRAEs can affect multiple organ systems (skin, gastrointestinal, lung, endocrine system, blood, nervous system, etc.), a detailed description of all iRAEs is beyond the scope of this review and we will instead focus on cutaneous toxicity.

Cutaneous iRAEs occur in one third/half of patients treated with immune checkpoint inhibitors (86).

The rashes are common in most cases. They present a wide range of clinical manifestations from focal to widespread/diffuse, with eczematous, psoriatic, lichenoid, erythrodermic and other variants. The rash is often itchy. More severe cutaneous toxicities have been observed, including bullous dermatitis, Stevens-Johnson syndrome/toxic epidermal necrolysis, Sweet's syndrome, and DRESS syndrome (drug eruption with eosinophilia and systemic symptoms) (87–89).

Interestingly, immune checkpoint inhibitors in melanoma were specifically associated with the development of hypopigmentation/vitiligo in 3–25% of cases (Figure 3) (90, 91). Hypopigmentation has been very rarely reported with the use of immune checkpoint inhibitors for other solid tumors, but appears to be significantly higher in melanoma. In addition, hypopigmentation occurs exclusively in melanoma in several case series (92–94).

This is believed to represent targeted extracellular immune recognition of overexpressed melanoma antigens on healthy melanocytes. Indeed, the development of vitiligo was associated with improved melanoma survival after immunotherapy in a number of small studies and a large meta-analysis (95).

Predictors of response and resistance to anti-PD-1 and other immunotherapies for skin cancer

Determining the mechanisms of resistance to immunotherapy and especially immune checkpoint blockade, including both early/primary and late/acquired resistance (73), is necessary to improve the results of immunotherapy in skin cancer and increase the proportion of patients cured. It is becoming increasingly clear that susceptibility and resistance to immune checkpoints and immunotherapy do not appear to be easily predicted by a single biomarker. Recently, significant progress has been made in understanding these mechanisms (Fig. 4).

Intracellular tumor factors

Many intrinsic properties of tumor cells are hypothesized to contribute to the sensitivity and resistance of immunotherapy.

Antigens. The basic presence of antigen visible to T cells is critical to the success of immunotherapy, further emphasizing the importance of T cell recognition as a component of an effective antitumor immune response. Tumors with low TMB are less responsive to immunotherapy (17), and tumor escape from immunotherapy is mediated by differentiation and antigen loss (96).

Antigen presentation Tumors must not only contain antigens for T cells, but also properly process and present these antigens bound to the major histocompatibility complex (MHC). Genetic (32, 97) and adaptive/transcriptional (98–100) mechanisms leading to poor antigen processing and/or presentation are often implicated in skin cancer. This is responsible for multiple forms of response to immunotherapy, including resistance to anti-PD-1, anti-CTLA4 and T-cell therapy. Active research is currently underway on means to improve antigen presentation.

Tumor metabolism Tumors with a high metabolic rate consume large amounts of glucose and secrete lactate. This simultaneously depletes CD8 + effector T cells and promotes Treg function (101). Another factor intrinsic to tumor cells is the expression of surface markers that suppress T cells. Melanomas and MCC have been described to express molecules known to inhibit CD8 + T cells, including PD-L1 (6) and CD200 (102, 103), among others.

T cell factors

Multiple T cell factors have been proposed as biomarkers to predict response to immunotherapy and patient outcomes.

CD8 + T cells The number and localization pattern of CD8 + T cells (Fig. 5) likely predicts sensitivity to anti-PD-1 in melanoma, other skin cancers, and other solid tumors (82, 104). Results on T cell clonality have been mixed and are not predictive (105, 106). CD8 + T cell avidity against MART-1 (107) and viral (108) antigens was positively associated with improved patient outcomes in a small series of patients with melanoma and VP-MCC, respectively.

In November 2022, researchers used single-cell technologies to study CD8+ T cell populations in melanoma patients responding and not responding to therapy. A subset of CD8 + T cells was identified that expressed the transcription factor TCF7, which is involved in the development of TSCm (memory T cell stem cells) (109), and which predicted response to immunotherapy (110).

