New Potential “Double Target” Immunotherapy in Neuroblastoma Uncovered

Neuroblastoma cell line labeled with fluorescent molecules
[Source: vshivkova/Getty Images]

A new immunotherapy using modified cells targeting two different antigens was highly effective in a mouse model of human neuroblastoma, according to a study led by researchers from the UNC Lineberger Comprehensive Cancer Center and the UNC School of Medicine. The new treatment restricted tumor regrowth and also prevented the neuroblastoma cells from evading protective immune cells.

“We know that certain CAR-T therapies are safe for patients with solid tumors, but so far treatments have not led to the degree of tumor regression we would like to see,” said Gianpietro Dotti, MD, professor in the UNC School of Medicine Department of Microbiology and Immunology and co-leader of the Immunology Program at UNC Lineberger. “We ultimately designed a strategy that simultaneously addresses the most challenging tasks in solid tumors, such as generating CAR-T cells that rapidly eliminate the tumor and persist in controlling tumor growth. Furthermore, our system prevents tumor recurrence.”

If this therapeutic approach is as promising in people as it has been in mice, the researchers said targeting three, four or more antigens expressed by tumor cells could be even more effective.

The research findings appeared today, Sept. 23, 2021, in Nature Cancer.

Neuroblastoma is a cancer of immature nerve cells and occurs mainly in children younger than six years of age. The tumors are typically found on top of adrenal glands but can also develop in the abdomen, chest, neck, pelvis, and bone. Approximately 500 to 1,000 cases are diagnosed annually in the United States.

“Tumor cells are characterized by a mixed expression of antigens, and we engineered dual immune-system T cells to maximize their capacity to prevent tumors from evading detection by the immune system,” said Hongwei Du, Ph.D., a postdoctoral fellow at UNC School of Medicine.

“Furthermore, the modified T cells were also able to receive important signals, which is somewhat unique as there have been many challenges in getting certain types of immunotherapies to overcome the unfriendly tumor environment found in solid tumors.”

The researchers used CAR-T cell (chimeric antigen receptor-T cell) immunotherapy, which involves harvesting immune-system T cells from a patient and genetically re-engineering them in the lab to recognize targets on the surface of cancer cells when they are re-infused into patients.

In this study, the scientists coupled the recognition of two antigens expressed by the tumor cells with the combination of two key co-stimulatory molecules: CD28, a protein expressed on T cells after early activation, and 4-1BB, an important co-stimulatory protein that is involved in T-cell survival and memory formation. Both CD28 and 4-1BB have been shown to be equally effective in clinical studies in patients with blood-borne cancers when used individually. However, the combination of CD28 and 4-1BB co-stimulation appears to be critical in solid tumors.

The scientists first looked at neuroblastoma cells in the laboratory to see how they responded to a combined immune cell attack, based on those results, they then looked at mice implanted with neuroblastoma to see how they would respond to co-stimulation by CD28 and 4-1BB modified T cells. The co-stimulatory cells were very effective in reducing cancer in mice bearing large numbers of neuroblastoma tumors.

“We are currently implementing clinical studies to look at several potential single targets,” said Dotti. “If these studies prove that the therapies are safe, we’ll then progress to the next logical step, which is looking to see if our therapy is effective against a combination of targets.”

This site uses Akismet to reduce spam. Learn how your comment data is processed.