A Pioneer in Developing Drugs for People with T-Cell Lymphoma

ACS Clinical Research Professor Profile: Owen A. O'Connor, MD, PhD

In July 2018, Owen O’Connor, MD, PhD, was awarded an American Cancer Society (ACS) Clinical Research Professor grant. He’s an international authority on both non-Hodgkin and Hodgkin lymphoma. For more than 20 years, his research has significantly contributed to the understanding and treatment of several types of lymphoma and T-cell lymphoma in particular. The grant provides research funding for at least 5 years and allows O’Connor to use the title ACS Clinical Research Professor for the rest of his life. It is considered the most prestigious grant from the ACS.

Untraditionally Trained: From Benzene to Lymphoma

Before O’Connor became the cancer drug developer he is today, he studied the link between environmental neglect and cancer. As an environmental chemist, he collected and tested water and soil samples for contamination with pollutants, like benzene, PCBs, and dioxins.

Knowing that these chemicals could cause cancer, including non-Hodgkin lymphoma, multiple myloma, and most types of leukemia,
he wondered how society could continue to expose such hazards to our air, water, and soil.

He was inspired by the writings of Rachel Carson. He met and was also inspired by environmentalists like folk singer Pete Seeger. He also met Robert Boyle, a naturalist known for protecting New York’s Hudson River from industrial pollutants.

He pursued answers to questions, such as, how could we use the environment to detoxify the environment? Could we use the bacteria in toxic places to convert hazardous chemical waste to harmless compounds? In his pursuit, he created new, natural ways to remove toxic chemicals from the environment.

During this work, he recognized a surprising coincidence. Many drugs used to treat cancer damage the cells and DNA of both normal and cancer cells precisely like benzene does. In fact, many drugs used to treat cancer can also cause cancer. 

“Cancer-causing and cancer-treating chemicals both damage DNA,” he explains. Chemotherapy drugs are designed to damage the DNA in cancer cells in order to kill them. 

Ironically, O’Connor later learned that the famous Scottish doctor and cancer researcher Sir Alexander Haddow had discovered the same paradox nearly 25 years earlier. But O’Connor’s personal realization was a pivotal point in his career. “I changed my focus. I shifted from studying how chemicals cause cancer to developing more refined, targeted drugs to treat cancer." 

Understanding T-Cell Lymphoma

Lymphoma is also called non-Hodgkin lymphoma. This cancer starts in cells that are part of the body’s immune system.

The most common type of lymphoma starts in B-cells. Only about 15% of lymphomas start in T-cells.

T-cell lymphomas tend to grow fast. That means by the time people are diagnosed, the cancer has usually spread throughout the body, where it can cause many symptoms.

O'Connor's been especially drawn to peripheral T-cell lymphoma (PTCL). PTCL is called peripheral because it starts in mature T-cells that have moved out of the bone marrow and into the lymph nodes, spleen, digestive system, or skin. PTCLs are rare, but aggressive.

People with B-cell lymphoma can be successfully treated with chemotherapy. For years, cancer researchers assumed that the same treatment would be effective for people with T-cell lymphoma. But it wasn’t.

O’Connor helped discover some of the first drugs to be approved to treat T-cell lymphomas. He's now building on this experience to change how scientists and doctors approach the disease.

Selection as an ACS Clinical Research Professor

“We awarded Dr. O’Connor the ACS Clinical Research Professor grant because he started a paradigm shift in how we improve the care and outcome of patients with peripheral T-cell lymphoma. His vision is creating biologically-directed treatments via dynamic translational research—moving back and forth from the lab to the bedside, as needed,” says Susanna Greer, PhD. Greer is the ACS scientific director who directs the peer review committee that nominates grant proposals about leukemia, immunology, and blood cell development for funding.

