Over the last decade, immunotherapy has revolutionized the way we treat cancer. Immunotherapy puts the body's own immune system to work to destroy cancerous cells. Often, the drugs for this therapy are administered systemically (via an intravenous drip), so that they reach the entire body via the blood. This method of administration is particularly suitable for tumors that have metastasized or resisted standard therapies such as radio- and chemotherapy.
Unfortunately, immunotherapy can cause undesirable side effects ranging from mild to even life-threatening in some patients. The risk of these autoimmune-related side effects has precluded its application in patients with early-stage melanoma so far. Therefore, Tanja de Gruijl, Professor of Translational Tumor Immunology and head of the Immunotherapy Lab, and Fons van den Eertwegh, Professor of Medical Oncology, and their team set out to investigate if local administration of immunotherapy could help these patients.
Local triggers
"Our immune system is almost always triggered locally first – for example by a virus - then it provides systemic protection by inducing specific T-cells to circulate in the blood in response and reach all parts of the body,” says Prof. de Gruijl. “Crucial to this process are the lymph nodes where the T cells first come into contact with the antigenic protein to which they are activated." In cancer, these are called the tumor-draining lymph node or sentinel lymph node (i.e. the one draining the tumor first).
Could local administration of immunotherapy (anti–CTLA-4 antibodies, i.e. immune checkpoint inhibitors) at a low dose reshape the immune landscape of the sentinel lymph node to boost anti-melanoma T cell activity without severe side effects? To find out, a Phase I clinical trial was conducted at Amsterdam UMC to see if this potential treatment would be safe and effective (NCT0427481).
Phase I clinical trial in early-stage melanoma
13 patients who had early-stage melanoma, where the primary tumor had already been removed, received injections of anti–CTLA-4 antibodies (tremelimumab 2-20 mg) in the skin at the tumor excision site a week before sentinel lymph node biopsy.
Subsequently, the sentinel node and patients’ blood samples were examined for anti-melanoma immunity. The results were striking, showing profound and lasting decreases of immune-suppressive T cells (regulatory T-cells) and increases in numbers and activation levels of anti-melanoma effector T cells in both the sentinel lymph node and peripheral blood.
“Importantly, the intradermal delivery of anti-CTLA-4 antibodies proved safe and was well tolerated by patients. In addition, the locally administered immunotherapy showed clear potential as it induced systemic immune responses in association with T cell activation and central memory T cell differentiation,” the authors report.
Next?
Although these early results are promising, the authors call for caution as more research is required to validate the new treatment “in view of the small numbers of patients enrolled in this phase 1 trial and the absence of randomized placebo controls”.
Nevertheless, the observed responses in this study are paving the way for further clinical trials aimed at local administration of checkpoint inhibitors to boost tumor-draining lymph nodes and systemic immune responses, particularly in the neoadjuvant (pre-operative) setting. The drastically reduced risk of side effects may also allow anti-CTLA-4 treatment to be combined with other cancer therapies to increase overall efficacy.
De Gruijl summarizes: "Immunotherapy by injection has been shown to be safe and to have the same or even better effects on tumor defense than administration by IV. Follow-up studies will have to show whether these effects in patients translate into equally (or possible even more) effective protection against tumor metastasis than can be achieved through administration of a higher dose via an intravenous drip."
For more information contact Prof. Tanja de Gruijl, or read the scientific article here:
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 73. DOI:10.1126/sciimmunol.abn8097
Amsterdam UMC researchers involved:
Dr. Kim van Pul*
Dr. Jessica Notohardjo,
Dr. Marieke Fransen
Dr. Bas Koster*
Anita Stam*
Dafni Chondronasiou*
Sinéad Lougheed*
Joyce Bakker
Vinitha Kandiah
Dr. Petrousjka van den Tol*
Prof. Fons van den Eertwegh
Prof. Tanja de Gruijl
* AmsUMC alumni
Funding for this work was supported by grants from the Harry J. Lloyd Charitable Trust and the Dutch Cancer Society (KWF).