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Priming Immune System Prior to Surgery May Improve Outcomes

Neff Newitt, Valerie

doi: 10.1097/01.COT.0000544335.47378.6d
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Tina Cascone, MD, PhD, traded life in her beloved native Italy for an opportunity to battle cancer on a grand scale at The University of Texas MD Anderson Cancer Center in Houston. An assistant professor and physician-scientist in thoracic medical oncology, her research aims to discover how lung cancers become resistant to immunotherapy and develop strategies for overcoming such resistance.

Cascone was born in Matera in southern Italy, also the region of her mother's birth; her father had been born not too far from the famed Amalfi coast. “My heart is split between the two places,” said Cascone who recalled having been “a simple and very happy girl growing up—and always ambitious to help people and make an impact for the well-being of the community.” She loved science studies in high school and found joy in the process of discovery and learning how things worked.

“I had a wonderful science teacher who once told me, ‘You will be a scientist one day.’ He made an impact on me and gave me confidence to step out of my comfort zone and expand myself.”

As a young woman, Cascone also was propelled toward oncology because of family history that included loss to disease. “No matter what we do or who we are, all of us have been affected by cancer. When someone had cancer I thought, ‘How does he or she feel? How do other family members feel?’ And yet there was nothing I could do about it. I wanted to be able to actually do something.”

She also questioned how it was possible that cancer could just start generating in the body and that mutations in the genes could lead to cancer.

“I was fortunate to have a mentor in medical school, the Second University of Naples (now named University of Campania Luigi Vanvitelli), who had gone abroad, studied at the NIH in the U.S., and trained me to similarly challenge myself to grasp new opportunities, learn new things, and explore what I could do with my ideas.”

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Accepting the Challenge

Having graduated medical school and started her first year of oncology training in Italy, Cascone learned of a research lab at MD Anderson recruiting physician scientists in training, so she applied for—and got—a position.

“My English was minimal; it was hard. But it was exactly the challenge I needed,” she noted. “I knew I wanted to be a good physician, but for me there could be no medicine without science. The two things could not be separated. I felt I could not make progress and move the field of oncology forward without studying the mechanisms of disease at the molecular level.”

So Cascone started asking questions. Specifically, she wondered how and why lung cancer becomes resistant or is naturally refractory to a particular type of therapy.

“My interest in science has evolved since I started because of the different types of therapies that we have in our pipeline to treat cancer,” she clarified. “Right now, I am trying to understand how I can help the immune system to better recognize cancer cells and destroy them.”

Unfortunately, so many patients do not respond to the therapies available in the clinic, including immunotherapy, said Cascone, noting her primary focus as a physician scientist is to understand how molecular basis of disease allows cancer resistance and to develop more effective treatment strategies.

Cascone and her team study the biology of human samples in the context of clinical trials (“... we enroll patients on number of different treatments and see the effects of these treatments in the patient samples...”) and study animal models to understand the molecular mechanisms that mediate resistance to therapy.

“We use genomic and transcriptomic sequencing, immunohistochemistry, and flow cytometry to understand the tumor alterations and the changes in the tumor microenvironment that might affect the response to therapy,” explained Cascone. “I study how different treatments can alter the immune microenvironment and cause immune cells to lose their ability to fight cancer. We are trying to understand what changes are occurring that may cause a patient to become resistant or unresponsive to immunotherapy.”

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Priming the Immune System

In her research, Cascone focuses on early-stage lung cancer. “This population of patients is potentially curable from the get-go. Yet down the road, more than 50 percent of these patients, despite surgery, chemotherapy or radiation therapy, will still relapse. So what can we do to improve the cure rate of these patients?” she asked. “I believe it is critical to prime the immune system when the tumor is in place—prior to surgery—to make sure we can trigger immune memory and help patients avoid recurrence of disease, and ultimately improve outcomes.”

An exciting major project that Cascone has undertaken—one with the potential for extreme translational impact—is the development of a platform of experimental models in which investigators can actually recapitulate the spontaneous development of metastatic disease just as it happens in a patient.

“We can ‘prime’ the immune system on these experimental models using immunotherapy, resect the lung tumor, and see what happens to the recurrence of the disease in models that have been treated with immunotherapy prior to the surgery as compared to immunotherapy after surgery,” detailed Cascone.

“We have found that when we administer immunotherapy prior to surgery, we can delay the onset of the recurrence of disease, prolong the survival of these experimental models, and make the immune system more effective in fighting the disease to a greater extent than when the therapy is administered after surgery,” she noted. “Using specific endpoints, we can measure the effects of immunotherapy prior- or post-surgery by looking at the metastases that form in the lung, by looking at how long the experimental models (in this case animals) live with one treatment versus another. I believe these results support additional studies to improve our understanding of how we can cure patients diagnosed with early lung cancer (not metastasized outside the chest). I think this is the future.”

Additionally, Cascone is excited to see how immunotherapy combined with other therapies will work in concert. As such, she is principal investigator of a clinical trial (NEOSTAR) in which single agent or combined immunotherapies are given to patients before they undergo surgical resection of their lung cancer. “We want to see if these patients will receive long-term benefit,” said Cascone of the MD Anderson investigator-initiated trial.

“My goal is not only to reach meaningful improvement of outcomes for patients who have been diagnosed with advanced metastatic disease, but also cure for those who have been diagnosed with early-stage tumors. We must use smart combinations of all the tools—chemotherapy, surgery, radiation therapy, immunotherapies, and novel agents. If we can combine them in the right population of patients, find markers in patients to tell us who will respond to this or that combination and why, we can improve outcomes and we can increase cure rates.”

It's a lot to contemplate. And Cascone thinks about the complexities of work when she embraces her current hobby—running. A Houston marathoner, Cascone said, “Running keeps me centered. It is a great stress reliever and helps me think about work collectively.” She paused to laugh before adding, “I guess I am still working even when I am running.”

Valerie Neff Newitt is a contributing writer.

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