The Pelotonia Institute for Immuno-Oncology (PIIO) at the OSUCCC – James is just getting started, but founding director Zihai Li, MD, PhD, is excited about its potential contributions to a burgeoning discipline that may hold the keys to controlling cancer.
Li’s confidence in the promise of the PIIO hinges on his belief that immunotherapy, with much refinement, could become another standard treatment modality for cancer along with the more traditional modalities of surgery, systemic therapies (e.g., chemotherapy and hormonal therapy), precision or targeted therapies, and radiation therapy.
Whereas those are innovations of modern medical science, Li says, immunotherapy derives from an ancient gift of nature: the human immune system — perhaps lending ultimate importance to this modality, which is widely considered to be the next frontier of cancer prevention and treatment.
“For however many years human beings have been walking on the planet,” he explains, “our immune system has been with us; without it we wouldn’t survive as a species.”
Historically, Li says, humans have viewed the immune system primarily as a natural means of fighting infection, but over the past several decades medical scientists have increasingly explored the concept of exploiting its potential against cancer. And recent advances, he adds, have brought immunooncology to the forefront of cancer research.
“Immuno-oncology as a discipline started seriously in the 1950s when people were becoming convinced about the power of vaccines to deal with infectious diseases,” Li says. “So the question was, can cancer be dealt with similarly?”
With the development of genetically similar animals (in-bred rodents) for vaccine experimentation, he says, scientists learned that they could induce immunity against cancer. “That was interesting, and it conceptually began giving people confidence in the possibility of immunotherapeutic care for cancer, but many were still skeptical,” Li says.
In succeeding decades, he continues, other forms of cancer treatment that could be considered immunotherapy arose, such as bone marrow transplantation and cytokine therapy.
“But it wasn’t until the early 1990s — so recently — that we were finally able to isolate human T cells that recognized tumors,” Li says. “This was a breakthrough in our understanding that the immune system could indeed recognize cancer.”
Additional developments followed, such as the discovery of co-stimulation signals that can activate the immune system, and the identification of co-inhibitory signals, or so-called immune checkpoints like the programmed cell death protein 1 (PD-1) that can serve as a brake to the immune response against cancer in the tumor microenvironment.
“Now we had three immunity signals: tumor recognition, co-stimulation and co-inhibitory signals that constrain the immune system,” Li says. “Then people started to experiment: What would happen if we removed this inhibitory signal, this checkpoint? We did, and suddenly the immune system started to attack the tumor. Those discoveries and many others have led us to where we are today.”
And where we are today, he says, is at the threshold of the next frontier in cancer research: immuno-oncology, to which he has devoted his career.
“We finally realize that what keeps patients alive for a long time, meaning cure, is not about how good are surgery, chemo or radiation therapy, but how good is our immune system,” Li says. “Those other modalities are very important and help manage cancer, but it’s really the immune system that ultimately takes care of everything. It comes down to your own body’s defense. Without the immune system, we couldn’t talk about cure.”
Hence the importance of the PIIO, which is committed to studying the immune system and optimizing its potential.
Li, a renowned medical oncologist and immunologist with primary research interests in the mechanisms of immune regulation in cancer, says being recruited to Ohio State from the Medical University of South Carolina (MUSC) last April to establish and direct the institute “is a dream come true. You are doing something that’s so important, something you’ve been working on for many years, something you can keep contributing to. It’s hard to describe how excited I am.”
The PIIO — a comprehensive bench-to-bedside research initiative focused on harnessing the human immune system to fight cancer at all levels, from prevention to treatment and survivorship — was launched last summer through a pledge of $102,265,000 from Pelotonia, an annual grassroots cycling event that raises money for cancer research at the OSUCCC – James. The largest portion of the pledge, $65 million, will directly fund the PIIO. The OSUCCC – James is also supporting it with a $35 million commitment to expand and sustain research infrastructure.
Plans call for hiring 30-35 scientists over the next five years to support the PIIO. Li says the number of new recruits is already approaching 10, “and I’m negotiating with others, hoping to convince them to join us soon.”
PIIO investigators will work in five centers being established within the institute: Immunogenomics, Synthetic Immunology, Systems Immunology, Translational Immunology and Cancer Microbiome. Their studies, along with work by OSUCCC – James scientists who had been conducting immunotherapy research before Li’s arrival, will contribute to what Li and others consider to be the main types of immunotherapy:
- Monoclonal antibodies (drugs that attach to cell targets and create an immune response that destroys cancer cells);
- Cytokine therapy (increases a patient’s cytokines, or the protein molecules that help the immune system bolster its defense against cancer);
- Adoptive cell transfer (removing T cells from a tumor or blood, reproducing or altering them in a lab and returning them to stimulate the immune system);
- CAR T-cell therapy (a type of adoptive cell transfer that involves genetically improving a patient’s white blood cells with protein “receptors” that recognize and eliminate abnormal cells);
- Vaccines (biological preparations that protect the body from cancer recurrence or help the immune system destroy antigens within abnormal cells);
- Drug therapy (administering agents that block mechanisms that enable cancer cells to hide from the immune system).