Finally, it is clear that tissue specificity of CD8 + T cells may contribute to tumor-specific immunity. Indeed, recent studies in animal models demonstrate the importance of tissue-resident (in the case of cutaneous melanoma) CD8 + T cells in controlling melanoma progression (111). The impact of these factors on immunotherapy in humans is an area of ​​active study.

CD4+ T cells. Basic research in the 1980s demonstrated that CD4 + T cells mediate protective immunity against cancer (112). Given the difficulties in studying CD4+ T cells in human tumors, the role of CD4+ T cell function in responses to PD-1 therapy remains poorly understood. CD4 + T cell infiltration alone did not provide any definitive results (113).

However, in melanoma patients who received neoantigen-specific vaccines, followed in some cases by immune checkpoint inhibitors, tumor-specific CD4 + T cell responses predominated, supporting the conclusion that this subset plays an important role (55) . More research is needed in this area.

Tregs. Not surprisingly, Tregs were inversely correlated with PD-1 response. Improved clinical outcomes in melanoma patients treated with PD-1 correlated with the relative paucity of Tregs in these patients (114).

Other A number of other ligand-receptor interactions have been reported as modulators of tumor-specific T cells, including those involving ICOS, TIM3, BTLA, A2aR, and others (115).

Microenvironmental factors

Macrophages Macrophages are thought to mediate CD8 + T cell inhibition through PD-L1-PD-1 interactions, CTLA4 signaling, cytokine production, and other factors (116).

The role of macrophages in PD-1 resistance and susceptibility remains to be determined. The contribution of macrophages is likely complex in that patients with higher numbers of PD-L1-expressing macrophages may be more likely to respond to anti-PD-1 therapy, whereas macrophage compartments expand and repolarize during responses to immunotherapy in preclinical trials ( 117, 118).

The role of macrophages in other skin cancers is less well defined. Macrophages have been reported to cause immunosuppression and to correlate with positive T cell responses in MSS. The influence of macrophages on PD-1 sensitivity in MCC and cSCC has not been reported (103, 118).

Fibroblasts Cancer-associated fibroblasts (CAFs) make up a significant portion of the stroma in most skin cancers, including melanoma. These fibroblasts have been shown to contribute to an immunosuppressive microenvironment through chemokine production and extracellular matrix (ECM) production (119, 120). Preclinical studies have shown a significant contribution of CAF to PD-1 resistance in melanoma ( 121 ). No human studies have been reported yet.

Dendritic cells and Langerhans cells Dendritic cells and Langerhans cells contribute to tumor-specific immunity through antigen cross-presentation. This fact was used in the development of topical imiquimod (a TLR7 agonist), which was approved by the FDA for BCC (122). These cells have recently been demonstrated to positively influence anti-PD-1 sensitivity in both a mouse model and in human melanomas ( 123 ).

Endothelial Cells Endothelial cells can reduce the immune response by limiting the functioning of CD8+ T effector cells.

Natural killer ( NK ) peripheral NK cells have been associated with the clinical efficacy of therapy using inhibitors of IL-2, interferon-α (124), and PD-1 in human melanoma (123). In addition, melanomas in mice lacking the mouse equivalent of HLA-E, inhibitors of NK function overexpressed by human melanoma (125), do not develop resistance to PD-1 (126), and MCC has been shown to overexpress HLA-E during escape from immunotherapy (99). This supports a model in which antigen-specific T cells and NK cells cooperate to clear tumors, with NK cells being required to clear tumor clonotypes that have lost HLA class I expression.

Conclusion Skin cancer is highly immunogenic due to the presence of tumor antigens, mutations and/or viral gene expression. As a consequence, skin tumors escape immune clearance, and therefore immunotherapy, which dampens immune responses, is extremely effective. Melanoma is a solid tumor.

Immunotherapy for this pathology was effective. Other skin cancers are treated similarly successfully with anti-PD-1 immune checkpoint inhibitors, confirming their underlying immunogenicity. However, despite great progress, most patients are not cured by these treatments. Barriers to the effectiveness of immunotherapy include several facts regarding T cells and the microenvironment. Promising research into these mechanisms continues. Combination treatment regimens offer hope of increasing response rates and prolonging the duration of successful response.

