Tag: macrophages

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A Suit of Armor for Cancer-fighting Cells

by Nathi Magubane

Chimeric antigen receptor T cell (CAR T) therapy has delivered promising results, transforming the fight against various forms of cancer, but for many, the therapy comes with severe and potentially lethal side effects. Now, a research team led by Michael Mitchell of the School of Engineering and Applied Science has found a solution that could help CAR T therapies reach their full potential while minimizing severe side effects. (Image: iStock / Meletios Verras)

In recent years, cancer researchers have hailed the arrival of chimeric antigen receptor T cell (CAR T) therapy, which has delivered promising results, transforming the fight against various forms of cancer. The process involves modifying patients’ T-cells to target cancer cells, resulting in remarkable success rates for previously intractable forms of cancer.

Six CAR T cell therapies have secured FDA approval, and several more are in the pipeline. However, these therapies come with severe and potentially lethal side effects, namely cytokine release syndrome (CRS) and neurotoxicity. These drawbacks manifest as a range of symptoms—from high fever and vomiting to multiple organ failure and patient death—posing significant challenges to broader clinical application.

Now, a research team led by Michael Mitchell, associate professor in the School of Engineering and Applied Science at the University of Pennsylvania, has found a solution that could help CAR T therapies reach their full potential while minimizing severe side effects. Their findings are published in the journal Nature Materials.

“Addressing CRS and neurotoxicity without compromising the therapeutic effectiveness of CAR T cells has been a complex challenge,” says Mitchell.

He says that unwanted interactions between CAR T and immune cells called macrophages drive the overactivation of macrophages, which in turn result in the release of toxic cytokines that lead to CRS and neurotoxicity.

“Controlling CAR T-macrophage interactions in vivo is difficult,” Mitchell says. “So, our study introduces a materials engineering-based strategy that involves incorporating a sugar molecule onto the surface of CAR T cells. These sugars are then used as a reactive handle to create a biomaterial coating around these cells directly in the body, which acts as a ‘suit of armor,’ preventing dangerous interactions with macrophages.”

First author Ningqiang Gong, a postdoctoral researcher in the Mitchell Lab, elaborates on the technique, “We attached this sugar molecule to the CAR T cells using metabolic labeling. This modification enables the CAR T cells to attack cancer cells without any hindrance.”

“When symptoms of CRS begin to manifest, we introduce another molecule—polyethylene glycol (PEG)—to create the suit of armor, which effectively blocks dangerous interactions between these engineered T cells, macrophages, and the tumor cells themselves,” Gong says.

Read the full story in Penn Today.

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Engineered White Blood Cells Eliminate Cancer

by Melissa Pappas

“Macrophages killing cancer cell” photographed by Susan Arnold.

By silencing the molecular pathway that prevents macrophages from attacking our own cells, Penn Engineers have manipulated these white blood cells to eliminate solid tumors.

Cancer remains one of the leading causes of death in the U.S. at over 600,000 deaths per year. Cancers that form solid tumors such as in the breast, brain or skin are particularly hard to treat. Surgery is typically the first line of defense for patients fighting solid tumors. But surgery may not remove all cancerous cells, and leftover cells can mutate and spread throughout the body. A more targeted and wholistic treatment could replace the blunt approach of surgery with one that eliminates cancer from the inside using our own cells.

Dennis Discher, Robert D. Bent Professor in Chemical and Biomolecular Engineering, Bioengineering, and Mechanical Engineering and Applied Mechanics, and postdoctoral fellow, Larry Dooling, provide a new approach in targeted therapies for solid tumor cancers in their study, published in Nature Biomedical Engineering. Their therapy not only eliminates cancerous cells, but teaches the immune system to recognize and kill them in the future.

“Due to a solid tumor’s physical properties, it is challenging to design molecules that can enter these masses,” says Discher. “Instead of creating a new molecule to do the job, we propose using cells that ‘eat’ invaders – macrophages.”

Macrophages, a type of white blood cell, immediately engulf and destroy – phagocytize – invaders such as bacteria, viruses, and even implants to remove them from the body. A macrophage’s innate immune response teaches our bodies to remember and attack invading cells in the future. This learned immunity is essential to creating a kind of cancer vaccine.

But, a macrophage can’t attack what it can’t see.

“Macrophages recognize cancer cells as part of the body, not invaders,” says Dooling. “To allow these white blood cells to see and attack cancer cells, we had to investigate the molecular pathway that controls cell-to-cell communication. Turning off this pathway – a checkpoint interaction between a protein called SIRPa on the macrophage and the CD47 protein found on all ‘self’ cells – was the key to creating this therapy.”

Read the full story in Penn Engineering Today.

Multiple members in the biophysical engineering lab lead by Dennis Discher, including co-lead author and postdoctoral fellow and Penn Bioengineering alumnus Jason Andrechak and Bioengineering Ph.D. student Brandon Hayes, contributed to this study. The research was funded by grants from the National Heart, Lung, and Blood Institute and the National Cancer Institute, including the Physical Sciences Oncology Network, of the US National Institutes of Health.