Immunotherapy: rebooting the immune system to fight melanoma

More than just a covering, our skin guards our very core. It is a multifunctional organ. It fends off infection and protects us from scorching temperatures. Beneath its surface, it helps preserve fat, water, and even vitamin D. It also keeps our internal thermostat in check, orchestrating our internal temperature, ensuring we stay cool when the heat's on and warm when the wind bites.¹

Our skin compromises three distinct layers: the outermost epidermis, the middle dermis, and the deepest hypodermis, also known as the fatty layer.

Melanoma

Cancer is a group of diseases that is considered one of the most devastating and challenging diseases. It is characterised by uncontrolled cell growth invading normal tissues which leads to a pathological condition. Massive research has been conducted till now to find the answers to its secrets and provide a cure but with limited success.

Melanoma is a type of cancer that develops from the pigment-producing cells known as melanocytes (melanin is the pigment that gives skin its natural colour) a type of cell found in the outermost epidermis.¹

The most distinct feature of melanoma is moles. Those moles may have irregular edges, and change in size, shape, and colour. They may also bleed or ulcerate. Other features may include a change in pigmented (coloured) skin and satellite moles (new moles that grow near an existing mole).²

Causes³

UV radiation

Exposure to UV radiation may cause DNA damage leading to melanoma, so wearing sunscreen and avoiding tanning beds is a must-measure to protect us from developing melanoma.

Genetics

Genetics also plays a vital role in the predisposition to develop the disease, so if one of your family develops the disease, it will make you more likely to develop the disease compared to others who do not have a family history.

Risk Factors³

Excessive Sun Exposure: Whether basking in the sun or seeking a tan, prolonged exposure, especially without sunscreen or protective clothing, invites trouble. Remember, a tan is your skin's distress signal after UV bombardment.

Certain Chemicals: Exposure to certain substances, like arsenic, can also play a role in skin cancer development.

Fair Skin: Though everyone deserves the sun's warmth, those with lighter complexions have less melanin, nature's built-in sun shield. This makes them more susceptible to ultraviolet (UV) damage, especially if they have blond or red hair, light eyes, or freckles.

Weakened immunity: A compromised immune system can leave your skin vulnerable.

Family History: If skin cancer touches your family tree, you may inherit a higher risk.

Sunburn Scars: A blistering sunburn in childhood or adolescence leaves a lasting mark, increasing adult skin cancer risk.

Precancerous Patches: Rough and/or scaly patches are your skin's pre-cancer warning signs. These sun-damaged patches, often found on fair faces, heads, and hands, need attention.

A multitude of Moles: Having many moles, especially irregular or larger-than-normal moles, raises the risk. These atypical moles deserve close watch for potential changes.

Previous Skin Cancer: Once you've battled skin cancer, vigilance is crucial, as recurrence is possible.

Stages of melanoma⁴

Melanoma is mostly localised in the skin, but it may penetrate to other organs during the disease progression stages. In the late stages of the disease called "metastasis", cancerous cells may travel from the skin to lymph nodes and the lymphatic system and invade other organs.

Diagnosis³

By skin test, the doctor will examine those features and take a biopsy (a procedure during which the doctor removes the abnormal tissue and a small amount of normal tissue around it) and send it for histopathological examination.

Traditional treatments and their limitation⁵

Melanoma is mostly localised in the skin, but it may penetrate to other organs during the disease progression stages. In the late stages of the disease called "metastasis", cancerous cells may travel from the skin to lymph nodes and the lymphatic system and invade other organs.

Excision

Primary melanoma treatment revolves around surgery, with the approach tailored specifically to the tumour's thickness. This thickness measurement guides the extent of the excision, as wider margins are necessary for thicker tumours. As tumour thickness increases, the risk of metastasis and consequently, the impact on survival, also escalate. The procedure is followed by a long-term follow-up for further assessment.

Chemotherapy and radiation

Chemotherapy such as Dacarbazine was approved by FDA approval in 1975 for metastatic melanoma treatment. Although radiation therapy is used to kill cancerous cells.

