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Out of the Box

By Lisa Merkl

Shaun Xiaoliu Zhang, M.D. Anderson Professor of Biology and Biochemistry

Beginning his career as a physician, Zhang developed an interest in viruses and the immune system during his years in practice as an infectious disease specialist. This led him to take on immunotherapy as a novel way to combat cancer.

“Immunotherapy is very hot in cancer treatment in recent years, and the field is getting increasingly more interesting,” Zhang says. “If immunotherapy works, it’s the holy grail of cancer treatment. The main problem of current conventional cancer treatment is the unwanted toxicity of radiation and chemotherapy, because it’s not specific enough. By contrast, the immune system is one of the most specific recognition systems. If it works, it can precisely pick out tumor cells and destroy them, with little or no toxicity to normal tissue.”

Disagram of t-cells
The illustration shows the process by which the T-eCAR technology modifies T–cells to specifically target tumor blood vessels.

Zhang explains that the immune system is the body’s natural, built-in defense system. It’s primarily developed to protect against invading pathogens, such as bacteria, viruses and parasites. It also serves to defend against malignant disease. With cancer, however, the immune system seems to struggle. One reason, he says, is because the malignant cells originate from normal cells and look almost identical, so the immune system has difficulty recognizing them. Immunotherapy is designed to help the immune system recognize tumor cells better or make it more effective at responding to and destroying malignant cells.

“The body has a defense mechanism in place that makes it reluctant to launch an attack on itself due to the fear of developing an autoimmune disease, which is brought on by an overreaction of the immune system,” Zhang says. “Since the body considers tumor cells as part of itself, it just tolerates the tumor, which then is free to grow, unhindered, in the body. While under normal circumstances, this reluctance is a good safety mechanism to have in place, it becomes problematic in cancer, causing a person’s immune system to underreact to the malignant cells.”

In recent years, Zhang says there have been two major developments in cancer immunotherapy. Both manipulate T-cells, which are a type of white blood cells that protect the body from infection. The first development has been in checkpoint inhibitors. The immune system depends on multiple checkpoints to avoid developing autoimmune diseases that attack healthy cells. These checkpoints, however, also prevent the immune system’s T-cells from functioning properly against tumors. With checkpoint inhibitors, researchers have developed antibodies to block two major checkpoint molecules that, in turn, free T-cells to attack tumors.

The second approach is to modify T-cells directly, introducing a gene to help the T-cells recognize tumor cells. Unlike the more traditional cancer vaccines that rely on the reluctant body to generate specific T-cells to recognize and attack tumor cells, Zhang’s tactic is to use genetic engineering in combination with gene transduction. By doing this, they instantly convert T-cells into tumor fighters, no longer relying on the body.

“We put ourselves in the driver’s seat by forcing T-cells to fight tumor cells,” Zhang says. “We take the T-cells out and transduce them with a gene, called a chimeric antigen receptor (CAR). The unique CAR we have created is called eCAR. It contains a tiny ingredient called echistatin, the key component for bonding to the cells of tumor blood vessels.”

This eCAR technology modifies T-cells to specifically target tumor blood vessels, which is different from similar mainstream approaches that only recognize and kill tumor cells. The mainstream approaches are a one-to-one situation. While they work well, they need a lot of T-cells to do the job, and this has been proven to be quite challenging from a practical standpoint. Instead of just individual tumor cells, the T-cells Zhang’s team is creating can recognize and destroy tumor blood vessels that affect millions of tumor cells, cutting off the blood supply, which is where their nutrients come from. Without blood supply, the solid tumor cannot grow any bigger and shrinks.

“Unlike other therapies that count on the body to come up with something useful, we convert the T-cells into tumor fighters,” Zhang says. “We give them a guided weapon rather than rely on the T-cell to pick up the weapon.”

Zhang recently formed two biotech companies for translating his group’s research into the clinical arena. With the patent-pending T-eCAR approach now licensed, he expects it to go into clinical trials within a year.

Additionally, he and Bose are working together under a $1.2 million CPRIT grant to combine the T-eCAR immunotherapy with the phosphaplatins chemotherapy. They hope that by destroying the tumor blood vessels with the immunotherapy, they will be able to facilitate the delivery of the chemotherapy to be preferentially delivered into the tumor cell so that the drug level in the tumor will be higher than in the normal cells. This would help them lessen the toxicity of the drug to normal tissue.

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