Nobel Prize 2018 elevates awareness of immunotherapy research

Nobel Prize 2018 elevates awareness of immunotherapy research

December 10, 2018

  • Checkpoint inhibitors, a crucial weapon in the anti-cancer arsenal of immunotherapy, were discovered by Tasuku Honjo and James P. Allison. The pair was recently awarded the Nobel Prize for this revolutionary advance. This graphic shows the basics of the process.

    Checkpoints are binding sites that allow the body to regulate the behavior of T-cells. These warriors of the immune system can be switched on to combat disease but must be capable of being switched off to avoid damage from autoimmunity.

    Cancer cells are able to exploit this delicate system, turning off T-cells at their immune checkpoints (left). But new drugs are now being used to occupy checkpoint binding sites, preventing cancer cells from switching off T-cell activity (right). The T-cells, freed of their restraint, can now aggressively attack the cancer.

    Graphic by Shireen Dooling


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  • Joe Blattman is a researcher in the Biodesign Center for Immunotherapy, Vaccines and Virotherapy


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  • Grant McFadden is the director of the Biodesign Center for Immunotherapy, Vaccines and Virotherapy


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  • Stephen Albert Johnston is the director for the Center for Innovations in Medicine at The Biodesign Institute and a professor in the School of Life Sciences, 


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  • Karen Anderson is a medical oncologist and an associate professor of medicine at Mayo Clinic Arizona and a researcher in the Biodesign Virginia G. Piper Center for Personalized Diagnostics


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December 10, 2018

Researchers at the Biodesign Institute are searching for new ways to diagnose, treat – and even cure – cancer patients using processes related to immunotherapy. According to the National Cancer Institute, immunotherapy is “a type of therapy that uses substances to stimulate or suppress the immune system to help the body fight cancer, infection, and other diseases.”

The burgeoning field of immunotherapy was recently recognized at the highest level with the announcement of the 2018 Nobel Prize in Physiology or Medicine. Tasuku Honjo of Kyoto University and James P. Allison of the University of Texas MD Anderson Cancer Center, two pioneers in the field, were awarded for their discovery of checkpoint inhibitors, chemicals that essentially release the brakes on the immune system in order to strengthen the body’s own cancer-fighting ability.

Biologists, virologists and oncologists at the Biodesign Institute are also in hot pursuit of new ways to stimulate the body’s immune system in order to subdue cancer, one of the greatest health challenges facing humanity today. For patients who have not experienced success with other forms of cancer treatment, immunotherapy offers new hope for survival.

Interest in immunotherapy can be traced to the 19th century, as earlier scientists looked for ways to activate stronger immune responses in their cancer patients. Lacking a deep enough understanding of immune complexities, however, researchers lost interest in the field until promising discoveries were made in the latter half of the 20th century.

It was in the 1990s when Honjo and Allison independently discovered separate protein mechanisms that revolutionized how scientists can influence cell interactions and immune responses. In 1992, Honjo discovered PD-1 in Japan. CTLA-4’s cancer fighting inhibitory abilities were proven four years later by Allison while working at the University of California at Berkeley. They demonstrated that blocking these specific proteins were able to open the floodgates for an immune response to cancer. Their work has inspired researchers around the world to follow suit, identifying even more ways to fight off and shrink tumors.

But inducing the correct response level in patients is a delicate and costly balancing act. An issue that can occur within the body is the overabundance of white blood cells that attack the cancer. These T cells can clog arteries, damage organs or activate an autoimmune disease if they become too abundant or over-active. Treatment may not be effective in all patients or types of cancers, and new ways are being investigated to induce more patients to respond to immunotherapies.

Biodesign researchers like Joseph Blattman, Grant McFadden, Stephen Albert Johnston and Karen Anderson are taking on the challenges and opportunities that immunotherapy offers.

Driving immune responses

Blattman is an expert in T cell immune responses. He analyzes how the body can activate or deactivate different immune responses in order to best recognize cancerous cells and attack them.

“My research studies how you can understand the rules of the immune system so that you can manipulate them and fool the immune system into responding to cancer when it normally doesn't,” Blattman, a researcher in the Biodesign Center for Immunotherapy, Vaccines and Virotherapy, said.

One of Blattman’s “aha” moments came during his graduate studies, when he determined that T cells can become exhausted.

 “There were dots on the screen. Where dots were displayed, that meant there were still cells there, but they were turned off. To realize that the cells were still in place, but had just exhausted themselves, that was a big moment,” Blattman said.

The implication of this discovery meant that it could be possible to re-energize these cells, or get players back in the game, rather than adding new cells to the mix. This reduces the likelihood of a dangerous and overwhelming cascade effect from the immune system.

Although Blattman doesn’t work directly with patients, he enjoys hearing successful reports from the Phoenix Children’s Hospital and feels rewarded by knowing that his research can save lives for young osteosarcoma patients, who typically must undergo amputation surgeries in order to defeat their cancers.

Blattman’s related work profiling unique cells in cancer progressions resulted in a startup company, Gemneo, which is ASU’s 100th spin-off.

