Scientists are exploring a new treatment approach for patients with early-stage melanoma, the most serious type of skin cancer.1 Doctors hope that by applying anti-cancer drugs directly into the tumor site, they can cut toxic side effects and improve cancer recurrence rates.
Currently, the way melanoma-targeting immunotherapy drugs are administered to patients causes whole-body side effects. In a much anticipated report of phase I clinical trial results, doctors say they have found a way to apply an existing immunotherapy drug to the melanoma without triggering toxicity throughout the whole body. The results of the trial published earlier this year in the prestigious Science Immunology journal demonstrate that this approach could be the start of a new chapter in the melanoma story.
The first line of treatment for this condition is typically to remove the melanoma. Afterwards the doctors will biopsy the nearby lymph nodes to check if and where the cancer has spread. If cancer cells are found in the lymph nodes, patients will receive additional treatments, for example immunotherapy drugs (e.g., avelumab and tremelimumab), delivered via injections into the vein, skin, or muscle.3 Since these cancer drugs then circulate around the patient’s whole body, they can cause debilitating whole-body side effects. This can disrupt day-to-day living and decrease overall quality of life.
If the patients’ lymph nodes don’t contain cancer cells, then they receive a provisional “all clear” and no more treatment is needed. Unfortunately, one of the challenges associated with early-stage melanoma is that the cancer makes a comeback in 16-30% of cases. The 10-year survival rate can be as low as 75%, depending on individual risk factors.4,5
Why? Because of metastasis. Even when given the “all clear”, there’s a possibility that microscopic cancer cells have already spread beyond the original tumor site and are undetectable by current imaging techniques. Melanoma cells are like pests that are very good at navigating through the roads of the lymphatic system to invade and nest in many parts of the body.6 They can hitch a ride through the bloodstream, or in the case of “in-transit metastasis” they also spread within the skin itself.
Strategies for out-maneuvering these escaped cancer cells need to balance powerful cancer-fighting properties against harm to the patient. Oncologists say they need new treatment approaches for patients with early-stage melanoma to reduce side effects, improve their chances of long-term survival, and reduce the risk of recurrence.
In their study, Dr. van Pul and his colleagues at Amsterdam University chose a specific immunotherapy drug, tremelimumab, and showed that delivering it through an injection directly into the skin, was safe and effective in patients with early-stage melanoma.7 Instead of the usual method of injecting the immunotherapy drug into the bloodstream, they delivered it precisely into the skin around the area where the melanoma tumor had been surgically removed. By doing this, they were successfully able to kick-start the patient’s immune system to fight the melanoma, which worked by targeting specific immune cells in the lymph nodes near the tumor site.
Tremelimumab: cancer solution or problem?
Standard practice is to give melanoma patients a combination of drugs that block PD-1 and CTLA-4 proteins in order to attack cancer cells that have reached far throughout the body.3,4
PD1-1 and CTLA-4 act like failsafes on our immune system’s T cells. T cells are part of the body’s anticancer arsenal, patrolling the body and watching out for any cells carrying cancer tags. The failsafes prevent them from accidentally attacking healthy cells and causing unnecessary damage to the body while they’re on patrol.
Sometimes, they stop T cells from attacking even harmful cancer cells that have disguised themselves as “healthy” cells. That’s why some anticancer drugs block PD1-1 or CTLA-4. By removing “failsafes” from the T cells, it helps them fight and destroy cancer cells better.8
But there’s a catch: removing the failsafes means that any healthy cells that look “iffy” will be attacked and taken out along with the cancerous cells, causing damage throughout the body. This is what causes a wide range of side effects depending on which organs or systems are affected.
Tremelimumab specifically blocks CTLA-4, and its delivery to the whole body can cause these nasty side effects: muscle or back pain, allergic reactions, diarrhea, constipation, nausea and vomiting, skin rashes, and the list goes on.9
The researchers realized that if doctors are going to use intense doses of such powerful anticancer drugs, then they need to find a better way to deliver them.
Local administration of tremelimumab is a more targeted and potentially safer approach to cancer immunotherapy, like sending a special team of sniffer dogs directly to the source of the pest nest. This method takes advantage of the immune system’s natural ability to learn and remember threats, leading to a more effective and less harmful way to fight cancer.
