Scientists at Stanford University developed a new CAR-T therapy that can eradicate many types of childhood tumors in a mouse study, which was published in Clinical Cancer Research on January 17, further demonstrating the potential of such cellular immunotherapies to combat solid tumors, including brain tumors.
The research of solid tumors becomes a hotspot
In 2017, the US FDA approved two CAR-T therapies (Kymriah and Yescarta) for the treatment of childhood and young adult B-cell acute lymphoblastic leukemia, as well as certain types of non-Hodgkin’s lymphoma.
However, although CAR-T technology has brought new hope to blood cancer patients, it shows barely unsatisfactory results, often leading to severe side-effects, such as cytokine storms, a potentially lethal inflammatory response that may cause Childhood Tumorsorgan failure in some patients.
How to expand the application range of CAR-T therapy? Can CAR-T technology treat solid tumors? These are questions that many scientists are exploring. Dr. Robbie Majzner of Harvard Medical School and his colleagues have been trying to develop CAR-T technology to treat brain tumors and solid tumors in children.
Find fundamental cancer cell “signals”
The CAR of CAR-T therapy is a “navigation” capable of specifically recognizing cancer cells, and T refers to a T cell that exerts an anticancer effect. To successfully kill cancer cells, a “signal” on cancer cells is indispensable for the “navigation,” which is called a “target.”
The ideal “signal” is highly expressed on cancer cells but not expressed or rarely expressed in healthy cells. In this case, CAR-T cells can only attack cancer cells without attacking healthy cells, thereby achieving a safe anti-cancer effect.
In the study, scientists screened 388 childhood tumor samples to detect expression of a target in cancer cells, called B7-H3 that has been proved for its practicability in previous studies. The analysis showed that 84% of the samples expressed B7-H3, and 70% of the samples had high expression levels of B7-H3. Mainly, scientists have found high expression of B7-H3 in many types of childhood cancer, including Ewing’s sarcoma (bone tumor), rhabdomyosarcoma, nephroblastoma, neuroblastoma, and medulloblastoma ( brain tumor).
Multiple tumors “disappeared”
After determining the target, the scientists designed six CAR-T cells that target B7-H3 and tested them in culture dishes. The best performing CAR-T cells were used for further studies. They then tested prominent CAR-T cells with several childhood cancer xenograft models. Xenografts refer to transplanting human tumors into mice.
In mice transplanted with osteosarcoma or Ewing’s sarcoma (both bone tumors), CAR-T cells eradicated tumors, and the life of the treated mice was significantly longer than that of the control mice. “The tumors in all mice disappeared, which is very exciting,” Dr. Majzner said.
The researchers further confirmed that the testing on whether CAR-T cells can kill cancer cells that spread to the lungs after surgically removing orthotopic tumors from mice with osteosarcoma still presented good anticancer effects. The life of the treated mice was significantly longer than that of the control mice.
They also tested CAR-T cells in mice transplanted with medulloblastoma. The results show that CAR-T cells injected into the blood can cross the blood-brain barrier and destroy the tumor. This blood-brain barrier is the body’s natural defense system, making it difficult for drugs to reach the brain.
Phase I clinical trials are being planned
In addition, studies have shown that such CAR-T cells do not attack cells with low B7-H3 expression levels, which is good news because some healthy cells express low levels of B7-H3. So, can the CAR-T therapy targeting B7-H3 be used for the treatment of human cancer? The research team is planning a series of Phase I clinical trials to answer this question.
It should be pointed out that there is a risk in this therapy: some rare cancer cells that do not express B7-H3 may remain in the body, leading to cancer recurrence. In response to this problem, scientists are developing CAR-T cells that recognize multiple cancer cell “signals” to prepare for future clinical trials. It’s believed that in the future, this innovative therapy will bring benefits to patients with recurrent or metastatic cancer.