Blattman is clearly driven to pursue answers to this vexing disease. “As we've gotten more into the immunotherapy side of things, I do know that if I don't show up to work, that's one fewer person that I can have any effect on,” he said. “There's one other person that could die. Knowing that drives you.”

Going viral

Grant McFadden, director of the Biodesign Center for Immunotherapy, Vaccines and Virotherapy, focuses on how viruses interact with the immune system. He is also starting to develop human clinical trials that use virotherapy to improve stem cell transplantation therapies for cancer, and hopefully improve how immunotherapies work in more cancer patients.

“Virotherapy is based on the premise that some viruses like to grow better in cancer cells than normal cells. If you put it into a host or a tumor bed within the host, the virus will grow and kill cancer cells in a way that can help stimulate immune responses against the cancer,” he said.

However, there are logistical challenges to deliver viruses to hard-to-reach cancers. Scientists are now focusing on using harmless viruses to alert the immune system to the presence of tumors. By essentially waving a flag and signaling that the body should react, the virus can make a cold tumor turn hot and appear on the immune system’s radar.

“When that happens, everyone is a winner, but you need both immunotherapy and virotherapy to accomplish it,” said McFadden.

McFadden’s lab works with a virus in the poxvirus family called myxoma. Myxoma is non-fatal and harmless in almost all species, except rabbits. It can have a similar killing effect on human cancerous cells but the virus is harmless in people unless they carry cancer cells that allow the virus to grow.

“About 15 years ago, our lab stumbled upon the fact that if you put this virus into a tumor bed, it operationally behaves as it does in a rabbit, where it infects, kills and spreads from cell to cell. But when it gets to the normal cells in normal tissues, it stops. It can't replicate in those,” McFadden said.

With the launch of his new ASU startup company, OncoMyx, McFadden is moving toward making his technology commercially available and launch clinical trials in cancer patients, including those who do not respond to immunotherapy alone.

Vaccinating against cancer

Stephen Albert Johnston, director for the Center for Innovations in Medicine at The Biodesign Institute and a professor in the School of Life Sciences, and his team have developed and new type of peptide array that detects antibody responses to neoantigens in the tumor using only a small amount of blood.  Neoantigens are the basis for the patient’s response to immunotherapeutics and the components of personal cancer vaccines

Johnston’s team has shown that these arrays have the potential to detect can early as a diagnostic.  In collaboration with MD Anderson they are applying the arrays to prediction of the response of patients to immunotherapeutic treatment.  Initial data supports that the arrays can be used to predict response to therapy and adverse events.  

 “Our diagnostic system has the advantages of not requiring tumor tissue to DNA sequence and the same array can be used for any application” Johnston says.

The arrays are also the basis for designing therapeutic and preventative vaccines. The neoantigens that react with antibodies on the arrays have been shown to be good vaccines in mice.  By screening hundreds of patient samples, Johnston and his team have designed therapeutic vaccines for major cancers in humans and will be initiating clinical trials next year. They have even produced a vaccine they predict could prevent cancer in the first place. They are testing this in a large trial in dogs.

Working with patience

Karen Anderson is a physician researcher who also runs a busy oncology practice at the Mayo Clinic.

Her work involves finding various biomarkers that can signal the presence of cancer early on in the body. By looking at these biomarkers, Anderson can develop diagnostic and prognostic tools that can alert patients to health concerns.

Timeliness is an essential component for physicians to provide optimal results. Matching patients to the most beneficial therapies as soon as possible leads to increased rates of remission and survival.

“We don’t really understand why some people respond to immunotherapy and why some people don’t,” Anderson said. “These are very expensive therapies, so we need ways of knowing who’s going to respond and how to tailor your therapy to them.”

Doctors are now exploring ways to combine cancer-fighting methods to increase efficacy, by pairing virotherapy with immunotherapy or using chemotherapy to activate local immune responses.

Car-T therapy has been an early and powerful approach for clearing leukemia. Inserting T cells that are specifically directed and designed to fight leukemia has provided “mind-blowing” results in children.

Other uses and applications within the field of immunotherapy include clearing oncogenic viruses such as HPV, developing vaccines to prevent cancer reoccurrences or to enhance other therapies, or to deal with preventative issues and pre-cursors to cancer.

“The Nobel Prize was about one particular pair of gatekeepers in immunotherapy,” Anderson said. “But as a result, we now have therapies to deal with this.”

“There’s no question that having diversity in your therapy improves the efficacy. If you only target one thing, there’s a greater chance of evasion for the cancer. The immune system is built to fight a diverse set of problems,” she said.

Evasion is a fundamental mechanism of all cancers, which must avoid being targeted by the immune system in order to grow and survive.

“It’s fascinating because these cancers have to grow up next to an immune system that’s capable of seeing them,” Anderson said. “They evolved to hide and cloak themselves.”

But the science of oncology is also rapidly evolving and developing more solutions than ever before by using the body’s own immune mechanisms.

“It’s an incredible system,” Anderson said. “The idea that we can harness it and go after anything is very powerful.”

 

Written by: Sabine Galvis