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Engineered Macrophage Cells Tested in Cancer Trial

Macrophage

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

18 Mar. 2021. A clinical trial is underway testing immune system cells called macrophages, with added cancer-killing proteins, as a treatment for solid tumor cancers. The trial, conducted by Carisma Therapeutics Inc. in Philadelphia, is the first test of this experimental immunotherapy in humans, according to the company.

Carisma Therapeutics, a five year-old spin-off enterprise from University of Pennsylvania medical school, develops cancer immunotherapies that harness macrophages, white blood cells from the immune system. While other cancer therapies work with engineered T-cells, also white blood cells in the immune system, 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 large white blood cells surround and consume invading microbes, and last for months at a time, acting as a early defense against further infections.

As with many T-cell immunotherapies, the Carisma technology genetically engineers the macrophages by adding chimeric antigen receptors or CARs, a type of cancer-fighting protein. When encountering tumors, says the company, the engineered macrophages, called CAR-Ms, are absorbed into tumor tissue unleashing the CARs, then also activating and recruiting T-cells from the immune system to further attack tumor cells.

Designed to treat solid tumor cancers that over-express HER2

Carisma’s scientific founders Saar Gill and Michael Klichinsky led a UPenn team that tested the engineered macrophage concept in lab mice, reported by Science & Enterprise in Mar. 2020. The mice were 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 were shown to 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.

The company’s lead product, code-named CT-0508 is designed to treat solid tumor cancers that over-express HER2 proteins. The early-stage clinical trial is enrolling 18 individuals with solid tumor cancers over-expressing HER2 proteins, at UPenn or University of North Carolina medical center in Chapel Hill. The patients’ tumors are either metastatic or recurring, and do not respond to other treatments. Participants are randomly assigned to receive either a full dose infusion of CT-0508 with 5 billion CAR-M cells, or escalating doses of CT-0508 totaling 5 million cells, spread out over 5 days.

The research team led by Carisma’s chief medical officer Debra Barton is looking primarily for adverse effects of the treatments for up to 14 months following administration, including cytokine release syndrome, a large and sometimes severe release of enzymes from the immune system that can be life-threatening. The study team is also evaluating the feasibility of manufacturing CT-0508 for a clinical setting, and tracking reductions in tumor size and progression-free survival time for patients in the following 24 months.

“This is the first time this kind of technology is being explored in humans,” says Gill in a company statement released through Cision, “and we are excited to collect important data from this trial that will help to validate the platform as a potential new therapeutic approach for these patients.” Gill is a scientific adviser to Carisma, while Klichinsky is the company’s vice-president for research.

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