Immunotherapy has emerged as a promising new treatment option for melanoma, a type of skin cancer that can be deadly if not caught early. Immunotherapy works by harnessing the power of the immune system to fight cancer. This article will examine the success rates of the main types of immunotherapy used for melanoma – checkpoint inhibitors, cancer vaccines, and adoptive cell transfer. We’ll look at response rates from key clinical trials and real world data to understand how well immunotherapy is working today. Bringing the immune system into the battle against melanoma has led to significant improvements in outcomes for many patients. However, not everyone responds to immunotherapy and more work is needed to increase success rates. Understanding current success rates can help patients and doctors make informed treatment decisions.
What is melanoma?
Melanoma is a type of skin cancer that develops from melanocytes, the pigment-producing cells that give skin its color. While melanoma accounts for only about 1% of skin cancer cases, it is responsible for the majority of skin cancer deaths, as it can spread quickly to other organs if not caught early. The American Cancer Society estimates over 100,000 new cases of melanoma will be diagnosed in 2022 in the United States.
Melanoma has a 5-year survival rate of 92% when detected in early stages before it has spread beyond the skin. However, the prognosis is much poorer once the melanoma has spread to lymph nodes or other organs, with 5-year survival dropping to 62% and 28% respectively for regional and distant stage disease.
Surgery is effective for early stage melanoma confined to the skin. But historically there have been very limited treatment options once melanoma has advanced. That has changed with the advent of immunotherapy, which has become a game changer for metastatic melanoma.
Checkpoint inhibitor immunotherapy
Checkpoint inhibitor immunotherapy works by blocking proteins on immune T cells or cancer cells that shut down active T cells. This releases a brake on the immune system, allowing T cells to recognize and attack the melanoma cancer cells.
Ipilimumab (Yervoy) was the first checkpoint inhibitor approved by the FDA in 2011 for advanced melanoma. It targets CTLA-4, a protein receptor that dampens T cell activity. In a phase 3 trial of patients with previously treated metastatic melanoma, ipilimumab improved median overall survival to 10 months compared to just 6 months for those receiving an experimental vaccine. The survival rate at 2 years was 18% for ipilimumab compared to 8% for the vaccine.
Even more impressive results have been seen with drugs blocking the PD-1/PD-L1 pathway, which stops T cells from attacking other cells that express PD-L1. The PD-1 inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo) were both approved in 2014 after doubling median overall survival compared to chemotherapy in metastatic melanoma trials.
In the KEYNOTE-006 trial, pembrolizumab achieved a 2-year overall survival rate of 55% compared to 43% for ipilimumab and 34% for chemotherapy in patients with advanced melanoma. Similarly, Opdivo delivered a 2-year survival rate of 58% versus 45% for chemotherapy in previously untreated metastatic melanoma in the CheckMate 067 study.
Real world data on checkpoint inhibitors for advanced melanoma shows similar survival rates to those found in clinical trials. A 2021 study looking at outcomes for 655 patients treated with anti-PD-1 checkpoint inhibitors at a US cancer center from 2013 to 2019 found an objective response rate of 41% and a complete response rate of 19%. The median overall survival was 23 months and 2-year overall survival rate was 51%.
Response rates
* Ipilimumab: 11-15% response rate
* Pembrolizumab: 33-44% response rate
* Nivolumab: 32-44% response rate
* 2-year survival with anti-PD-1 inhibitors: 50-58%
Cancer vaccines
Cancer vaccines are another type of immunotherapy that work by stimulating the immune system to recognize and destroy cancer cells. They are made from molecules found on the melanoma tumor surface. When injected into a patient, the goal is for the immune system to mount a response against any cancer cells displaying these molecules.
Sipuleucel-T (Provenge) was approved in 2010 as the first cancer vaccine for metastatic prostate cancer. It is customized for each patient using their own immune cells. Approval was based on a 4 month improvement in median survival compared to placebo.
While Provenge paved the way, cancer vaccines have proven less successful than checkpoint inhibitors for metastatic melanoma. A number of melanoma vaccines have been tested in clinical trials but none have yet been approved by the FDA.