Opdivo

Opdivo (also known as Nivolumab) is a monoclonal antibody drug approved by the FDA at the end of December 2014.

In 2014, this drug received the following statuses: “fundamentally new drug”, “orphan drug”, “accelerated review”. Nivolumab, like Keytruda, was approved under an accelerated procedure.

How does Opdivo work?

According to the mechanism of action, the drug is an analogue of Keytruda. It blocks the PD-1 receptor, which reduces the activity of T lymphocytes, preventing them from recognizing and attacking immune cells.

In what cases is Nivolumab planned to be used?

Indications for use of the drug:

• progressive inoperable melanoma;
• lack of effect from treatment with ipilimumab;
• melanoma in which there is a mutation in the BRAF gene, but the use of BRAF inhibitors is not effective.

How effective is Nivolumab?

The effectiveness of Opdivo was studied in a study that included 120 patients with unresectable metastatic melanoma. During the use of the drug, 32% of patients experienced a significant reduction in tumor size. The effect lasted for 6 months.

Safety

A study was also conducted to evaluate the safety of the drug. 268 patients received Nivolumab, 120 received classical chemotherapy. The most common side effects reported in patients taking Opdivo: itching, skin rash, upper respiratory tract infection, cough, fluid retention (edema). Severe disorders of the lungs, colon, liver, kidneys and endocrine glands are rarely observed. These side effects are associated with the effect of the drug on the immune system (source of research data - https://www.medicalnewstoday.com/releases/287399.php).

Treatment of advanced melanoma

For inoperable or metastatic melanoma without a gene mutation or with unknown genetics, treatment begins with the immuno-oncology nivolumab (Opdivo) or pembrolizumab (Keytruda). ipilimumab (Ervoy) shows good results

For BRAF mutations, targeted therapy with a two-inhibitor regimen is offered in the first line: cobimetinib with vemurafenib or trametinib with dabrafenib. When their effectiveness is exhausted or they are insensitive, mAbs are used: either nivolumab (Opdivo) every two weeks or pembrolizumab (Keytruda) every three weeks. And only in the third line of melanoma progression do they resort to chemotherapy .

CKIT gene mutation nivolumab (Opdivo) or pembrolizumab as the first agent . If the patient prefers tablet forms, you can start with daily imatinib . In case of progression of the metastatic process, they switch to what was not used in the first line - immuno-oncological drugs are replaced with imatinib, imatinib - with immuno-oncological drugs. In the third line comes chemotherapy .

Yervoy

Yervoy (other names: Ipilimumab, MDX-010, MDX-101) is a drug for the treatment of advanced melanoma, approved by the FDA in March 2011. Ipilimumab is currently widely used to treat metastatic and unresectable advanced melanomas.

How does Yervoy work?

Like other drugs from the group of monoclonal antibodies, Ipilimumab does not act on the tumor itself, but on the immune system. The body begins to independently destroy degenerated cancer cells.

On the surface of immune cells, T-lymphocytes, there is a special receptor CTLA-4. Ipilimumab, being an antibody, perceives this receptor as an antigen and attaches to it, thereby activating the lymphocyte. When using Yervoy, the five-year survival rate of patients reaches 16%. The drug has an effectiveness of 80% or more: this is manifested in a decrease in the size of metastases, a decrease in cancer intoxication, and an increase in the quality of life. Yervoy has a slower effect than Zelboraf and other BRAF inhibitors (see below). But it lasts longer.

In most cases, the drug is well tolerated by patients. Possible side effects, such as: general malaise, skin rashes, loose stools. Rarely, more severe lesions of the skin, mucous membranes, liver, peripheral nerves, and endocrine glands occur

Zelboraf

Zelboraf (Vemurafenib) is a BRAF inhibitor drug used for immunotherapy of advanced metastatic melanoma. It was approved by the FDA in August 2011 and by the European Medicines Agency in 2012. Mechanism of action. What are BRAF inhibitors?