O’Connor’s Research Contributions

Developing new drugs early in his career. O’Connor’s drug discoveries started during his fellowship in medical oncology at Memorial Sloan Kettering Cancer Center (MSKCC) in New York, New York. To date he has contributed to the development and FDA approval of 4 drugs for lymphoma. All these drugs are targeted therapies, meaning they target a unique aspect or action of a cancer cells compared with chemotherapy drugs, which affect healthy cells as well as cancer cells. "I wanted drugs that aimed at the unique biology of the cancer cell to spare damage to healthy cells." These drugs continue to help patients today, and they also paved the way for the development of similar drugs. 

bortezomib [bore-TEZ-oh-mib]
Brand name: Velcade
Used for: Mantle cell lymphoma, which is fast-growing and usually affects the digestive system and bone marrow of middle-aged or older people
How it works: Targets proteasomes, which help control how quickly cells divide. Proteasome inhibitors are drugs that block or slow down proteasomes.
How bortezomib was new: First targeted drug approved to treat people with mantle cell lymphoma that had recurred (relapsed) or hadn’t respond to chemotherapy (chemoresistant). Also, the first proteasome inhibitor approved by the Food and Drug Administration (FDA)

vorinostat [vor-IN-oh-stat]
Brand name: Zolinza
Used for: Cutaneous T cell lymphoma (CTCL) which affects the skin. It can occur at any age, but most learn they have it in their 50s or 60s.
How it works: It targets histone deacetylase (HDAC). HDACs are enzymes that affect genes, allowing cancer cells to grow out of control. HDAC-inhibitor drugs influence genes to help slow down HDAC activity, which causes cancer cells to die.
How vorinostat was new: This was the first HDAC-inhibitor approved by the FDA. After O’Connor’s discovery, other HDAC inhibitors have been developed to treat T-cell lymphoma.

pralatrexate [PRA-luh-TREK-sayt]
Brand name: Folytn [FALL-a-tine])
Used for: Peripheral T cell lymphoma (PTCL)
How it works: Pralatrexate is a newer type of an older drug that interferes with the way the body uses the B vitamin, folate. It appears to kill T-cell lymphomas by influencing genes, causing the cancer cells to die.
How pralatrexate was new: It was the first drug to be approved by the FDA for patients with PTCL. 

belinostat [be-LIN-oh-stat]
Brand name: Beleodaq [Ba-lee-OH-dik
Used for: Peripheral T cell lymphoma (PTCL) that has stopped responding to other treatment or that has recurred
How it works: Belinostat kills more cancer cells than normal cells because it blocks HDAC. Like vorinostat, it interferes with the genes in cancer cells, causing them to die.
How belinostat was new: It was another HDAC-inhibitor that resulted in the remission of PTCL, often with far fewer side effects for patients.

Working in the lab and at the bedside. In the lab, O’Connor and his team study mice and grow cells taken from human tumors. They continue to learn what goes wrong inside the T cell that leads to abnormal growth and cancer. As they develop new drugs or drug combinations, they study them in patients through clinical trials. The process of taking knowledge learned in the lab and “translating”—using and testing it—in patients is known as translational research. O’Connor’s recognized as an international authority on translating new scientific concepts to patient care.

O’Connor’s currently looking for solutions to the ingenious ways cancer cells avoid being found and destroyed by the immune system. He’s especially excited about combining different classes of drugs that he’s shown work well together and help each other work.  

“Cancer cells have developed clever ways to run stealth, escaping detection by normal T-cells,” he explains. “So first,” we use an epigenetic drug to make the cancer cell more visible to the immune system. Then, we use new drugs that stimulate the immune system called immune checkpoint inhibitors. Combining these drugs gives us a chance to kill the cancer, without using the more toxic chemotherapy drugs.”

“My vision for the future is to figure out how to couple these new drugs that address the underlying biology of the disease with truly new immunologic interventions,” said O’Connor. “That for me is the forefront. As an old-time scientist very focused on chemistry, and now learning this new immunology, I’m highly convinced that this will be the future.”

Extending his research to help patients around the world. Interestingly, certain types of PTCL occur more frequently in specific parts of the world. “Because PTCLs are so rare and have almost 30 subtypes, we need to have more global harmonization to work together as one,” O’Connor says. That’s why he’s assembled  a Global T-Cell Lymphoma Consortium with his other renowned colleagues Pier Luigi Zinzani from Italy, and WonSeog Kim from Korea. Using Columbia University as the coordinating site, O’Connor meets with leading researchers from premier institutions in Europe and Asia.

“The consortium gives us the opportunity to agree on which clinical trials are the most important to do next. And it helps us have enough patients to put in those trials,” he says. “That way we can identify the best and most effective new treatments and treatment combinations for distinct subtypes of lymphoma.”

O’Connor’s leading several international studies, and some are the largest ever done with various sub-types of lymphoma.