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Wednesday, October 9, 2019

Immunotherapy: New Technology for Cancer Treatment



Johns Hopkins scientists have invented a new class of cancer immunotherapy drugs that are more effective in harnessing the power of the immune system to fight cancer. This new approach, as stated in Nature Communications, results in a significant decrease in tumor growth, even against cancers that do not respond to conventional immunotherapy.

"The immune system is usually capable of detecting and removing tumor cells. Nevertheless, virtually all cancers— including the most common cancers, from lung, breast, and colon cancers to melanomas and lymphomas — are emerging to combat and overcome such immune surveillance by co-opting and amplifying the natural mechanisms of immune suppression, "says Atul Bedi, M.D., M.B.A., associate professor of otolaryngology-head and neck surgery at the Johns Hopkins University School of Medi.


The major way tumors invade the immune system is through regulatory T cells (Tregs), a subset of immune cells that deactivates the immune system's ability to destroy tumor cells. Tumors are often invaded by Tregs, and this is strongly correlated with poor outcomes in several types of cancer.



Some tumors produce high levels of a protein that facilitate the production of Tregs. Bedi's team argued that since Tregs in the tumor shuts down immune responses to tumor cells, switching Tregs off may help to make immunotherapy work better.

"This is particularly challenging because Tregs is not only caused by TGFbeta (transforming growth factor-beta) protein formed by tumor cells but also allows TGFbeta to maintain its own identity and function in the tumor," says Bedi. Tregs also produce cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) which prevents anti-tumor immune cells from functioning.


To address this issue, scientists have invented a new class of immunotherapy drugs called Y-traps. Every Y-trap molecule is an antibody shaped like a Y and fused to a molecular "trap" which traps other molecules in the vicinity, making them useless.



The researchers first designed a Y-trap that targets CTLA-4 and traps TGFbeta. This Y-trap disables both CTLA-4 and TGFbeta, which allows anti-tumor immune cells to battle the tumor and disables Treg cells.

The group transplanted human cancer cells into mice designed to have human immune cells to test Y-traps. Researchers found that their Y-trap killed Treg cells in tumors and delayed the growth of tumors that did not respond to ipilimumab, the latest immunotherapy drug that targets the CTLA-4 protein.



"Tregs have been a thorn in the hand of cancer immunotherapy for a long time," says Bedi. "We finally found a way to conquer this hurdle with this CTLA-4-targeted Y-trap."

Antibodies to another immune checkpoint protein, PD-1 or its ligand (PD-L1), are at the core of modern cancer immunotherapy. Although they work in some patients, they do not work in the vast majority of patients.



The research team developed the Y-trap targeting PD-L1 and the trapping of TGFbeta. Tested against the same engineered mice, they found that their Y-trap works better than PD-L1-targeting drugs atezolizumab and avelumab. Once, this Y-trap delayed the growth of tumors that had not previously reacted to drugs.

"These first-in-class Y-traps are only the start. We have already discovered a whole family of these multifunctional molecules based on the technology of Y-trap. Because immune dysfunction mechanisms are shared across many types of cancer, this approach could have a large effect on improving cancer immunotherapy, "says Bedi. "Y-traps could also provide a therapeutic strategy against tumors that are resistant to existing immune checkpoint inhibitors."


"This technique appears to be a groundbreaking method and an exciting technical achievement to target multiple tumor microenvironment suppression mechanisms," says Robert Ferris, MD, Ph.D., Professor of Oncology and Director of the Hillman Cancer Center at the University of Pittsburgh. Ferris was not related to the report. "I look forward to seeing its introduction to the hospital." Bedi plans to use Y-traps not only for the treatment of advanced metastatic cancers but also as neoadjuvant therapy to create a "vaccine" effect— that is, to give them to patients before surgery to prevent recurrence of the disease.


Other members of the study are Rajani Ravi, Kimberly Noonan, Vui Pham, Piotr Wysocki, Ranee Mehra, Sridhar Nimmagadda, Luigi Marchionni, David Sidransky, Ivan Borrello and Evgeny Izumchenko of Johns Hopkins University, Alex Zhavoronkov, Ivan Ozerov, Eugene Makarov, Artem Artemov of Insilico Medicine, and Rishi Bedi of Stanford University.


The research was funded by the National Institutes of Health Grants R01 CA184199 and SPORE P50 DE019032 and the Maryland Innovation Initiative Award from the Maryland Technology Development Corp. to Atul Bedi and Rajani Ravi. 



COI: Bedi and Ravi are inventors of U.S., European and Japanese patents for antibody ligand traps awarded to Johns Hopkins University and licensed to Y-Trap Inc., a company developing the Y-Trap Technology Platform. Bedi and Ravi, along with Evgeny Izumchenko, Ivan Borrello and Kimberly Noonan, are the founders and investors of Y-Trap Inc.






















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