Zelboraf became the first BRAF inhibitor drug for the treatment of melanoma. BRAF is a gene that encodes an enzyme protein of the same name. It ensures cell reproduction under the control of hormones and growth factors. As a result of mutation of the BRAF gene, disorders occur:

• excessive cell division;
• erroneous resistance of cells to apoptosis - programmed natural death.

This leads to the development of a cancerous tumor. Vemurafenib blocks the BRAF protein. The drug acts very quickly: after starting to take the pills, the size of the tumor usually decreases significantly within a month. At the same time, the patient’s condition normalizes and cancer intoxication decreases.

Indications for use

Zelboraf is used to treat advanced melanoma. The drug is effective only if the patient has a BRAF gene mutation. If this gene is normal in melanoma cells, then the drug can, on the contrary, accelerate tumor growth. Therefore, before prescribing Vemurafenib, a molecular genetic study is always performed. Today, the FDA approved the innovative THxID BRAF Kit developed by bioMérieux.

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Dabrafenib

Dabrafenib (Tafinlar) is a new drug for immunotherapy of advanced melanoma, belonging to the group of BRAF protein inhibitors. It was approved by the FDA in 2014.

How does Tafinlar work?

Dabrafenib, like Zelboraf, blocks a protein that is formed as a result of a mutation in the BRAF gene. According to statistics, about 50% of all patients with late-stage melanoma have a mutation of this gene. Its prevalence depends on the location of the tumor:

• patients with melanoma on the skin have the mutation in more than 50% of cases;
• mucosal melanoma contains mutated cells in 5% of cases;
• ocular melanoma is never accompanied by such a mutation.

When is Dabrafenib used?

Indications for use of the drug:

• metastatic melanoma in advanced stages;
• inoperable melanoma.

Other types of melanoma treatment, such as immunotherapy, radiation therapy, and chemotherapy, are not prescribed when using Dabrafenib.

In 2012, the Lancet journal, one of the most authoritative medical publications, published results comparing the effectiveness of Dabrafenib and Dacarbazine, the drug most often used to treat melanoma. The survival rate of patients taking Dabrafenib was significantly higher. In 2014, scientists published updated results of the study. Over a 2-year period, the survival rate for patients treated with Dabrafenib was 45%, and for those treated with Dacarbazine, it was 32%.

The most common side effects when taking Dabrafenib are skin thickening (hyperkeratosis), fever, headache, joint pain, hearing loss, and skin papillomas. The most severe possible side effects, which are rare: drop in blood pressure, severe chills, dehydration, severe kidney dysfunction, increased blood sugar. Before prescribing the drug, a test is always carried out to help ensure that the patient has a BRAF gene mutation. The THxID BRAF Kit test is widely used.

Euroonko cooperates with Israeli, European and American doctors who have accumulated significant experience in treatment with the latest generation of immunotherapy drugs.

Interferon immunotherapy for melanoma

Interferon-alpha and interleukin-2 (IL-2) are drugs that belong to the class of cytokines, substances that stimulate the immune system. They are administered intravenously or under the skin. Cytokines can be prescribed in two cases:

1. For stage IV melanoma. Interferon and interleukin can reduce tumor size by approximately 10–20%. They can be combined with chemotherapy drugs.
2. As adjuvant therapy after surgery. Cytokines are used for melanomas that grow deep enough into the skin, resulting in an increased risk of recurrence after surgical treatment. Interferon-alpha and IL-2 help prevent relapse, but there is no evidence yet that they improve survival.

During treatment, side effects may occur such as fever, pain, chills, depression, and fatigue. Sometimes the functions of the liver and heart are impaired.

When is immune therapy indicated?

After surgery, preventive drug treatment is not carried out only in cases of favorable melanoma in the initial stages - I-II; in all other situations, preventive treatment is necessary, and it must be started no later than 9 weeks after the operation. The duration of therapy is 1 year, if the patient is able to tolerate it.

Prophylaxis or adjuvant therapy can be carried out with interferon alpha or ipilimumab (Yervoy), which in clinical studies has shown a clear advantage in overall and disease-free survival and in reducing the likelihood of death from melanoma.

Contraindications for immunotherapy: severe chronic diseases of the heart, kidneys or liver, autoimmune processes and psoriasis, mental illness and pregnancy.

