Chimeric antigen receptor (CAR) T-cells, cells that are genetically engineered to recognize a specific protein expressed by tumor cells, are an emerging field of immunotherapy that has been showing considerable success in a number of cancers. Now, researchers have shown that these cells can do more than just attack cancer cells.
The study, “Loss of the HVEM Tumor Suppressor in Lymphoma and Restoration by Modified CAR-T Cells,” published in Cell, found that CAR T-cells can also be engineered to produce specific anti-tumor molecules, working as vehicles for precise therapeutic delivery.
Indeed, the researchers demonstrated that CAR T-cells can be used to restore a pathway that, when affected, appears to lead to lymphoma development. Such restoration resulted in better anti-tumor responses than those obtained with CAR T-cells that did not restore the pathway.
Most human lymphomas arise from B-cells within germinal centers, areas of the lymph nodes and spleen where mature B-cells proliferate, differentiate, and become specific to a foreign antigen — a molecule that is recognized by immune cells.
A number of studies have increasingly suggested that the microenvironment of the germinal center is critical for most aspects of B-cell function, and likely contributes to the development of lymphomas. However, the precise mechanisms through which this microenvironment is involved in lymphoma are largely unknown.
Mutations in the HVEM receptor gene are among the most common genetic alterations found in germinal center lymphomas, such as diffuse large B-cell lymphomas (DLBCL) and follicular lymphoma. These mutations also appear to change patients’ prognosis.
The researchers hypothesized that the loss of HVEM may lead to lymphoma development through loss of the HVEM-BTLA suppressive pathway; when a cell expressing HVEM interacts with another immune cell expressing BTLA, the function of both these immune cells is suppressed.
Results revealed that nearly 75 percent of human follicular lymphomas analyzed were negative for either HVEM or BTLA. In mice, the loss of this suppressive pathway was found to lead to lymphoma growth and to the development of a supportive microenvironment.
But the investigators noticed that delivering a soluble form of HVEM to lymphoma cells, injected inside the tumor, significantly blocked their growth. Therefore, they developed CAR T-cells that recognized CD19-positive cells (a protein highly expressed in lymphoma cells) to continuously produce this HVEM protein and locally deliver it into tumors.
Importantly, these CAR T-cells where more effective at inhibiting tumor growth than control CAR T-cells or CD19 CAR T-cells.
These findings reveal not only that restoring the HVEM-BTLA pathway is a promising approach to put the brakes back on lymphoma cells, but more important, that CAR T-cell can be used as vehicles, or “micro-pharmacies,” to deliver anti-tumor proteins. The researchers said further studies need to explore this approach as a platform for therapeutic delivery.
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