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How can we help our immune system recognize and destroy cancer better? That was the goal of Mara Nicolasen and Lucrezia Gatti during their PhD research at UMC Utrecht. Working side by side, Mara improved a special bispecific molecule that helps immune cells to better recognize and attack tumors, while Lucrezia studied how immune cells move into tumors and how to guide them more effectively. Together, their work brings new ideas for improving cancer treatments.  

Immunotherapy uses the body’s own defense system to fight cancer by boosting or training immune cells. “The immune system is incredibly powerful, but tumors have many ways to hide from it”, says Mara Nicolasen, who just earned her PhD last week in the team with , and .   

“Most immunotherapies use common immune cells that find tumors by looking for specific markers”, says Lucrezia Gatti, who also recently earned her PhD under Jurgen Kuball and . “But tumors sometimes lose these markers to escape detection”, she says. Mara continues: “Gamma delta T cells, a lesser-known type of immune cell, spot cancer in a completely different way. Instead of looking for specific markers, they sense when a cell is acting abnormally, based on their metabolism.” 

A molecule that acts like a bridge 

Inspired by gamma delta T cells, Mara worked on a special molecule that connects tumors with immune cells. “The molecule, called a bispecific engager, acts like a bridge”, she says. “One end recognizes the tumor by its metabolism, like gamma delta T cells do, and the other end attracts and activates common T cells.” This helps even more immune cells find and attack the tumor.  

Mara fine-tuned the molecule to make it bind more strongly to the immune cells and tumor cells. “The adjustments to the molecule made the T cells attack the tumor much more efficiently. We saw stronger recognition and better tumor killing in mice, without harmful side effects”, Mara explains. “The basic design of the molecule was already there when I joined the lab, but being able to improve it myself was really exciting.”  

It depends on the type of tumor how well immune cells do their job

Immune cells behave differently  

In their PhDs, Mara and Lucrezia worked closely together. Mara studied glioblastoma, an aggressive brain tumor, while Lucrezia focused on colorectal cancer, both solid tumors. Although their projects started from the same idea, the biology turned out to be completely different. “We also wanted to see what kind of immune cells are present in the two different tumors”, Lucrezia says. “We could really see how different tumors behave”, says Lucrezia. “The results and even the direction of the research varied so much between them.”   

Mara adds: “We saw that a subtype of the gamma delta T cells that worked very well in glioblastoma did almost nothing in colorectal cancer. And the ones that were very active in colorectal cancer were barely present or functional in glioblastoma. So, it really depends on the type of tumor how well immune cells do the job.” 

Finding how immune cells reach the tumor 

Lucrezia also looked at how and from where immune cells find their way to the tumor. “Even if T cells are powerful, they need to get to the right place first”, explains Lucrezia. She studied how chemokines, chemical signals, guide immune cells into the area around primary colorectal cancer. Together with researcher Zsolt Sebestyen, Lucrezia explored how changing the receptors (ccr5) for these signals could help immune cells enter tumors more easily. 

“These receptors can be used to improve T cells that are engineered to fight cancer, such as CAR T cells”, Lucrezia explains. “We found a way to help killer T cells migrate better into solid tumors and attack cancer cells more effectively. It’s a first, but important step toward making these therapies work for more patients.” 

We really complemented each other. In the end, Mara became one of my closest friends

From lab to clinic 

After completing her PhD, Mara stays in the field, in the team of neurosurgeon . She’s now helping design a clinical trial for glioblastoma patients, based on findings from her PhD. “We saw that certain immune cells can recognize brain tumors, especially when you add a drug that changes the tumor’s metabolism”, she explains. “That drug already exists for bone resorption. Now we want to see if it can make brain tumors more visible to the immune system.” For Mara, this step is especially meaningful. “It’s amazing to see our findings move toward real patients”, she says. “That’s what makes all the effort worth it.” 

Lucrezia is now continuing her work in Switzerland. “Now I focus on improving T cell therapies and bringing them to the clinic”, she says. “For example, we’re replacing viral systems with new, non-viral approaches that could go straight into clinical use.” 

A partnership in science and friendship 

Mara and Lucrezia’s projects grew side by side, and so did their friendship. “We really complemented each other”, Lucrezia says. “We discussed data, compared findings, and built the projects from the ground up. In the end, Mara became one of my closest friends.” 

Both hope their research will one day help bring smarter, safer immunotherapies to more patients. “The field is moving really fast”, Mara says. “When I started, gamma delta T cells were still seen as something exotic, now they’re real potential for treating different types of cancer.”