The treatment cannot be called easy, but over time, the tolerance of alpha-interferon improves for the majority - the temperature normalizes, aches in the muscles and joints go away, but the biochemical composition of the blood may worsen and weakness remains.

Advantages of immunotherapy for melanoma over classical chemotherapy

Perhaps the main advantage of immunotherapy over the “classic troika” of cancer treatment - chemotherapy, surgery and radiation therapy - is that it acts more physiologically. While classical treatments disrupt and suppress natural immune defenses, immunotherapy, on the contrary, activates it.

Another benefit of immunotherapy is that it has what is called a “ memory effect .” Due to this, the therapeutic effects in the body persist for a long time after the course of treatment is completed. This helps improve survival rates.

The methods used in immunotherapy, unlike chemotherapy drugs, do not attack healthy cells. Thanks to this, there are usually fewer side effects and they are not as serious . As a rule, they can be more easily managed with supportive therapy.

Finally, immunotherapy opens up great prospects in the treatment of cancer in the future. Human immunity and its interactions with cancer cells is an area of ​​science in which there remains a lot of scope for research; a lot of new things still remain to be learned. Scientists and doctors remain hopeful that perhaps one day this will help radically change approaches to cancer treatment, create more effective methods and save more lives.

Immune tolerance

Active separation of pathological cells of neoplasms, as well as their rapid spread, can serve as a prerequisite for the occurrence of melanoma. The immune system of a healthy person provides the ability to protect the body from the development of various cancer pathologies. However, in some cases, the immune system is not able to cope with its task, resulting in the formation of malignant neoplasms.

During the life of the tumor, cancer cells further suppress the immune system. This leads to the fact that the immune system is deprived of the ability to recognize cancer cells, perceiving them as normal. This condition is called “immune tolerance” in medicine.

Reviews of immunotherapy for melanoma at Euroonco

I had a mole removed in a salon. This is not the first mole that I have had removed, so there seemed to be nothing to worry about. But it turned out that it was melanoma. It is not known more precisely whether the mole itself was a melanoma, but this procedure (cryodestruction) seemed to awaken it. At the clinic, of course, they told me what a “smart” decision I made then, but nothing can be done. The worst thing is that the separated mole itself was not left - it was destroyed. This is a note to housewives who entrust such procedures to cosmetologists. Never do this.

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Only the hospital. There they will send this mole for examination and tell everything about it. So, they wanted to treat me with chemistry. That is, not what they wanted, but the doctor said that chemotherapy would definitely be necessary. Just in case, I went to a private clinic, and they told me right out of the gate that I couldn’t do any chemotherapy. It works only in 10% of cases, and the damage to the body is ten times greater than the benefit. Now there are immunotherapy drugs. This is when the body can cope on its own, it just needs help. Not all hospitals have them yet, which is why the previous one prescribed me chemotherapy. But this is, as they say, the old fashioned way. But I agreed to immunotherapy and decided to be treated here. And for good reason, as you can see. I feel great. The treatment itself was not that difficult - they removed the area of ​​skin from which I had removed the mole (now under the shoulder blade there is just a very light spot with such thin skin against the background of my many years of tanning). And then the drug. The result, so as not to jinx it, is the best. According to the latest tests, the disease has gone away. But I still can’t sunbathe and eat some things. Yes, somehow I don’t even want to, after such adventures. I don't think about what would have happened if it weren't for these great doctors. And I don’t advise anyone to think too much - just look for solutions and they will appear.

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The main causes of melanoma development

Exposure to solar radiation

Ultraviolet radiation is the most common cause of skin cancer. Staying in the open sun for a long time without using special sunscreens, as well as visiting a solarium, often serves as an impetus for the development of melanoma.

Heredity

People whose relatives have been diagnosed with melanoma are at increased risk and should be regularly examined by a dermatologist to prevent the development of cancer, as well as take care of skin health and avoid damage.

Injuries to age spots or birthmarks

In more than half of the cases, gross damage to the mole (for example, a cut with a razor) is the main reason for the degeneration of normal mole cells into malignant ones.