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Engineered Blood Cells Created for Cancer Therapies

Macrophage

Macrophage with single nucleus (Public Health Image Library, CDC)

23 Mar. 2020. An academic lab and spin-off company are developing engineered white blood cells with added cancer-killing proteins to attack solid tumor cancers. Researchers from University of Pennsylvania medical school and the company Carisma Therapeutics Inc. both in Philadelphia, report their findings in today’s issue of the journal Nature Biotechnology (paid subscription required).

A team from the lab of UPenn cancer researcher Saar Gill is seeking to produce the same kind of results with chimeric antigen receptors or CARs shown when these cancer-fighting proteins are added to genetically engineered T-cells, white blood cells in the immune system. These CAR T-cells are shown to be effective against blood-related cancers, such as leukemia or lymphoma, but so far returned only mixed results with solid tumor cancers, e.g. lung and breast cancer.

For this task, Gill and colleagues chose another immune system cell, called a macrophage as the vehicle. Like T-cells, macrophages are white blood cells, but macrophages work differently. When encountering tissue damage or infections, precursor white blood cells known as monocytes enter the affected regions and transform into macrophages. These transformed white blood cells are large, surround and consume invading microbes, and last for months at a time, acting as a early defense against infections.

With tumors, say the researchers, macrophages are drawn into tumor tissue, but then are exploited to protect the tumor against attackers. The team decided to use this ability of macrophages to penetrate tumor tissue, with chimeric antigen receptors, the cancer-killing proteins in CAR T-cells, added through genetic modification. For these CAR macrophages or CAR-Ms to work, however, the researchers needed to overcome another characteristic of macrophages, their ability to resist infection.

This resistance to infection prevents adenoviruses from delivering macrophages in their natural state. Adenoviruses are benign viruses to most humans that are often used in cell and gene therapies for their ability to penetrate cell nuclei and deliver genomic payloads. To overcome this obstacle, the UPenn-Carisma team further engineered their CAR-Ms to adapt, rather than resist, adenovirus infections, making the modified macrophages weapons against tumors, rather than protectors.

To prove the concept, researchers first tested the engineered CAR-Ms in lab cultures, then in lab mice grafted with tumors expressing human epidermal growth factor receptor 2, or HER2, a protein often over-expressed in breast, ovarian, bladder, pancreatic, and stomach cancers. The results show mice treated with a single infusion of engineered CAR-Ms reduce their tumor burdens and survive for longer periods. CAR-Ms, says the team, express inflammatory proteins inside the tumor, turning macrophage bystanders into attackers, remodeling the supportive tumor environment, and attracting T-cells to join in the attack on cancer cells.

First author Michael Klichinsky, a doctoral candidate in Gill’s lab during the study says in a university statement, “Finding ways to draw the rest of the body’s powerful immune system into the fight would mean an even greater impact than what a cellular therapy can do on its own, so our future research will include efforts to better understand this possibility and how we might be able to exploit it to kill cancer.”

Gill and Klichinsky founded Carisma Therapeutics in 2016 to commercialize the CAR-M technology. In a statement released through PR Newswire, the biotechnology company says it’s developing a therapy candidate code-named CT-0508 as a treatment for tumors expressing HER2 proteins.

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