Cell therapy pioneer: Modality could be solution to ‘pretty large cadre’ of diseases

The basic science discoveries to which Helen E. Heslop, MD, DSc (Hon), has contributed place her firmly on the Mount Rushmore of pioneers in the field of gene and cell therapy.

She is a leader in the lab and the clinic, and — perhaps most importantly — an advocate for the science she works so tirelessly to advance.

Heslop — deputy director and co-leader of the cancer cell and gene therapy program at Baylor College of Medicine’s Dan L. Duncan Comprehensive Cancer Center and director of the Center for Cell and Gene Therapy — has been a part of clinical chimeric antigen receptor T-cell therapy research since its infancy, and she was an IND sponsor on Baylor’s first study in 2004.

Her research has played a fundamental role in the development of the technology, and she oversees a center with more than 20 active cell therapy trials. However, she is quick to acknowledge the contributions of those who designed the receptors and other essential components of the novel immunotherapy.

“The development of all cell therapies requires a lot of people who do different things to bring them from the bench to the bedside,” Heslop said.

No regrets

Heslop — a New Zealand native whose father was a surgeon and mother was an immunologist — didn’t always want to be a physician.

Her interest in science blossomed in secondary school and — after a year of undergraduate study — she applied to medical school.

“I was just always brought up to know I could do anything I wanted to do,” Heslop told Healio.

Women made up about one-third of her medical school class in 1980. She said she is thankful for the progressive environment her native country afforded. Despite a few “less-than-optimal” interactions, she experienced no obstacles due to her gender during medical school or early clinical training.

“New Zealand's is probably a more favorable environment for females than most places,” she said. “We were the first country where females could vote.”

Heslop has spent her entire professional career in the United States — first at St. Jude Children’s Research Hospital and then Baylor College of Medicine — and she said she has no regrets about not returning to New Zealand when the opportunity arose.

“I think my career would have been very different,” she said. “Although I miss it, if I had gone back, I don’t think I would have been able to do the sort of cell therapy studies that I've done in the U.S.”

‘A once-in-a-lifetime experience’

Heslop developed an interest in hematology as a medical student while caring for patients with leukemia. The promise of bone marrow transplant to improve outcomes especially intrigued her.

“There was a lot of room for improvement in the care that we were providing,” she said. “The whole concept of replacing the immune system was a new area that I thought had a lot of potential.”

Her entrée into cell therapy came while trying to develop a treatment to overcome Epstein-Barr virus-induced lymphoproliferative disease, a viral infection that occurred among patients with non-Hodgkin lymphoma undergoing hematopoietic stem cell transplant.

Along with a colleague — Cliona M. Rooney, PhD, director of translational research laboratories at Center for Cell and Gene Therapy — Heslop was among the first group of researchers to demonstrate that genetically modified, antigen-specific cytotoxic T cells could be used to kill malignant cells.

“We were looking for a solution, and there was a lot of team science involved,” Heslop said. “A lot of people collaborated to help make sure that this approach could be tested in the clinic.”

Heslop considers this to be her greatest scientific achievement, and finds it extremely gratifying when she hears from patients she treated in the mid-1990s who had their disease eradicated and continue to lead healthy lives.

“It’s very satisfying anytime you participate in a new study and you get promising results like we did,” she said.

Malcolm K. Brenner, MD, PhD, Fayez Sarofim distinguished service professor at Baylor College of Medicine and founding director of Center for Cell and Gene Therapy, served as both a colleague of and mentor to Heslop during the time of this research.

Brenner said that Heslop and Rooney — Brenner’s wife — came up with the idea of treating these viral infections with T cells from a donor’s bone marrow.

“It was sort of magical when it disappeared,” Brenner told Healio.

“It was a once-in-a-lifetime experience for a clinical researcher,” Brenner added. "This new treatment was spectacular and had a huge impact — both for us personally and professionally but, more importantly, for our patients.”

Standardizing the field

Despite achievements in the lab, Heslop’s greatest impact on the field may be her ability to demonstrate that cancer cell therapies can be provided in a professional manner and to a high standard, Brenner said.

In the 1990s, a series of issues prompted questions about the safety of gene therapy that almost derailed the sector, he noted.

Heslop was a “major player” in the development of Foundation for the Accreditation of Cell Therapies (FACT). Without that progress, “there would have been more catastrophes and the field would have hit a brick wall,” Brenner said.

Heslop’s efforts helped gene and cell therapy progress safely and effectively while ensuring those involved received proper training using standard procedures, he added.

Heslop has held leadership positions in nearly every gene and cell therapy society. She also has dedicated her professional life to expanding access to these therapies while training future leaders in the field, according to Rayne H. Rouce, MD, pediatric oncologist at Texas Children’s Hospital and associate professor at Baylor College of Medicine.

