10 years of immunotherapy brings new treatment options, new challenges

A lot can happen in 10 years. And in the world of immunotherapy to treat cancer, a lot has. But in a “what have you done for me lately” world, the question is what may immunotherapy do in the coming years to help cancer patients?

Consider the dramatic changes and advancements that have occurred in your world over the past 10 years. Your phone is now a powerful computer and camera. Maybe you have a voice-activated digital assistant at home to play music, manage home security or control your lights and appliances. Oh, and your child or grandchild born in 2010 is now in fifth grade. A lot can happen in 10 years. And in the world of immunotherapy to treat cancer, a lot has. Since 2010, new immunotherapy treatments have changed the direction of cancer care. The first cancer-specific vaccine was developed. Re-engineered T-cells, or CAR T-cells, are now a treatment option for several blood cancers. Drugs called checkpoint inhibitors may now be used to treat more than a dozen cancers.

“Immunotherapy, and specifically checkpoint inhibitors, have had a remarkably impressive, positive impact on clinical outcomes in an ever-increasing number of clinical settings, specifically in metastatic non-small cell lung cancer and melanoma,” says Maurie Markman, MD, President of Medicine & Science for City of Hope. “CAR-T therapy has had a major favorable survival impact in the management of a limited group of hematologic malignancies.”

But in a “what have you done for me lately” world, the question is not what has immunotherapy done to advance cancer care in the past 10 years, but what may it do in the coming years to help produce positive outcomes for cancer patients?

What is immunotherapy?

The concept of immunotherapy isn’t new. In the 1890s, a physician named William Coley began exploring ways to use viruses to jumpstart the immune system to fight cancer. While his methods then were crude, he set the groundwork for much of the cancer immunotherapy research and treatments of today. Cancer cells are the body’s own cells that have mutated and are growing out of control. Because the cells are native to the host, the immune system may not recognize them as harmful. Immunotherapy is a type of precision cancer treatment designed to do some or all of the following:

  • Activate or energize dormant or exhausted T-cells
  • Disrupt chemical signals cancer cells use to evade the immune system
  • Help the immune system better recognize cancer cells as harmful
  • Attract immune cells to a specific location in the body
  • Re-engineer T-cells so they attack specific cells

Learn more about precision medicine.

What does the future hold?

In 2015, former President Jimmy Carter announced that doctors found no evidence of his metastatic melanoma after his treatment with radiation therapy and a checkpoint inhibitor. The news telecast immunotherapy’s promise to the masses. “Everybody wants immunotherapy,” says Arturo, Loaiza-Bonilla, MD, Vice Chair of the Department of Medical Oncology at CTCA®. “Patients often ask about it.” But immunotherapy has its limitations. For one, the treatment is not approved for all cancers or all types or subtypes of cancer. A checkpoint inhibitor, for example, may be an option for patients with colorectal cancer with specific genetic features, but not for other types of colorectal cancer. Also, immunotherapy may work dramatically different in two patients with the same type of cancer. Checkpoint inhibitors, specifically, do not always work in patients with cancers for which the drugs are approved.

Still, immunotherapy has produced positive outcomes in many patients with historically difficult-to-treat cancers, such as melanoma. So, if immunotherapy has revolutionized cancer care over the past 10 years, what developments are been envisioned for the next 10 years?

Types of immunotherapy
Vaccines: There are two types of cancer vaccines: those that attack viruses that may increase the risk of cancer and those that stimulate an immune response to a known cancer.
Cytokines: These are naturally occurring proteins that send messages to the immune system to launch an attack. In cancer care, cytokines are made in a lab and injected in larger amounts than the body would normally produce.
Checkpoint inhibitors: These drugs block certain receptors that cancer cells and immune cells use to exchange signals. When the signals are blocked, the immune system may better recognize the cancer cells as harmful and attack them.
CAR T-cell therapy: Chimeric antigen receptor T-cells are immune cells removed from the body and re-engineered to recognize and attack certain cancer cells.

Finding working combinations

If one immunotherapy drug produces a positive outcome, could two such drugs produce a better outcome? If one cancer treatment shows results, might two show better results? Some research suggests they may. Doctors and researchers have discovered that combining checkpoint inhibitors that target different receptors may energize the immune system more than a single drug that targets one receptor. Combinations of immunotherapy drugs already are approved to treat specific types of melanoma and other cancers.

