Revolutionary T-Cell Therapy Delivers Amazing Results in Fighting Cancer

The game-changing treatment used a variety of human immune cells, known as natural killer (NK) cells, with amazing results. (CREDIT: Creative Commons)

Immune checkpoint inhibitors, such as Keytruda and Opdivo, work by releasing the T cells of the immune system to attack tumor cells. Their introduction ten years ago marked a significant advance in cancer treatment, but only 10-30% of treated patients show long-term improvement. In an article published online in the Journal of Clinical Investigation (JCI) today, scientists at the Albert Einstein College of Medicine describe findings that could improve the effectiveness of immune checkpoint therapy.

Instead of rallying T cells against cancer, Einstein’s research team used a variety of human immune cells known as natural killer (NK) cells and achieved astonishing results. “We believe that the new immunotherapy we have developed has great potential to move into clinical trials involving various types of cancer,” said study leader Xingxing Zang, M.D., Ph.D., head of the Department of Cancer Research and professor of microbiology and immunology, oncology, urology and medicine at the Einstein University and a member of the Cancer Therapy Program of the Montefiore Einstein Cancer Center.

Distinguish friend from foe

Immune cell surfaces are littered with receptors known as “checkpoint” proteins that prevent immune cells from deviating from their usual targets (pathogen-infected cells and cancer cells). When checkpoint receptors on immune cells bind to proteins expressed by the body’s own normal cells, this interaction inhibits potential immune cell attack.

Ironically, most types of cancer cells express proteins that bind to checkpoint proteins, fooling immune cells into not attacking the tumor.

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Immune checkpoint inhibitors are monoclonal antibodies designed to short-circuit the interaction of immune cells and cancer cells by blocking either tumor proteins or immune cell receptors that bind to tumor proteins. Immune cells without brakes can attack and destroy cancer cells.

New focus on natural killer cells

The limited effectiveness of checkpoint inhibitors prompted Dr. Zang and others to investigate checkpoint pathways involving NK cells, which, like T cells, play an important role in eliminating unwanted cells. Soon their attention was drawn to a cancer cell protein called PVR. “We realized that PVR could be a very important protein that human cancer cells use to keep the immune system from attacking,” said Dr. Zang.

The PVR protein is usually absent or very deficient in normal tissues, but is found in abundance in many types of tumors, including colorectal, ovarian, lung, esophageal, head and neck, gastric, and pancreatic cancers, as well as myeloid leukemia and melanoma.

The image on the left shows the binding of the PVR tumor cell protein to the NK cell receptor KIR2DL5 to prevent NK cell attack. In the image on the right, the monoclonal antibody short-circuits the interaction between tumor cells and NK cells, allowing NK cells to attack and destroy tumor cells. (CREDIT: Tatiana Harris/Albert Einstein College of Medicine)

Moreover, PVRs appear to inhibit T cell and NK cell activity by binding to a checkpoint protein called TIGIT, prompting attempts to interrupt the TIGIT/PVR pathway using anti-TIGIT derived monoclonal antibodies. There are currently over 100 clinical trials targeting TIGIT worldwide. However, several clinical trials, including two large Phase 3 clinical trials, have recently failed to improve cancer treatment outcomes.

Recognition of the role of the new receptor

At the same time, it was found that the PVR cancer cell protein has another “binding partner” with NK cells: KIR2DL5. “We hypothesized that PVR suppresses NK cell activity not by binding to TIGIT, but by binding to the newly discovered KIR2DL5,” said Dr. Zang. To find out, he and his colleagues synthesized a monoclonal antibody targeting KIR2DL5 and performed in vitro and in vivo experiments using this antibody.

In their JCI paper, Dr. Zang and colleagues demonstrated that KIR2DL5 is a commonly occurring checkpoint receptor on the surface of human NK cells that PVR cancer proteins use to suppress immune attack. In studies involving humanized animal models of several types of human cancer, researchers have shown that their anti-KIR2DL5 monoclonal antibodies—by blocking the KIR2DL5/PVR pathway—allow NK cells to vigorously attack and shrink human tumors and prolong animal survival (see accompanying illustration). .

“These preclinical data give us hope that targeting the KIR2DL5/PVR pathway was a good idea and that the monoclonal antibody we developed could be an effective immunotherapy,” said Dr. Zang.

Blockade of the KIR2DL5/PVR immunosuppressive pathway induces potent antitumor immunity mediated by human NK cells (CREDIT: Journal of Clinical Investigation)

Einstein has applied for a patent on the KIR2DL5/PVR immune checkpoint, including antibody preparations, and is interested in partnering to further develop and commercialize this technology.

Dr. Zhang has previously developed and patented over 10 immune checkpoint inhibitors. One of these inhibitors is currently being tested in China in a phase 2 clinical trial involving several hundred patients with advanced solid cancer (non-small cell lung cancer, small cell lung cancer, nasopharyngeal cancer, head and neck cancer, melanoma, lymphoma) or recurrent cancer. . /refractory blood tumors (acute myeloid leukemia, myelodysplastic syndromes). Dr. Zang’s other immune checkpoint inhibitor will be evaluated next year in cancer clinical trials in the United States.

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Note. Materials provided above by the Albert Einstein College of Medicine. Content can be edited for style and length.

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