Natural Born Cancer Killers

Emily BurkeCancer, CAR-T, FDA, Immunotherapy, The WEEKLY

Further Down the Cancer Treatment Road with CARs

This past August, to much fanfare, the FDA approved the first chimeric antigen receptor (CAR) T-cell therapy for blood cancer. Called Kymriah (Novartis), it promises to revolutionize treatment by genetically altering a patient’s own cells to fight cancer. Less than eight weeks later, Kite Pharma, now a part of Gilead Sciences (Foster City, CA), had its new CAR T-cell therapy, Yescarta approved as well.

Meanwhile, biotech companies continue to push the boundaries of immunotherapy by creating engineered immune cells.

A CAR That Does What?

But first, what exactly is a chimeric antigen receptor? CARs are manufactured proteins that molecular biologists and others engineer to appear on the surface of a white blood cell such as a killer T-cell. This new, revved-up receptor then targets the white blood cell to attack cancer cells.

A CAR consists of:

  • Targeting domain: This part of the CAR exists outside the white blood cell. It is composed of an antibody that recognizes and docks onto a specific cancer surface protein.
  • Activation domain: This component kicks into gear once the targeting domain locks onto the intended cancer surface protein. In CAR-T cells, the activation domain signals T-cells to do three things: 1) make copies of themselves; 2) release signaling molecules called cytokines (proteins that prompt other white blood cells to attack the tumor); and 3) finally—the really good bit– kill cancer cells.

Need reminding how CAR-T cells work? Check out our WEEKLY on the topic.

Natural Born Killers

Our immune system inherently includes NK (natural killer) cells. They are the body’s first responders. At the first sign of illness, NK cells attack the infection for two reasons. First, pathogens lack surface proteins called MHC1 that the body identifies as normal. Second, the presence of abnormal proteins tells the body that the invader poses a threat.

Many immunologists believe that prompt action by NK cells helps eliminate cancer cells early on– before they grow into a serious problem. However, in the early stages of tumor development, there are often not enough red flags – abnormal proteins on the cancer cell surface – to tag them as dangerous. Engineering NK cells to display a CAR “trains” them to recognize and respond to tumor cells. Once activated, the CAR-NKs behave much like killer T-cells, releasing cytokines that bolster the immune response to the cancer cells–killing the nasty cells by injecting even nastier toxins.

Homegrown Isn’t Always Best

CAR-NK cells have two important advantages over CAR-T cells: safety and accessibility. CAR-T cells must come from the patient’s own T-cells to avoid triggering graft-versus-host-disease (GVHD). This potentially deadly illness occurs when the patient’s immune system responds badly to foreign tissue. Donor NK cells, in contrast, don’t appear to cause GVHD.

Besides avoiding potentially life-threatening reactions in already very ill patients, medical professionals can obtain donor NK cells relatively easily—for example, from umbilical cord blood. Labs modify these donor cells to express a CAR, which can then be given to the patient. Removing and engineering a patient’s own T-cells, then transfusing them back into the patient is much more time-consuming. The ability to more easily use donor NK cells means that biotech companies can create “off-the-shelf” products for this type of CAR therapy more readily. In addition, the resulting lower production costs mean more available treatments.

Test-Driving CAR-NKs

This past June, scientists at the MD Anderson Cancer Center (Houston, TX) started a Phase I/II trial of CAR-NK cells. The research focuses on patients with chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), or non-Hodgkin lymphoma. The trial cells contain a “suicide” gene that is triggered by excessive inflammation. Researchers hope this built-in safety feature will reduce problems caused by overactive immune responses in patients from earlier trials of CAR-T cells.

Researchers elsewhere are also looking into the development of CAR-NK cells that treat other cancers—specifically targeting the HER2 protein in breast and ovarian cancers.

Chowing Down on Disease

Of course, NKs, modified or otherwise, aren’t the only white blood cells going toe-to-toe with cancer. Another approach involves the immune system’s scavengers or macrophages. “Macrophage” comes from Greek, meaning “big eater.” These cells kill invading or diseased cells by surrounding and digesting them. Leftover fragments of the alien cell’s proteins or antigens are displayed on the macrophage’s surface. These leftovers help activate some of the immune system’s other defenses, such as killer T-cells.

Mmm…Cancer?

Researchers are now exploring the potential power of CAR-macrophages to destroy specific cancer cells. The enhanced macrophages will simultaneously activate other immune cells to also recognize and attack those same antigen-bearing cells. Like other macrophages, CAR-macrophages can penetrate solid tumors much more effectively than “plain old” T-cells.

If a typical T-cell does make it into a solid tumor, the cancer’s own defenses makes short work of it. In contrast, by modifying macrophages to treat solid tumors, doctors may be able to effectively get at cells inside the tumor. At the same time, the super-powered macrophages will “wake up” the patient’s suppressed T-cells to fight the cancer as well.

Preclinical data from CARMA Therapeutics (Philadelphia, PA) shows that its scientists can modify CAR-macrophages to recognize and engulf different types of solid tumor cells. They’ve also demonstrated that infusing cancerous mice with tumor-specific CAR-macrophages leads to long-term tumor control and longer survival. CARMA plans to begin clinical testing the effect of CAR-macrophages on specific ovarian cancers in 2019.

As biotech companies continue to translate these new applications of CAR into treatments, both patients and doctors can look forward to seeing an increase in the number of different types of cancer that respond to these cutting-edge immunotherapies.