Out with the old, in with the new

WEST LAFAYETTE, Ind.—A new approach to treating cancer has the potential to be a universal therapy for solid tumors, according to two Purdue University scientists who jointly developed and tested immune system cells that actually feed the tumor, while blocking other immune system cells from destroying it.

Philip Low, Purdue's Presidential Scholar for Drug Discovery and Ralph C. Corley distinguished professor of chemistry, and Timothy Ratliff, the Robert Wallace Miller director of the Purdue Center for Cancer Research, led this work, which was published recently in Cancer Research.

“The novel aspect of our strategy is that we have targeted a very potent immune system activating drug selectively to tumor associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) within the tumor microenvironment, thereby reprogramming these strongly immunosuppressing cells into potent tumoricidal immune cells,” Low tells DDN. “Importantly, toll like receptor 7 agonists cannot be administered systemically in their nontargeted forms because they would activate all macrophages and T cells in the body and thereby cause a dangerous overstimulation of the immune system that could lead to excessive cytokine release and perhaps autoimmune disease.”

“Not surprisingly, no TLR7 agonist has been approved by the FDA for systemic administration (i.e. only topical application to lesions on the skin are allowed),” he says. “We are therefore the first to overcome this restriction by targeting the TLR7 agonist specifically to TAMs and MDSCs within the tumor microenvironment, where reprogramming and concomitant over-stimulation of immune cells will be highly beneficial.

“We are moving the drug as rapidly as possible towards human clinical trials. We hope to enroll our first patient in either late 2021 or early 2022.”

According to Low, “Our short-term goals are to employ the targeted FA-TLR7 agonist to treat both solid tumors and fibrotic diseases. However, we will have to optimize the formulation of the drug and then run it through preclinical development before we can introduce it into human clinical trials.”

“Because our FA-TLR7 agonist reprograms the immune system in the tumor microenvironment from a tumor-supporting to a tumor-inhibiting phenotype, we have explored the use of our drug to enhance the potencies of other cancer immunotherapies,” he notes, adding that encouraging data from these unpublished studies have indicated that perhaps the most beneficial indication for FA-TLR7 might lie in augmenting other cancer immunotherapies.

Low states that the new treatment is "totally unique" and has been shown to work in six different tumor types. So far, the treatment has been tested in human tumor cells in the laboratory and in human tumors in animal models.

This approach targets immune cells that the body uses to put the brakes on an immune response, he explains—in other situations, after an illness or injury, the body employs these immune suppressor cells to stop the normal healing response in order to prevent the response from careening out of control, just as you would use brakes in a car. But in cancerous tumors, these cells have an unwelcome and disastrous effect: they hit the brakes at the wrong time and stop the body's own defenses from killing the tumor.

"We can reprogram the immune cells within the tumor to help kill the tumor instead of allowing these cells to help the tumor grow," Low comments. "It's just been realized recently that as a global approach to eradicating a solid tumor, we need to also treat the healthy, non-malignant cells in the tumor.”

Low tells DDN that depending on the type of cancer, 30 to 80 percent of the cells in a solid tumor are not cancer cells and are used in normal functions in other tissues.

"The difference—and this is a very important difference—is that after these cells infiltrate a solid tumor mass, they are retrained by the cancer cells to facilitate tumor growth," he points out. 

"But even though the cancer cells are very specific to the type of cancer, so that the treatment for breast cancer is different from the treatment for brain cancer, which is different from the treatment for lung cancer, etc., these nonmalignant cells within the tumor microenvironment are often very similar from one tumor to the next,” Low says. “So a drug that corrects the misbehavior of these nonmalignant cells could be used to treat most solid tumors."

In this technique, an anticancer drug that would normally be too toxic for human use is linked to folate, which is a type of vitamin B. Almost no normal cells have a receptor for the folate.

"We use the vitamin folate to target attached drugs specifically to these nonmalignant cells within a tumor mass that, unfortunately, promote tumor growth,” Low explains. “These tumor-associated macrophages love folate. They have an enormous appetite for it. They take it up right away, and if they don't, the compound passes in the urine within about 30 minutes. So, we're using folate as a kind of Trojan horse to trick the tumor-promoting immune cells into eating a drug that will reprogram them into tumor-fighting immune cells."

Part of the drug development effort will be to ensure that the drug payload, which would be lethal to a patient by itself, is released solely within the tumor-promoting macrophage cells.

According to Ratliff, this treatment may prove to be more universally effective than current cancer immunotherapies.

"There are therapeutic antibodies that are used on some types of cancer,” Ratliff says. “And many people have heard of checkpoint immunotherapies, which block certain parts of the immune response.

“When I talk to groups, I always point out that former President Jimmy Carter had metastatic brain cancer, and he went through immunotherapy, and it eliminated the cancer for him. But the problem is, only about 20 percent of the patients actually respond. So, we need to take a different approach to modulating the immune response."

The folate-targeted approach is exciting, as per Ratliff, because it is the first research project that has found a way to target the cells that boost tumor growth in the tumor environment.

"These are cells that are important to the tumors, but they aren't the tumor cells themselves," he stated. "By targeting these myeloid cells within the tumor, we have a universal process because these cells are present in all of the solid tumors."

Ratliff noted that getting a therapy like this to market usually takes a decade, but “I think there's a reasonable chance this could make it to the public within seven years or something like that. It would probably cost a couple hundred million dollars, at the very least, to develop and test this drug. 

“It's not going to be cheap, and it's not going to be easy, but this drug has enormous potential to save many lives. So, we will do our best."