Scientists in the past few years have gained unprecedented control over how to make the human immune system accelerate, and what causes it to slow or stop. This knowledge has spawned new immunotherapy drugs that are delivering dramatic benefits to some patients with advanced cancers.

It has become possible to treat someone who has stage IV metastatic cancer and halt the cancer – and manage it more like a chronic disease using, for example, Checkpoint blockers, drugs that disable the brakes that cancer cells use to fend off an attack on them by immune system T cells.

But beyond the impressive but limited successes of recent immunotherapy advances lies the potential to bring the strategy to more patients and more kinds of cancer. Knowledge of the powerful immune system’s intricate and complex set of controls remains to be discovered.

Two main questions are-

First, why do some patients with tumors– like melanoma, lung, bladder and kidney – not respond to immunotherapy? Why is it only 20 or 30 or 40 percent? Why don’t all of them respond?
Second, why do some cancers not respond at all, like pancreatic, prostate, ovarian, and breast cancer, glioblastoma, and colon cancer other than patients with Lynch syndrome?”

Despite those unanswered questions, the science behind immunotherapy is far more advanced than it was even a decade ago. For nearly 100 years, since the idea first emerged, efforts to harness the immune defenses as a cancer treatment met with many failures and limited success – even though the immune system, which evolved mainly to combat infectious viruses and bacteria, is capable of eliminating body cells that have become cancerous.

Early strategies focused on stimulating the immune response with vaccines or removing T cells from a patient, “educating” them in the laboratory, and returning them to the body to seek out and destroy cancer cells. But except in a few instances, these measures didn’t spark an effective immune reaction.

Real progress started when it was recognized that the best way to activate the immune system was not by stepping on the gas pedal – but by removing the brakes. Scientists learned that cancer cells evade the immune forces by activating molecular “checkpoints” that both conceal the identity of the cancer cells and switch off the immune response. These natural checkpoints are crucial to health – without them, people would be much more vulnerable to misguided attacks on normal tissue, as in autoimmune diseases like lupus. The role of one of those checkpoints on cancer cells, PDL-1, was identified in 2000 when it was discovered that it partnered with another molecule on T cells, PD-1, to stave off attack by immune T cells. Another checkpoint, CTLA-4, also switches off the immune response. The T cells get exhausted, and go into a state where the tumor is masked from the immune system, or the tumor secretes substances that create a highly immunosuppressive microenvironment around the tumor which prevents killer T cells from invading the tumor, is composed of many kinds of suppressor cells including macrophages, dendritic cells, endothelial cells, and others. Research has identified key molecular signaling pathways in the tumor microenvironment that are hijacked by cancer cells as protection. Currently researchers are exploring strategies for “reprogramming” the environment to boost the immune response against tumors.

The discoveries of checkpoints that allow cancer to escape immune attack rapidly led to the development of “checkpoint blockade” antibody drugs that free T cells to attack and kill cancer cells. A groundbreaking clinical trial showed that ipilimumab (Yervoy), which blocks CTLA-4, could slow advanced melanoma in a significant number of patients and prolong their survival. Several other antibody drugs that block the PD-1/PD-L1 interaction have now been approved, including pembrolizumab (Keytruda), nivolumab (Opdivo), and atezolizumab (Tecentriq). These drugs have found a place in treating non-small cell lung cancer, kidney cancer, bladder cancer, head and neck cancer, and Hodgkin lymphoma, and are being tested in other forms of cancer.

While many other checkpoint blockers are in company pipelines or clinical trials, researchers are exploiting the power of the immune system in other ways.

One approach that has gotten a lot of attention because of some early dramatic successes is CAR T cells. The patient’s T cells are removed and genetically modified in the laboratory to produce special receptors on their surface that recognize a specific protein on tumor cells. Then billions of the CAR T cells are infused into the patient to seek out and destroy the cancer. In some patients with very advanced blood cancers this strategy has had remarkable success, but it also can produce severe side effects that need to be closely managed.

Cancer vaccines continue to intrigue immunologists. Even though there are effective vaccines against the human papilloma virus (HPV), which causes cervical cancer, and some head and neck and anal cancers, only a minority of people at risk have undergone vaccination

Researchers are discovering effective vaccines for non-viral cancers, but the field is still in its infancy. Such vaccines would provoke the immune system to react against proteins displayed on the surface of cancer cells. Ultimately the solution may be a combination therapy, just as it was for HIV/AIDS. The key to turning HIV from a lethal disease to a chronic disease was realizing you have to attack it with several drugs at the same time.

The potential of immuno-oncology is just beginning to be realized. Uncovering more will take both a much more detailed understanding of how the immune response is controlled and the tools or treatments to manipulate it for clinical benefit.