Now researchers are looking at ways to combine immunotherapy drugs with chemotherapy, targeted therapy and radiation therapy to treat specific cancers. For instance, research in ovarian cancer shows that combining a checkpoint inhibitor with a targeted therapy drug called a PARP inhibitor may have more potential than using just one of the therapies. PARP—poly (ADP-ribose) polymerase—is a protein that helps DNA in damaged cells repair itself. Drugs that inhibit PARP prevent DNA repairs in those cells, often leading to cell death.

New checkpoints, new targets, new cancers

Currently, checkpoint inhibitor drugs are designed to seek out two targets: the CTLA-4 receptor and the PD-1/PD-L1 pathway. But cancer cells and immune cells have other receptors that may also be targets for immunotherapy. Research is continuing on TIM-3 (T-cell immunoglobulin and mucin-domain containing-3), a potential immunotherapy target found on immune cells. Chinese researchers suggest that combining a TIM-3 blockade along with one that targets PD-1 may produce a desired response.

“A growing body of evidence supports the relevance of targeting Tim-3 in human cancer. It is now well established that Tim-3 along with PD-1 marks dysfunctional T cells in multiple cancer types,” the researchers wrote. “Tim-3 blockade may also induce an anti-tumor immune response and mediate tumor regression in situations where anti-PD-1 or anti-CTLA4 does not work, such as in colorectal carcinomas.”

Scientists at The University of Texas MD Anderson Cancer Center are researching a potential immunotherapy target called VISTA, which has been found on immune cells in pancreatic tumors, among the most difficult cancers to treat. Dr. Bonilla also is involved in ongoing research into the use of checkpoint inhibitors to treat pancreatic cancers with high tumor mutational burden (TMB), which are tumors that have multiple cell mutations.

Reigning in side effects

The immune system is a potentially powerful tool to identify and attack cancer cells. But sometimes it doesn’t know when to stop. When immunotherapy is used to treat cancer, the side effects of an empowered immune system may be severe. CAR T-cell therapy, for instance, may trigger a condition known as cytokine release syndrome (CRS), which may be life-threatening. Cytokines are proteins that help regulate the immune system. CAR T-cell therapy patients may be flooded with cytokines that begin to attack healthy cells, resulting in a variety of difficult flu-like side-effects, such as high fever, neurological side effects and other serious conditions.

The FDA requires hospitals that use CAR T-cell therapy to have staff certified and trained to recognize and manage CRS. CAR T-cells may also attack healthy B-cells, increasing the risk of infections in some patients. The use of checkpoint inhibitors may induce side effects in patients similar to autoimmune diseases, such as colitis. The National Comprehensive Cancer Network and the American Society of Clinical Oncology have combined to create a series of guidelines to help doctors and patients better understand potential side effects and ways to treat them.

Immunotherapy timeline

While the concept is not new, the speed with which new therapies are being developed and have been approved to treat an increasing number of cancers has accelerated in the past 10 years.

August 2010: The FDA approved the first vaccine specifically developed for the treatment of cancer. Sipuleucel-T (Provenge®) may be a treatment option for certain cases of advanced prostate cancer.

March 2011: The FDA approved ipilimumab (Yervoy®) to treat patients with metastatic melanoma. It is the first checkpoint inhibitor immunotherapy drug approved by the FDA. Ipilimumab blocks the CTLA-4 checkpoint receptor on cancer cells, allowing the immune system to better recognize and attack cancer cells.

September, December 2014: Two new checkpoint inhibitors—pembrolizumab (Keytruda®) and nivolumab (Opdivo®)—got FDA approval to treat advanced melanoma. Unlike ipilimumab, these drugs target PD-1 checkpoint receptors to unleash an immune response.

October 2015: The FDA approved the first oncolytic virus therapy, T-Vec (Imlygic®), for patients with melanoma. Oncolytic virus therapy uses modified viruses—in this case, the herpes virus—to generate an immune response.

May 2017: The FDA approved pembrolizumab to treat advanced solid tumors that have the genetic features, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). This is the FDA’s first “site-agnostic” approval based not on where in the body the cancer is believed to have originated, but rather on the cancer’s specific genetic feature.

August, October 2017: The first CAR T-cell therapy was approved for young adult patients with acute lymphoblastic leukemia. Chimeric antigen receptor T-cells are the body’s own immune cells that have been re-engineered to recognize and attack cancer cells. Later, a second CAR T-cell therapy was approved to treat certain cases of non-Hodgkin lymphoma.

May 2016-September 2018: Four more checkpoint inhibitors were approved to treat a variety of cancers, including lung cancer, squamous cell carcinomas and bladder cancer.

Learn more about how immunotherapy may help elderly patients.