A 2005 phase 3 trial tested the experimental melanoma vaccine Canvaxin alongside a chemotherapy drug. The vaccine only improved median overall survival by 2 months compared to chemotherapy alone. The 1-year survival rate was 67% with the vaccine versus 62% for chemotherapy. Based on these results, Canvaxin was not approved.
Similar disappointing results have been seen in trials of other vaccine candidates like the MAGE-A3 vaccine and DERMA vaccine. While vaccines can stimulate an immune response, benefits on survival in metastatic melanoma have been modest at best. Combining vaccines with checkpoint inhibitors is being investigated to try to improve efficacy.
Response rates
* Canvaxin: no difference in response rate vs. chemotherapy
* MAGE-A3 vaccine: no difference in response rate vs. placebo
* 1-year survival with Canvaxin: 67% vs. 62% for chemotherapy
Adoptive cell transfer
Adoptive cell transfer (ACT) is a highly personalized immunotherapy approach that involves taking T cells from a patient, genetically modifying them to enhance their tumor-fighting abilities, growing large numbers of these cells in the lab, and infusing them back into the patient. It aims to build up a robust army of cancer-killing T cells within the body.
ACT has shown promising results in clinical trials for advanced melanoma. In a 2006 study, 51% of metastatic melanoma patients experienced an objective response after receiving lymphocyte-activated killer cells. A further trial in 93 patients using tumor-infiltrating lymphocytes (TILs) genetically selected for reactivity against the melanoma resulted in an impressive 72% response rate, with 20 patients experiencing a complete response.
These TIL ACT trials have reported durable response rates as high as 40% as well as impressive complete response rates of up to 22% in patients with widespread disease. Smaller trials using T cell receptor engineered T cells have also reported complete response rates of 30 to 67% along with durable long-term remissions.
The downside is that ACT is highly complex, logistically challenging, and expensive, requiring custom-made individualized cell therapy products. It is currently only available at specialized academic centers. If the challenges of taking ACT into the mainstream can be solved, it has significant potential for further improving the success rate of immunotherapy for melanoma.
Response rates
* Lymphocyte-activated killer cells: 51% response rate
* Tumor-infiltrating lymphocytes: 72% response rate, 20% complete response rate
* Engineered T cells: 30-67% complete response rate
Factors affecting immunotherapy success
While immunotherapy has come leaps and bounds in extending survival for metastatic melanoma, there remains plenty of room for improvement. Response rates vary widely – some patients appear to be basically cured with extremely durable remissions measured in years, while others derive little benefit. Ongoing research aims to understand why immunotherapy works spectacularly well for some patients but not for others.
Key factors being investigated include:
* Cancer genomics – Tumors with higher mutation loads, and thus more neoantigens for the immune system to recognize, tend to respond better to immunotherapy. BRAF mutations may also increase immune sensitivity.
* T cell presence – Patients with T cells capable of infiltrating and recognizing cancer cells pretreatment appear to respond better.
* Tumor microenvironment – Inhibitory factors in the tumor environment preventing T cell activity reduce immunotherapy effectiveness.
* Gut microbiome – There is emerging evidence that differences in gastrointestinal bacteria may impact immunotherapy response.
* Immunosuppressive cells – High levels of suppressive immune cells like myeloid-derived suppressor cells appear to blunt immunotherapy effects.
* PD-L1 expression – Higher PD-L1 levels seem to be correlated with better anti-PD-1 response, but it is imperfect as a biomarker.
Ongoing trials around combining different immunotherapies or chemotherapy aim to cut off these escape pathways and further improve outcomes. Biomarker research to better predict responders versus non-responders is another important avenue.
Conclusion
Over the past decade, immunotherapy has rapidly become a vitally important component of treatment for metastatic melanoma. Checkpoint inhibitors targeting CTLA-4 and PD-1/PD-L1 have demonstrated survival benefits on the order of months to years compared to prior therapies. Long-term survival rates of 50% at 2 years and beyond are now possible. Adoptive cell transfer offers promise that cure rates may be further increased.
This is an encouraging start. However, there remains substantial room for progress, as the majority of patients either do not respond durably or eventually relapse. Further research to enhance response rates and develop combinatorial approaches is critical to continue the recent momentum and make immunotherapy successful for more melanoma patients.