In addition, Heslop has developed “a sustainable model of bench‐to‐bedside translation that is hard to duplicate,” added Rouce, a member of the Healio | Cell Therapy Next Peer Perspective Board.

‘The importance of representation’

Heslop’s prowess as a leader for the science of cell therapy is evident in her ability to lead those with whom she collaborates.

Rouce said Heslop taught her an indigenous phrase — kia kaha — that she has subsequently imparted to those she has mentored. It means “stay strong” in Mori.

“Helen recognizes the importance of representation and has a long list of strong women mentees that are now mentors themselves,” Rouce said. “She coined the phrase ‘mentor ladder’ and ensures that her mentees understand that they must pay it forward.”

Heslop also recognizes the importance of diversity in science and medicine, and she makes a special effort to encourage the career development of underrepresented women in the field of cellular therapy, Rouce added.

Brenner agreed, adding that Heslop is a “gender-neutral” mentor with a lengthy track record of guiding the careers of both male and female early-career researchers.

Not only is Heslop “an outstanding clinician,” she is adept at building teams, energizing her colleagues to do the work commensurate with their roles, Brenner added.

Heslop said it’s not her own accomplishments that give her professional satisfaction; rather, it is seeing those with whom she works achieve their goals — whether that be securing funding through a new grant or publishing an important paper.

Diversity in the field of medicine has improved since Heslop started her career, but she insisted that more progress is required.

“I think we are conscious that we need to look more like our patients,” she said. “We certainly do at the research coordinator and the nursing level but, at the physician level, there is more work to do.”

Heslop is encouraged that more women are attending medical school, but disparities — particularly with regard to race and ethnicity — still exist within academia at the professorial level, she said.

“I remember the first time I went to the ASH Annual Meeting. I was talking to a colleague from New Zealand and he suddenly said to me, ‘Do you realize we haven't seen a single Black hematologist yet?’”

Although the imbalance has improved since then, the racial and ethnic makeup of those in hematology still does not accurately reflect the patients they treat.

Future of cell therapy

Heslop has yet to have an agent she has worked on approved for commercial use by the FDA.

Still, Brenner said the therapies she has helped develop have successfully treated hundreds — if not thousands — of patients, saving lives and improving patients’ quality of life.

“These patients have been treated more as a practice of medicine than as a commercial venture and that may be the way that most cell therapies are used — just as cardiac surgery isn't a drug owned by a company but rather is something that is done professionally at an institution,” he told Healio.

When asked if cellular therapy is providing cures for some patients, Heslop expressed cautious optimism.

“Everything is potentially curable if you get the right combination, and sometimes it's going to result in disease control rather than a cure,” she told Healio. “There have been patients who have gone even 15 years with control of their disease using CAR T cells, so it can produce really good long-term results. I'm always a little bit loath to say ‘cures’ because I don't want to jinx things.”

Whether CAR-T can produce similar benefits for patients with solid tumors as it has for those with blood cancers remains unanswered. However, Heslop said the potential exists for positive outcomes and she believes CAR-T will have “much broader uses” in the future.

Numerous strategies are being evaluated to improve the efficacy of CAR T cells, including investigations using different cell types, allogeneic CAR T cells and novel methods to traffic modified therapeutic cell therapies to the site of disease.

“Longer term, I think gene editing has a lot of potential to really accelerate the field,” Heslop said.

She sees promise in a CD30-targeted cell therapy that is moving into later-stage trials for treatment of non-Hodgkin lymphoma. She also pointed to the success using tumor-infiltrating lymphocytes as a treatment for melanoma.

“There's no reason why you can't apply CAR T cells to other diseases,” Heslop said. “Cellular immunotherapy is not the solution to everything, but I think it could be a solution to a pretty large cadre of diseases.”

References:

Heslop HE, et al. Nat Med. 1996;doi:10.1038/nm0596-551.
Heslop HE, et al. Blood. 2010;doi:10.1182/blood-2009-08-239186.
Ramos CA, et al. J Clin Oncol. 2020;doi:10.1200/JCO.20.01342.

For more information:

Malcolm K. Brenner, MD, PhD, can be reached at Houston Methodist Hospital, Blood, Marrow and Cell Therapy Center, 6565 Fannin St., Suite 800, Houston, TX 77030; email: mbrenner@bcm.edu.

Helen E. Heslop, MD, DSc (Hon), can be reached at Baylor College of Medicine — Feigin Center, 1102 Bates Ave., Room: TXFC-164004, Houston, TX 77030; email: hheslop@bcm.edu.

Rayne H. Rouce, MD, can be reached at Texas Children’s Hospital, 6701 Fannin St., Suite 1510, Houston, TX 77030; email: rhrouce@texaschildrens.org.