The immune system is now called the “fifth pillar” of cancer therapy. It is the newest, and some say the most promising, of therapies available to patients, which include surgery, radiation, chemotherapy and targeted therapy.
According to Dr. Antoni Ribas, who leads the Parker Institute for Cancer Immunotherapy Center at UCLA and is a professor of medicine in the division of hematology-oncology at UCLA, the key to using the immune system against cancer is understanding more and more about the immune system.
So far, Dr. Ribas has helped test a number of cancer immunotherapy drugs including the anti-PD-1 antibody pembrolizumab — commercialized as Keytruda — to treat advanced melanoma. He was the principal investigator on the trial that tested this agent with 600 patients in the U.S., Europe and Australia, and even though the study was only a Phase I clinical trial (usually placebo-controlled, randomized Phase III trials are needed), the FDA-approved Keytruda as a “breakthrough therapy” in September 2014.
The drug is a so-called checkpoint inhibitor. It joins other recombinant antibodies approved to treat melanoma, lung cancer and kidney cancer.
Cancer induces the errant expression of “checkpoint” proteins (PD-1 in some tumors, CTLA-4 in others) in T cells. PD-1 and CTLA-4 normally are responsible for stopping an immune response, but when induced in the tumor microenvironment, they allow the cancer to “hide” from the immune system. These new recombinant antibodies take the brakes off T cells in the blood and inside tumors so they can more effectively attack the cancer.
Checkpoint inhibitors are changing what defines success thanks to:
In the past, a new cancer therapy was considered to be a success if it prolonged the life of an advanced cancer patient by a few months. Combining checkpoint inhibitors with other agents is expected to offer even more benefits.
Compared to traditional chemotherapy, the newest drugs can also have remarkably few side effects. In fact, some patients don’t notice any toxicity at all. It is expected that there are other cancers where this type of therapy will become a standard of care.
Researchers are also testing other members of the checkpoint inhibitor family, believing that it might be possible to one-day match patients with the inhibitors most likely to act on the proteins expressed by their individual cancers.
“For the cancer patients who are responding to these checkpoint inhibitors, I don’t consider other therapies,” Dr. Ribas says. “Some years ago we had nothing for melanoma. Now we have a choice.”
If there is one focus in many of the transplantation studies underway at UCLA, it is the thymus. The thymus is the gland that sits in front of the heart, in the middle of the lung’s lobes. It educates the adaptive immune system, coaching immune T (“T”hymus) cells to become “warriors” that recognize and kill abnormal cells or invading microbes.
In recent years, it has become clear that a second class of T cells is also created in the thymus that turns off an immune response when needed. Dr. Crooks calls them “peacemakers.” Peacemakers are further trained in the body’s periphery — perhaps the gut, perhaps the lymph nodes — to modulate and downplay an immune reaction. After all, if there were only warriors, we wouldn’t survive for very long due to rampant autoimmunity.
In organ transplantation, doctors tend to suppress the warriors. However, researchers are now trying to train the system better, either at the thymus level or in the periphery, to engage the peacemakers. This is the opposite of cancer immunotherapy, which is designed to disrupt the peacemakers and arm the warriors.
But even these immune-based therapies will not be sufficient for many patients because they require an immune system that still has some gas left after the brakes are released. Patients who have had multiple previous treatments often cannot mount a strong immune response.
Conventional treatments like chemotherapy attack dividing tumor cells, but also stem cells in the bone marrow, which generates all of the cells of the immune system. Natural immunity has been beaten down by continuous cytotoxic chemotherapies. For patients who can only weakly respond, researchers are designing ways to combine a checkpoint inhibitor with a vaccine that strengthens the immune attack.
Working with researchers from other disciplines, UCLA oncologists are also deeply focused on new T cell-based therapies. Investigators are honing a strategy known as adoptive cell transfer that gives cancer patients without a working immune system functional killer T cells.
Here’s how it works:
When put back in the patient through an infusion, their numbers expand even more.
There are several approaches to “building” these cancer-specific T cells. They include:
Circumventing the weaknesses of a patient’s natural immune response by creating that army of specialized T cells is a very promising and exciting new area of tumor immunology at UCLA, with some already using adoptive cell transfer technology in a Phase I clinical trial to treat patients diagnosed with soft-tissue sarcoma and melanoma.
However, sometimes cancer cells do not display any targets that can be recognized by the immune system — even if the system’s brakes are off. So researchers at UCLA Jonsson Comprehensive Cancer Center have induced cancer cells to express targets that are efficiently recognized by T cells. That is, they have placed a target on glioblastoma cancer cells that are normally invisible to the immune system, and then engineered T cells to find that target.
They did this by treating the brain cancer with the chemotherapy drug decitabine, which forced the tumors to express the protein NY-ESO-1 (New York esophageal squamous carcinoma). Decitabine removes inhibitory methyl groups from the DNA of tumors, which then induces the expression of a set of proteins like NY-ESO-1. The T cells are then genetically modified to recognize and attack the NY-ESO-1 targets.
The new method was about 50 percent effective at eliminating glioblastoma in the animal models — a very promising advance. The T cells crossed different fiber tracts in the brain just to reach cancer cells that had migrated away from the main tumor mass. This cannot be done with surgery or chemotherapy today.
One doctor described this as if a fog had lifted from the tumor and the body’s defense forces, newly armed with advanced missiles, could suddenly see the cancer — and destroy it.