New Approach to Monitoring Skin Cancer

Patients with melanoma, the most concerning form of skin cancer in which pigment-producing cells start to grow out of control, can benefit from existing immunotherapies, but by far not all of them do. More than 50% of patients do not respond to current immunotherapy drugs and among those that initially respond, many become resistant to the drugs’ effects. 

Because cancerous skin lesions of melanoma patients are easily accessible, an effective way to eradicate them could be to apply immunotherapies locally, instead of systemically infusing them into the blood circulation. Also, monitoring the immune system’s reaction to the therapy right at the tumor site, by sensitively and continuously measuring different biomarkers that signal the intended immune cell activation and a desirable inflammatory response, could enable better and more personalized patient care.

Now, a research team at the Wyss Institute at Harvard University, MIT, and Brigham and Women’s Hospital in Boston has developed a new approach that integrates a minimally invasive, painless microneedle platform capable of absorbing the cell-surrounding, biomarker-containing fluid from deeper layers of the skin with an ultra-sensitive, single-molecule detection method (Simoa) that detects often rare, yet relevant biomarkers with higher sensitivity than conventional methods. The researchers provided proof-of-concept for their approach in a mouse melanoma model in which they treated cancerous lesions with a novel therapy. The therapy acts locally on tumor lesions in that it combines non-invasive focused ultrasound (FUS), which generates heat at the tumor site to instantly kill tumor cells, with the delivery of a previously developed nanoparticle-bound activator of an inflammation-inducing protein known as stimulator of interferon genes (STING). 

Natalie Artzi, Ph.D. and her group first developed a locally applied immunotherapy for melanoma that leveraged some of their previously pioneered methods and expertise. In a recent publication, which built on the known fact that activation of the inflammation-inducing STING protein contributes to tumor cell killing, they reported a significantly more effective way to activate the protein in immune cells. Natural activators (agonists) of STING are not sufficiently stable in the body and need to be given in high doses that also can produce side effects. The group’s solution was to deliver multiple copies of a synthetic STING agonist, called a synthetic cyclic dinucleotide (CDN), via nanoparticles (NP) that easily traverse the plasma membrane and, with the help of an engineered enzymatic reaction, release their cargo inside cells. This CDN-NP therapeutic can be directly injected in or close to cancerous skin lesions to additionally increase the drug concentration in tumors.

The team first showed that the focused ultrasound (FUS) treatment, which transiently and in small areas increases the temperature up to 60°C, potentiated the effects of CDN-NP treatment in co-cultures of immune and cancer cells in a dish, and in melanoma tumors in mice, that they treated with the combination. Importantly, 60 days following the treatment, all animals that received only FUS therapy had died, while 75% of animals receiving only the CDN-NP therapy were still alive — the combination treatment allowed 100% of animals in their group to survive.

“The Artzi lab’s remarkable microneedle technology containing engineered nanostructures, in principle, enables both, drug delivery and microsampling — a completely new concept for a theranostic, which provides an ideal, non-invasive and comprehensive solution to melanoma treatment,” said Walt, who also is the Hansjörg Wyss Professor of Biologically Inspired Engineering at Harvard Medical School.

“This new advance has the potential to raise the quality of cancer immunotherapy to the next level by directly assessing therapeutic efficacy in individual patients,” said Wyss Founding Director Donald Ingber, M.D., Ph.D.

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Sources:

Daniel Dahis, Michelle Z. Dion, Alexander M. Cryer, Pere Dosta, Tal Gilboa, Mariana Alonso, Michael Lewandowski, Núria Puigmal, Gonzalo Muñoz Taboada, Haim Azhari, Rushdy Ahmad, David R. Walt, Natalie Artzi. Monitoring Melanoma Responses to STING Agonism and Focused Ultrasound Thermal Ablation Using Microneedles and Ultrasensitive Single Molecule Arrays. Advanced Functional Materials, 2023; DOI: 10.1002/adfm.202301659

Wyss Institute for Biologically Inspired Engineering at Harvard. “Moving the needle on monitoring skin cancer.” ScienceDaily. ScienceDaily, 21 August 2023. <www.sciencedaily.com/releases/2023/08/230821135730.htm>.

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