Melanoma is the deadliest form of skin cancer and is one of the four most common cancers in patients between 20 and 39 years of age. By 2020, approximately 100,000 new melanoma cases will be diagnosed in the United States, accounting for more than 5% of all newly diagnosed cancers. Melanoma is a malignant tumor of pigment-producing cells in the skin. These cells, called melanocytes, produce melanin, produce the pigment melanin, which is responsible for the color of our skin.
A decade ago, there were few treatment options for metastatic melanoma. Nowadays, there are many, including immunotherapy, which can dramatically increase survival rates – if certain precautions are in place. Immunotherapy, also known as biological therapy, is the treatment of disease by activating or suppressing the immune system. Currently, there are eight FDA-approved immunotherapy options for melanoma.
FDA-approved Immunotherapy for Melanoma
PD-1 and PD-L1 inhibitors
Programmed cell death protein-1/ligand 1 (PD-1/L1) targeted immune checkpoint inhibitors have become the focus of tumor treatment due to their promising efficacy. PD-1/PD-L1 inhibitors are used to shift the balance toward immune activation, further enhancing tumor immunosurveillance, and anti-tumor immune responses. Currently, three PD-1/PD-L1 inhibitors have been approved for treatment of melanoma.
- ▶ Nivolumab (Opdivo®): approved for subsets of patients with advanced melanoma, including in combination with ipilimumab
- ▶ Pembrolizumab (Keytruda®): approved for subsets of patients with advanced melanoma, including in the adjuvant (pre-surgical) setting
- ▶ Atezolizumab (Tecentriq®): approved in combination with cobimetinib and vemurafenib for a subset of patients with advanced melanoma
- ▶ Interferon alfa-2b (Intron A®): a cytokine that targets the IFNAR1/2 pathway; approved for subsets of patients with melanoma
- ▶ Peginterferon alfa-2b (Sylatron®/PEG-Intron®): a cytokine that targets the IFNAR1 pathway; approved for subsets of patients with melanoma
Peginterferon alfa-2b, a pegylated alpha interferon, is a pleiotropic cytokine with immunomodulatory effects. The drug is a conjugate of recombinant interferon alfa-2b and monomethoxy polyethylene glycol (PEG); pegylation results in a longer half-life and permits less frequent injection compared with nonpegylated interferon.
Interleukin-2 (IL-2, Proleukin)
Interleukin-2 (IL-2), also known as aldesleukin or Proleukin ®, is an immunotherapy treatment for people with advanced and metastatic melanoma. IL-2 is a naturally occurring protein that is produced by a specific type of white blood cell, a T lymphocyte. Its normal function in the body is to increase the growth and activity of other white blood cells (T and B lymphocytes).
- ▶ Aldesleukin (Proleukin®): approved for patients with advanced melanoma
- ▶ Ipilimumab (Yervoy®): a checkpoint inhibitor that targets the CTLA-4 pathway; approved for subsets of patients with advanced melanoma, including as a first-line therapy and in combination with nivolumab
- ▶ Talimogene laherparepvec (T-VEC; Imlygic®): a herpes virus designed in a laboratory to make an immune-stimulating hormone. This virus can infect and destroy melanoma cells. T-VEC also helps stimulate the immune system to destroy other melanoma tumors.
However, despite of the significant progress recently obtained, cancer immunotherapy is still suffering a number of limitations. In case of ipilimumab challenges are a significant rate of on-site toxicity effects, leading to serious colitis and hypophysitis due to induced inflammation in up to 23 % of the patients. In co-therapy with dacarbazine, significant elevations in liver function tests in 20 % of the so treated patients were observed. Moreover, the stimulation of T-cell response with ipilimumab may take several months to occur, while treatment with conventional cytotoxic therapies may trigger rapid tumor shrinkage due to direct killing of cancer cells. The adverse effects with PD-1 blockade seem to be less pronounced, than with CTLA-4 blockade.
Future research will need to address a broad variety of open questions. Optimal combinations of antigens, adjuvants and delivery vehicles need to be determined, and combinations of complementary immunotherapies are required to induce robust and sustained anti-tumor responses. It is important to overcome immune tolerance and immune suppression.
PEG linkers are playing an important role in the development of new treatment options for cancer therapy. To support researchers and organizations focused on this field, Biochempeg offers a selection of PEG derivatives for cancer research including melanoma research. In addition, we offer a custom PEG derivative synthesis service.