Li believes cancer patients and their families, not to mention the medical community, should share his excitement for immunotherapy.
“In the past five years we have seen extraordinary results of immunotherapy for several deadly cancer types, including lung cancer, melanoma, leukemia and others,” he says. “For patients with stage IV lung cancer, median survival three years ago was four to six months. Now, with immunotherapy, some 20% of patients can live for five years. That’s an incredible number, even though it’s still small and not nearly enough.”
But even with the recent advances in immuno-oncology and the addition of substantial resources devoted to advancing it further, Li and colleagues realize there are “still many remaining critical unanswered questions” regarding this modality.
“The most important one is how to improve efficacy,” he says. “Why do only 10-20% of patients benefit from current immunotherapies overall? That implies that there are other mechanisms of immune escape or evasion that we need to learn about.”
As an example of a current immunotherapy with limited efficacy he cited PD-1, a checkpoint protein on T cells, which are immune cells that help the body recognize abnormal cells and disease. PD-1 normally acts as an “off switch” that keeps T cells from attacking other cells. PD-1 inhibitors are monoclonal antibodies that are used in oncology to selectively block this protein and boost immune response to attack cancer cells. But some cancer patients do not respond to PD-1 therapy because their fighter T cells (known as CD8 T cells) are unable to invade the tumor microenvironment.
In a recent study published in the Journal of Clinical Investigation, Yiping Yang, MD, PhD, who directs the Division of Hematology at Ohio State and is a researcher in both the PIIO and the OSUCCC – James, identified cellular mechanisms that limit the ability of CD8 T cells to infiltrate the tumor microenvironment. By blocking that cellular pathway (called hedgehog signaling), the researchers reversed the process and promoted CD8 T cell infiltration in preclinical models of liver and lung cancer.
“This is an important discovery with the potential to significantly enhance the efficacy of PD-1 therapy and guide new immunotherapeutic strategies in cancer,” Yang says. The researchers plan to conduct phase I clinical trials using combination strategies in PD-1 and hedgehog inhibitors for patients with lung and liver cancers.
Li sees this kind of work as central to the PIIO. “We need to better understand other obstacles for immunotherapy as well and figure out ways to block them so we can apply different strategies to patients who don’t respond well to PD-1 therapy,” he says.
Besides improving efficacy, he adds, another immuno-oncology problem that must be resolved involves resistance to therapy. “There are some patients who respond initially to immunotherapy and later lose responsiveness,” Li adds. “We need to learn about mechanisms of resistance and how to overcome them.”
Still other problems to be tackled, he adds, are managing immune-related side effects and determining whether immunotherapy can be more effective as initial therapy.
“At this point we often give immunotherapy for patients with metastatic disease almost as a last resort,” Li explains. “Could it be more effective if we give it for early-stage cancer? Can we incorporate it into standard practice in a smarter way?
“Right now the usual order of treatment is surgery followed by chemo, radiation and then immunotherapy,” he says. “How can we make immunotherapy a front-line modality? Can we sequence patient care in a way that’s guided by science? And could we one day generate immune strategy to prevent cancer from developing in the first place? Cancer vaccines are currently used to prevent recurrence, but I think eventually we can develop them to help prevent initial carcinogenesis.
“Sometimes things that seemed impossible yesterday are possible now. But the only way to answer our questions and continue advancing this discipline is through research and clinical trials. That’s the mission of the PIIO.”
Although still in its infancy, Li says, the PIIO is pursuing partnerships with pharmaceutical companies like Bristol-Myers Squibb, Pfizer, GlaxoSmithKline (GSK) and others, as well as with other academic medical centers. “And maybe it’s time to form a national alliance,” he adds. “I think we all need to work together to share our knowledge and determine the best ways to go forward.”
At any rate, he is happy to lead an institute that he says has “joined the global force of immuno-oncologists to make a difference.”
“When you have an ambitious goal such as we have, you need to back it up with resources and intense research so you can accelerate discovery,” Li says. “Discoveries will be made here. Rather than sit in Columbus and wait for others to make them, we will be on the front line of making major discoveries and translating them to clinical practice. We’re not going to sit still. We have to push ahead.”