Adjuvant therapy

Also called add-on-treatment is a kind of treatment approach in which this treatment is combined with the primary or initial therapy to boost or maximize its effect.

Targeted therapy

This treatment approaches the blocking of genes involved in pathways for tumour proliferation and survival.

Although those previously mentioned treatment approaches have been widely used, they still have limitations. Extensive surgery can leave disfiguring scars, and recurrence rates remain significant, especially in advanced stages. Radiation can damage healthy tissue and offer limited benefits for some patients. Additionally, targeted therapies, often face resistance mechanisms and lose their efficacy over time, although they are effective in some cases

Immunotherapy: unleashing the body's natural defense^6,7,8

Immunotherapy represents a paradigm shift in cancer treatment. Instead of directly attacking tumour cells, it harnesses the body's immune system of the body to recognize and destroy them. These treatment options are most often used in people with metastatic melanoma and significantly improve overall survival. This approach can be broadly categorized into three main types:

Cytokine Therapy: Imagine a general rallying the troops. Interferon alpha and interleukin-2, natural immune system boosters, take on this role. They stimulate T cell production and activity, turning them into an unstoppable force against melanoma. IL-2 (Proleukin) was the first new therapy approved (1990 EU, 1992 US) for the treatment of metastatic melanoma in 20 years.

Adoptive Cell Therapy: This strategy involves creating an elite squad of T cells. Patient T cells are extracted, genetically modified to recognise melanoma's unique antigens, and then reintroduced into the body. These CAR-T cells, armed with newfound precision, hunt down, and eliminate tumor cells with surgical efficiency.

Checkpoint Inhibitors: Prof. James P. Allison and Prof.Tasuku Honjo were jointly awarded the 2018 Nobel Prize in Physiology or Medicine for their distinguished discovery of a promising cancer therapy approach The immune response is a defensive mechanism of our bodies to counteract invaders like bacteria and viruses based on the " self and non-self " recognition property of the immune system, T-cells, a type of white blood cells that play a crucial role in that response. The regulation of T-cells is done by proteins acting as activators and inhibitors, in normal conditions, activators initiate the immune response, and the inhibitors function as a brake to avoid excessive activation of the immune system which is altered in autoimmune diseases.

Prof. James P. Allison studied the CLTA-4 protein on the surface of the T-cell; among other scientists, he observed that CLTA-4 acts as a brake on T-cells. He used this observation as a target to inhibit negative immune regulation. He discovered an antibody to bind to CLTA-4 to block it resulting in the activation of the T cell, this stimulated an immune response to attack the cancer cells. The results were astonishing with patients with advanced melanoma, a type of skin cancer.

Another amazing observation by Prof. Tasuku Honjoas he discovered another protein called PD-1 which also acts as a brake on T-cells, but with a different mechanism, afterward, he produced an antibody to block PD-1 as a treatment strategy for different types of cancer and the results were surprising as it was efficient even in stubborn cases like patients with metastatic cancer leading to long-term remission in several patients, this treatment strategy is known as "immune checkpoint therapy". This great discovery by the two laureates opened the gate to a new promising therapeutic approach for cancer that we hope will end the cancer myth.

To conclude, Immunotherapy for melanoma may be the missing part of the disease treatment protocol allowing physicians to reach the optimal long-term remission of patients with melanoma especially when accompanied by other therapies like adjuvant therapy.

Summary

Melanoma, a type of skin cancer originating from melanocytes, poses significant health risks due to factors like UV radiation and genetics. Traditional treatments such as surgery, chemotherapy, and radiation have limitations including scarring and recurrence. However, immunotherapy represents a transformative approach by leveraging the body's immune system to target and destroy cancer cells. This includes cytokine therapy, adoptive cell therapy, and checkpoint inhibitors like CTLA-4 and PD-1 blockers, which have shown remarkable success in improving survival rates, particularly in metastatic melanoma cases. Immunotherapy, alongside other treatments, offers promising potential for long-term remission in melanoma patients.