Cancer therapy is ever changing as technology improves to better understand our immune systems. Immunotherapy is a form of cancer treatment which redirects the immune system to recognize and target the tumor. To avoid detection, solid tumors are commonly known to polarize healthy immune cells around it. In many aggressive cancers the immune system not only fails to recognize the mass proliferation of cells, but even promotes disease progression through different pro-tumor mechanisms. These mechanisms include immune suppression, tumor metastasis, and immune evasion. Scientists in the field of immuno-oncology are working on how to overcome these immunosuppressive mechanisms.
Chimeric antigen receptor-T cell (CAR-T cell) therapy is a novel form of immunotherapy that targets tumors more specifically and overcomes tumor promoting signals. In CAR-T cell therapy, a patient’s immune cells (or T cells) are taken and engineers them to recognize and target cancer cells based on a tumor-specific marker. Once engineered, the cells are expanded in a lab and reinfused into the patient. This work has shown tremendous success in hematologic malignancies, but limited efficacy in solid tumors. However, the idea of engineering patient autologous cells has broadened the field. Scientists are now engineering other immune cells to target the tumor.
One specific immune cell engineered, besides T cells, are natural killer cells (NK). This cell population is part of the innate immune system and is one of the initial cells to respond to infection or disease. More specifically, NK cells have the ability to recognize and target cancer cells to halt their growth and subsequent progression. Unfortunately, cancer can also dysregulate NK cells and impede their ability to appropriately function. CAR-NK cells are generated and used similarly to CAR-T cells, which target aggressive tumors unrecognizable to the immune systems.
A recent article published in Cancer Discovery, by Dr. Katayoun Rezvani and others, demonstrated the mechanism that provides enhanced and extended anti-tumor CAR-NK cell activity. Rezvani is Professor of Medicine and the Sally Cooper Murray Endowed Chair in Cancer Research; Chief of the Section of Cellular Therapy in Stem Cell Transplant and Cellular Therapy; Executive Director of the Adoptive Cell Therapy Platform; and Director of Translational Research and Medical Director of the MD Anderson GMP and Cell Therapy Laboratory. Her lab focuses on NK cells and the inter- and intracellular mechanisms that mediate immunity against cancer.
Rezvani and her team concluded that the addition of a cell co-stimulating molecule, CD28, enhances CAR-NK cell therapy in both hematologic and solid malignancies. The CAR-NK cells target a tumor specific marker known as CD70 to avoid off-target toxicity. This marker was chosen as the target due to its role in tumor progression and immune evasion. Therefore, CD27, the CD70 receptor was incorporated in the CAR-NK cells to bind to tumor cells and with the CD28 stimulatory molecule would activate to lyse the tumor. The efficacy of the CAR-NK design was validated in multiple cancer models. Additionally, the team discovered the intracellular signaling pathway that led to enhanced anti-tumor activity. As a result, a Phase I/II clinical trial has been established to test this therapy in patients with hematologic and solid malignancies. Overall, this work provides a mechanistic understanding of an enhanced therapy for multiple cancer types and has the potential to extend longevity in patients with cancer.
