Department of Pathology

Exploring Low-Intensity Focused Ultrasound as a Novel Immunotherapy

Karin SkalinaUltrasound imaging—using high-frequency sound waves to produce images of structures in the human body—is well-known as a diagnostic and treatment tool. Recently, focused ultrasound has emerged as a promising early-stage therapeutic intervention in cancer, Parkinson’s and other diseases. Karin Skalina, a pre-doctoral fellow in the laboratory of Chandan Guha, MD, PhD, is exploring the potential of a specific type of ultrasound, called low-intensity focused ultrasound (LOFU), as a novel immunotherapy treatment against cancer.

“Many people haven’t thought about ultrasound beyond imaging babies in utero,” says Ms. Skalina. In fact, she notes, focused ultrasound is being used to treat Parkinson’s, essential tremor; uterine fibroids; benign prostatic hyperplasia; and breast, pancreatic and liver cancers. Some researchers are even exploring its use for cardiac ablation, to avoid open-heart surgery. “It’s safe and non-invasive, and the applications are almost endless,” she says.

In contrast to high-frequency focused ultrasound (HIFU)--a non-invasive ablative procedure that can be safe with image guidance--the LOFU procedure invented in the Guha lab is non-ablative and produces a combination of mechanical and thermal stress at the focal point, deep in the tissues, within 1.5-3 seconds of being applied.

Sensitizing Tumor Cells

Using a mouse model, Ms. Skalina and her colleagues are studying LOFU’s effects on tumor cells and ways to sensitize those cells to other treatment modalities. Having previously focused on melanoma, prostate and lung cancers, Ms. Skalina is currently leading a study on breast cancer.

LOFU when used by itself does not reduce tumor growth, Ms. Skalina explains. She and her team hypothesize that the ultrasonic stress produced by LOFU induces protein-unfolding in the endoplasmic reticulum, and that the resulting induction of chaperone proteins binds peptides generated from proteolysis (the breakdown of proteins into smaller peptides) of the unfolded proteins. The researchers posit that this process activates the immune system, triggering an immune response to the cancer.

After intervention with LOFU, the researchers see an increase in the unfolded-protein response—part of the endoplasmic reticulum stress pathway. Based on that, they create antigens for the immune system to use. “When we follow LOFU with radiation, we release all those misfolded proteins bound to chaperones, such as HSP70,” Ms. Skalina explains. “They’re taken out and processed by the immune system and presented as tumor antigens.”

Testing Different Combinations

The investigators started by testing the efficacy of LOFU in combination with radiation. “Our studies, in both a prostate cancer line and a melanoma line, showed that LOFU plus radiation reduces primary tumor growth, as compared with each treatment used alone,” says Ms. Skalina. Now, the research team is adding immunotherapies and chemotherapies to the mix.

“When we used LOFU with radiation, we saw an increase in PD-L1 on the tumor cells about 24 hours after treatment,” Ms. Skalina reports. (PD-L1 is an immunosuppressive biomarker that can be present on tumor cells or antigen-presenting cells. It suppresses the function of cytotoxic T cells, preventing them from acting against cancer cells.) This finding suggests that an anti-PD-1 therapy would be a good option for a trimodal therapy.

Ms. Skalina and her colleagues are also testing radiation both alone and in combination with LOFU. They will then compare the results with those yielded by the tri-modal therapy.
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Looking to the Future

“It’s very rewarding to talk with people about my research and to learn about focused ultrasound,” says Ms. Skalina, who expects to receive her MD, PhD degree from Einstein in 2019. “I truly believe in it as a future treatment for so many diseases.”

To that end, Ms. Skalina’s work ethic and dedication to her research win high praise from her mentor. “Karin approaches her work with the passion and persistence required of a successful physician-scientist,” says Dr. Guha, a professor of pathology and of urology, and professor and vice chair of radiation oncology at Einstein and Montefiore. “She is a creative and insightful thinker and a natural team leader. Her work on low-intensity focused ultrasound will help advance our knowledge of its potential as an effective targeted immunotherapy.”

Ms. Skalina, in turn, is inspired by Dr. Guha’s commitment to mentoring. “He is brilliant, but he explains the research in such a way that anyone can understand it and get excited about it. If something’s not working and you show him the data, he offers multiple ideas for how to make it start working again.”

“As an MD, PhD, he’s able to maintain a clinical practice while teaching and remaining active in the lab,” she adds. “That’s the kind of career I’d like to have.”

 

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