A Better Weapon in The Fight against Cancer

By Jane Farrell

Johns Hopkins researchers have invented a new class of cancer immunotherapy drugs that are more effective than existing methods at harnessing the immune system’s power to fight cancer. This new approach, reported in Nature Communications, results in a significant decrease of tumor growth, even against cancers that do not respond to existing immunotherapy.

“The immune system is naturally able to detect and eliminate tumor cells. However, virtually all cancers — including the most common cancers, from lung, breast and colon cancers to melanomas and lymphomas — evolve to counteract and defeat such immune surveillance by co-opting and amplifying natural mechanisms of immune suppression,” said the study’s senior author, Atul Bedi, M.D., M.B.A., an associate professor of otolaryngology — head and neck surgery — at the Johns Hopkins University School of Medicine.

A news release from Johns Hopkin Medicine explained that the major way tumors evade the immune system is via regulatory T cells (Tregs), a subset of immune cells that turn off the immune system’s ability to attack tumor cells. Tumors are frequently infiltrated by Tregs, and this is strongly correlated with poor outcome in multiple cancer types.

Additionally, many tumors produce high levels of a protein that promotes the development of Tregs. Bedi’s team reasoned that since Tregs in the tumor shut down immune responses against tumor cells, turning off Tregs may help immunotherapy work better.

“This is especially challenging because Tregs are not only induced by the TGF-Beta-1 (transforming growth factor-beta) protein made by tumor cells, but make their own TGF to maintain their identity and function in the tumor,” said Bedi. Tregs also make cytotoxic T-lymphocyte associated protein 4 (CTLA-4), which prevents anti-tumor immune cells from acting.

To address this problem, the researchers invented a new class of immunotherapy drugs they called Y-traps. Each Y-trap molecule is an antibody shaped like a Y and fused to a molecular “trap” that captures other molecules nearby, rendering them useless. Researchers first designed a Y-trap that targets CTLA-4 and traps TGF-Beta-1. This Y-trap disables both CTLA-4 and TGF-Beta-1, which allows anti-tumor immune cells to fight the tumor and turns down Treg cells.

To test the Y-traps, the team transplanted human cancer cells into mice engineered to have human immune cells. The researchers found that their Y-trap eliminated Treg cells in tumors and slowed the growth of tumors that failed to respond to ipilimumab, a current immunotherapy drug that targets the CTLA-4 protein.

“Tregs have long been a thorn in the side of cancer immunotherapy,” said Bedi. “We’ve finally found a way to overcome this hurdle with this CTLA-4-targeted Y-trap.These first-in-class Y-traps are just the beginning. We have already invented a whole family of these multifunctional molecules based on the Y-trap technology. Since mechanisms of immune dysfunction are shared across many types of cancer, this approach could have broad impact for improving cancer immunotherapy. Y-traps could also provide a therapeutic strategy against tumors that resist current immune checkpoint inhibitors.”