Melanoma, a type of skin cancer, has been historically challenging tumor to treat in the advanced setting due to an aggressive nature and resistance to conventional treatments. Current discussions in our clinics with patients who are newly diagnosed with melanoma are filled with hope and promise. These discussions include topics like clinical trials, FDA-approved therapies ranging from target therapies to various modalities of immunotherapies to harness our body’s own abilities to control advance melanoma. Clinical trials that have led to FDA approvals of targeted agents, immunotherapy with check point inhibitors (CPI), with future approval expected for adoptive T-cell therapy, and immTACs (immune mobilizing T-cell receptor against cancer), have improved the prognosis of many with melanoma.

Newer therapies are improving outcomes for patients with advanced melanoma.

Melanoma, the deadliest type of skin cancer, arises from the uncontrolled growth of melanocytes, the cells responsible for producing melanin pigment in our skin. Though this disease is uncommon (with lifetime risk of 2.6% for Caucasian people, which is 20 times higher than Black people), it leads to significant life loss.

Most early-stage melanoma does not recur, but as the primary melanoma invades deeper to into skin or moves to lymph nodes, its risk of recurrence and spread to other organs post-surgery increases. Once spread beyond skin or to other organs, traditional treatments, such as surgery, chemotherapy and radiation have limited success in advanced melanoma. However, new medications studied in clinical trials and approved by FDA have shifted the treatment landscape. Therapeutic developments have introduced novel approaches, such as targeted agents leveraging mutations in melanoma, immunotherapy beyond checkpoint inhibitors Including adoptive T-cell therapy and ImmTACs.

These innovations have led to prolongation of life for many with advanced melanoma. Ten years ago, less than 10% of the patients with advanced melanoma survived beyond five years; whereas now, roughly 50% of patients diagnosed with melanoma are alive beyond five years.

BRAF and MEK Inhibitors

As smart melanoma cancer cells are, they carry number of genetic mutations. Roughly 40 to 45% of skin melanomas harbor a mutation, called BRAF (BRAF V600 E/K most common) mutation. This mutation allows uncontrolled growth and spread of melanoma. One of the first advances in melanoma treatment has been the development of targeted agents designed to selectively inhibit BRAF molecular pathways and stop uncontrolled growth and spread of melanoma. Three combinations of BRAF and MEK inhibitors have been approved and are very effective in controlling melanoma harboring these BRAF mutations. Unfortunately, after an extended time on these BRAF/MEK inhibitors, patients can develop resistance to this approach.

Ongoing trials are trying to answer the question of how to prevent this resistance from developing to improve outcomes with BRAF mutated melanoma. Additionally, other targets, such as c-KIT and NRAS, NF-1 have also been explored in ongoing clinical trials, but effective therapies remain elusive.

Immunotherapy

Immunotherapy has shifted paradigm in cancer treatment in many different types of cancers by harnessing our body's immune system to recognize and eliminate cancer cells. Immune checkpoints are molecules that our body’s immune system uses for its own regulation and appropriate functioning. Cancer cells, however, take advantage of these regulatory pathways to avoid immune recognition leading to unchecked growth. Development of blocking antibodies toward these immune checkpoints enhances the activity of T cells, which then recognize and target cancer cells more effectively.

Engineered antibodies knowns as checkpoint inhibitors, such as anti-PD-1 and anti-CTLA-4 antibodies, reinvigorate the immune system to recognize melanoma, and have shown amazing activity in controlling it. Previous therapies (chemotherapy, target therapies) when effective, allowed control of disease for a short while. The most important benefit of checkpoint inhibitors has been their durability of responses that has led to significantly prolonged overall survival in melanoma patients, even those with metastatic disease. Ongoing clinical trials are attempting to answer questions such as:

• How long advance melanoma should be treated for?
• Who is best suited patient for immunotherapy?
• Who will have what type of toxicity for treatment?

T-Cell Therapy

Dr. Stephen Rosenberg of the National Cancer Institute is pioneering approach where T cells (immune cells) residing in the tumor (aka tumor-infiltrating lymphocyte; TiL) from a person’s melanoma are surgically harvested, enhanced and expanded outside of the patients and then re-infused. This approach led to improvement in melanoma control for some patients.

Another approach is chimeric antigen receptor (CAR) T-cell therapy, where T cells are engineered to express CARs (homing antibodies) targeting specific melanoma antigens. CAR-T therapy has shown encouraging results in clinical trials and approved in few hematological malignancies. Ongoing trials are evaluating benefit of this approach in metastatic melanoma refractory to other treatments. Nonetheless, challenges remain, including finding ideal target antigens and managing potential adverse events associated with this therapy.

ImmTACs are an innovative approach that aims to tailor cancer treatment to individual patients by identifying and targeting specific tumor antigens (proteins). These tumor antigens (for example gp100 and PRAME in melanoma) serve as a target for T cell engagement with melanoma cells. Simply put, a bispecific antibody (antibody that binds two targets) on one end binds melanoma antigen and other binds and activates T cell. This activity leads to melanoma cell death. Therapy built on this approach as already been approved based on improved overall survival in ocular melanoma.

The field of melanoma treatment has experienced significant breakthroughs with the introduction of targeted agents, immunotherapy, adoptive T-cell therapy, and ImmTACs. These innovative approaches have been possible only with clinical trial participation of courageous patients. While challenges such as treatment resistance and side effects persist, patient participation in ongoing clinical trials and collaborations among scientists, clinicians and industry stakeholders will continue to drive advancements and improve outcomes in melanoma treatment. The future holds great promise for combining these therapies, optimizing treatment sequencing, and identifying predictive biomarkers to ensure personalized and effective treatment strategies for melanoma patients.

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