Immunotherapy, which uses the power of the body’s immune system to fight disease, is gaining momentum in cancer treatment. Chief among cancer immunotherapies is a treatment known as CAR-T, or chimeric antigen receptor T-cell therapy. CAR-T therapy has had great success in treating blood cancers such as leukemia, especially in children and young adults. But using the therapy to fight solid tumors, including skin cancer, has proven much more difficult.
Now Yuri Sykulev, a professor of microbiology and immunology and medical oncology at Thomas Jefferson University and a researcher at the Sidney Kimmel Cancer Center, Jefferson Health and colleagues show that to kill melanoma cells efficiently, CAR-T cells need an abundance. of antigens-cancer-associated molecules overexpressed on target cells. The findings may lead to better immune therapies to treat solid tumors.
“CAR-T cells are very helpful in killing blood cancer cells, but we found that they need a lot of tumor-associated antigens to kill melanoma and very likely other solid tumors,” says Dr. Sykulev, who published the new research in August. 8 in the journal of biological chemistry.
CAR-T therapy draws its power from T cells, the workhorses of the immune system. T cells play a critical role in setting up the immune system’s response to infection, including killing infected cells. CAR-T cells are modified T cells that display portions of synthetic antibodies on their cell surface. These antibody fragments allow CAR-T cells to recognize and attach to specific proteins on tumor cells.
To make CAR-T cells for therapy, researchers isolate T cells from a patient and manipulate the cells to display the cancer-targeted antibodies. They then grow millions of these modified cells in the lab before infusing them back into the patient. The CAR-T cells continue to multiply in the patient’s body and, if all goes according to plan, recognize and kill the tumors that display the target antigen.
While CAR-T cell therapy has worked very well in patients with blood cancers, it has not been as successful in treating solid tumors, including skin cancers such as melanoma, the fifth most common cancer in the US and the deadliest type of skin cancer. .
In the new study, Dr. Sykulev and colleagues from Takami Sato’s lab developed CAR-T cells to recognize an antigen on melanoma cells called high molecular weight melanoma-associated antigen (HMW-MAA). Melanoma cells express varying amounts of HMW-MAA on their cell surfaces.
When the researchers evaluated how well the CAR-T cells killed the melanoma cells, they saw that the CAR-T cells efficiently knocked out melanoma cells that expressed high levels of HMW-MAA, but not those with lower levels of the antigen.
dr. Sykulev and colleagues then tested how well another type of immunotherapy known as TCR-T cells that use T cells designed to express a specific T-cell receptor killed target cells. TCR-T cell therapy works in the same way as CAR-T therapy, but recognizes different target molecules than HMW-MAA.
When the researchers treated melanoma cells with TCR-T cells, they found that the treatment killed the tumor cells easily, even in melanoma cell lines that expressed far fewer target molecules, related peptide-MHC ligands, than HMW-MAA antigens required for CAR-T detection. The results indicate that TCR-mediated cancer cell killing has a lower threshold than CAR-T therapy requires, although both are present on T cells at a comparable level.
The comparison showed that TCR-T is superior to CAR-T therapy for melanoma. “It turns out that CAR-T cells are not as good at killing target tumor cells as TCR-T cells,” says Dr. Sykulev. This difference could help make immune therapies more effective in treating solid cancers such as melanoma.
Our research paves the way for understanding how to improve CAR-T cell therapy in solid cancers, and especially to eliminate solid tumors with low levels of target molecules.”
dr. Yuri Sykulev, Professor of Microbiology and Immunology and Medical Oncology, Thomas Jefferson University
This work was supported by the Dean’s Transformational Science Award in Jefferson and by a grant from Hasumi International Research Foundation (Japan). The authors declare no conflicts of interest.
Thomas Jefferson University
Anikeeva, N., et al. (2021) Efficient killing of tumor cells by CAR-T cells requires a greater number of involved CARs than TCRs. Journal of biological chemistry. doi.org/10.1016/j.jbc.2021.101033.
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