Testing the theory
Doctors recruited thirteen patients with stage I/II melanoma. Seven days before a planned second surgery to remove more tissue and biopsy the nearby lymph nodes, each person was given a single dose of tremelimumab. They injected the drug directly into the skin around the scar where a melanoma tumor was removed. The drug doses were randomly assigned to the patients; they received either 2mg, 5mg, 10mg, or 20mg of the drug. These lymph nodes are the first line of defense against cancer, where the cancer-busting T cells hang out, and the most likely to contain cancer cells if it has spread. After the seven days, the tissues were biopsied to check for cancer cells, immune system cells and how they were functioning.
Doctors followed the patients to see if they experienced any unpleasant side effects one hour, one week, three weeks, and three months after the injection. The patients tolerated the local drug well.
Why is local tremelimumab injection better at fighting cancer?
By tightly targeting the area where the cancer started, tremelimumab acted like a sniffer dog, working straight at the source of the problem and hunting down cancer cells through the lymphatic back alleys.
The drug treatment helped T cells, key players in the immune system, both near the tumor site (in the local lymph nodes) and throughout the body (in the blood) chase down any escaped cancer cells. This effect was stronger with higher doses of the drug.
It also boosted the making of memory T cells, providing long-lasting protection against melanoma cells. These specialized cells “remember” the cancer cells, so the body can start a faster and more powerful immune response if the cancer were to return.
In a subset of patients, targeted delivery of tremelimumab helped their immune system recognize and target specific molecules called antigens that are found on melanoma cancer cells: NY-ESO-1 and MART-1. This is great, because local tremelimumab injection not only activated the immune system in general, but it also specifically directed it towards the melanoma cancer cells.
What’s so exciting about these results?
There is hope for doctors to use this approach as a precaution against the long-lurking escaped cancer cells that can cause reoccurrences. This is a shift from the traditional approach, where additional therapy was usually reserved for more advanced cases. Now, researchers believe that even patients with early-stage melanoma could benefit from this extra treatment to target any remaining cancer cells that might not be visible.
References
- World Health Organization. Radiation: Ultraviolet (UV) radiation and skin cancer. www.who.int. Published October 16, 2017. https://www.who.int/news-room/questions-and-answers/item/radiation-ultraviolet-(uv)-radiation-and-skin-cancer
- Wong, S.L., Kennedy, E.B. and Lyman, G.H. (2018) ‘Sentinel lymph node biopsy and management of regional lymph nodes in melanoma: American Society of Clinical Oncology and Society of Surgical Oncology Clinical Practice Guideline update summary’, Journal of Oncology Practice, 14(4), pp. 242–245. doi:10.1200/jop.2017.028241.
- Immune checkpoint inhibitors and their side effects (no date) American Cancer Society. Available at: https://www.cancer.org/cancer/managing-cancer/treatment-types/immunotherapy/immune-checkpoint-inhibitors.html#:~:text=Examples%20of%20drugs%20that%20target,Cemiplimab%20(Libtayo) (Accessed: 10 May 2024).
- Berger, A.C. et al. (2017) ‘Patient symptoms are the most frequent indicators of recurrence in patients with American Joint Committee on Cancer Stage II melanoma’, Journal of the American College of Surgeons, 224(4), pp. 652–659. doi:10.1016/j.jamcollsurg.2016.12.038.
- Jones, E.L. et al. (2013) ‘Long-term follow-up and survival of patients following a recurrence of melanoma after a negative sentinel lymph node biopsy result’, JAMA Surgery, 148(5), p. 456. doi:10.1001/jamasurg.2013.1335.
- March 27, 2024, March 21, 2024 and March 5, 2024 (no date) Melanoma cells that pass through lymph more likely to spread, Melanoma Cells that Pass through Lymph More Likely to Spread – NCI. Available at: https://www.cancer.gov/news-events/cancer-currents-blog/2020/melanoma-spread-lymph-nodes-ferroptosis#:~:text=Melanoma%20cells%20can%20spread%20from,system%20to%20form%20new%20tumors.&text=Melanoma%2C%20the%20most%20aggressive%20form,to%20distant%20organs%20and%20tissues. (Accessed: 07 June 2024).
- van Pul, K.M. et al. (2022) ‘Local delivery of low-dose anti–CTLA-4 to the melanoma lymphatic basin leads to systemic Treg reduction and effector T cell activation’, Science Immunology, 7(73). doi:10.1126/sciimmunol.abn8097.
- NCI Dictionary of Cancer terms (no date) Comprehensive Cancer Information – NCI. Available at: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/ctla-4 (Accessed: 19 May 2024).
- For the Patient: Tremelimumab (no date) BC Cancer. Available at: http://www.bccancer.bc.ca/health-professionals/clinical-resources/cancer-drug-manual/drug-index (Accessed: 01 June 2024).
