Genetic Engineering Publications - GEG Tech top picks

Following the approval from the Food and Drug Administration (FDA), doctors at the University of Washington's Siteman Cancer Center will administer tumor-infiltrating lymphocyte (TIL) therapy to treat certain adult patients with metastatic melanoma, an aggressive skin cancer that has spread to other areas of the body. The treatment is intended for patients with metastatic melanoma that cannot be treated by surgery and has continued to grow and spread despite having already been heavily treated with other approved strategies, including chemotherapy and immune checkpoint inhibitors. The first centers to administer TIL therapy are those with extensive expertise in treating patients with cellular immunotherapies, such as CAR-T cell therapy for blood cancers. For the therapy, doctors at an approved treatment center take a sample of the tumor and send the tissue to an Iovance manufacturing facility, where tumor-infiltrating lymphocytes are isolated from the tumor and then expanded outside the body. This TIL therapy cell product is then cryopreserved and returned to the patient. When returned to the patient's body via intravenous infusion, the tumor-specific T cells, now numbering in the billions, are much more effective at killing tumor cells throughout the body. 

In the new study, Dr. Sykulev and colleagues in Takami Sato's lab engineered 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. In their research, the researchers evaluated the extent to which CAR-T cells killed melanoma cells. They found that CAR-T cells effectively killed melanoma cells expressing high levels of HMW-MAA, but not those with lower levels of the antigen. The researchers then tested how well another type of immunotherapy, known as TCR-T cells that uses T cells engineered to express a specific T-cell receptor, killed the target cells. When the researchers treated melanoma cells with TCR-T cells, they found that the treatment readily killed tumor cells, even in melanoma cell lines that expressed far less HMW-MAA antigens than needed for CAR-T. The comparison thus revealed that TCR-T is superior to CAR-T therapy for melanoma.

Overall survival for patients with melanoma that has spread to the brain is only four to six months. Researchers have therefore investigated a new therapeutic approach to more effectively target melanoma in the brain. The therapy devised by the scientists uses a "twin stem cell model" designed to maximize an attack on cancer cells that have spread to a part of the brain known as the leptomeninges. A stem cell releases a cancer-killing virus (oncolytic). Using stem cells to deliver the virus amplifies the amount of virus that can be released, and ensures that the virus will not be degraded by circulating antibodies before it is released on cancer cells. However, the oncolytic virus also destroys the cells that release it, making it an unsustainable therapeutic option. Therefore, scientists have used CRISPR/Cas9 gene editing to create a second stem cell that cannot be targeted by the oncolytic virus and instead releases proteins (immunomodulators) that boost the immune system to help fight cancer. Twin stem cells can be delivered by intrathecal injection. Unlike other immunotherapies that have appeared in recent years, it does not need to be administered repeatedly. The researchers point out that this approach can be used in other cancers with metastases.