‘An opportunity for cure’ pushes cancer researcher to persevere

Kristen M. Hege, MD, is one of those rare individuals who excels at most of her endeavors.

She can get something done herself, and she can exhibit the leadership necessary to bring teams together to tackle problems that cannot be solved alone.

Hege is a physician, research scientist, teacher and mentor, as well as a wife and mother of two daughters. In her free time, she likes to scale mountains — or sometimes strap on a pair of skis and carve her own groove on the way back down.

Hege — senior vice president of early clinical development for hematology/oncology and cell therapy at Bristol Myers Squibb — helped develop idecabtagene vicleucel (Abecma; Bristol Myers Squibb, 2seventybio), the first commercially available chimeric antigen receptor T-cell therapy for treatment of advanced multiple myeloma.

The development of B-cell maturation antigen (BCMA)-targeted CAR T-cell therapies like idecabtagene vicleucel — often called ide-cel — may be the most clinically impactful advance for the disease.

“An opportunity for cure — I think that’s why we are all in this,” Hege told Healio | Cell Therapy Next.

The success of leading Bristol Myers Squibb’s ide-cel clinical program from first patient treated to regulatory approval made up for previous setbacks in the effort to translate CAR-T into an effective treatment for cancer. Although it is not clear whether CAR T cells are curing myeloma, the responses seen thus far are deep and durable for many patients and allows recipients to avoid taking a cocktail of drugs for months or even years.

“That line of sight to the success and the difference that you can make for patients and families keep you going through the inevitable failures, which are many because tackling and treating cancer is hard,” she said. “It’s nice to have the successes that remind you of what’s possible.”

Era of cancer genetics

Like many other physicians, Hege has a personal connection to her profession.

Both of her parents were physicians, and she developed an interest in science and medicine at an early age.

Hege lost her mother to a longstanding illness in high school. Her father died of gastric cancer a few years later while she was in her first semester of medical school.

As Hege explains, however, assuming these personal experiences impacted the direction of her research interests “would be a little too simplistic.” Timing, in her opinion, served as a significant intervening factor.

The rising importance of genetics in the treatment of cancer played as much of a role in her decision to become an oncologist as her father’s death.

“It was the dawn of the era of cancer genetics ... and it became clear that if we had a deeper understanding of what caused cancer, we could develop more targeted approaches to treat it,” she said. “That really drew me in toward this belief that we could move from very toxic standard chemotherapy approaches to more focused treatments through these deep molecular understandings.”

This promise, along with her love for being a physician, carried Hege to her current roles as a clinical researcher for Bristol Myers Squibb and clinical professor of hematology/oncology at University of California, San Francisco.

“I still am a physician, and I still see patients to this day,” she said.

A coalescing vision

Caring for patients came early for Hege, and it started out personal.

She became the primary caregiver for her brother when he contracted HIV early in the AIDS pandemic. He died of the disease as she finished her hem/onc fellowship at UCSF.

During this period, Hege also found out about the benefits of hematopoietic stem cell transplant and its ability to harness a patient’s immune system to fight blood cancers.

The first data about the utility of allogeneic transplants showed the major benefit came from the donor’s T cells attacking and killing cancer cells, not the chemotherapy administered as part of the regimen.

“Even if patients relapsed, we could just collect T cells from the donor, infuse them into the patient and their leukemia would often go back into remission,” she said.

Hege had witnessed both the destructive and recuperative capabilities of the body’s immune system, and these experiences solidified the trajectory of her life’s work into the field of cell therapy.

“It was the coalescence of those things that caused me to focus my career on trying to target and engineer the immune system to kill cancer at a time when, frankly, nobody else believed, and it was very much a niche field with a couple of core academic groups and just one small biotech company working in this space,” she said.

The “niche field” included groups at Memorial Sloan Kettering and Fred Hutchinson Cancer Center, as well as Steven A. Rosenberg, MD, PhD, at his group at NCI. Carl H. June, MD, first at the Naval Medical Research Center and later at University of Pennsylvania, also served as an early believer — and a lifelong collaborator with Hege.

Cell Genesys, a small biotech in the Bay area, was the only company focused on engineering the immune system to cure disease. Stephen A. Sherwin, MD, the company’s CEO, also was a clinical professor at UCSF and one of Hege’s attendings during a hem/onc fellowship rotation at a local county hospital.

The two discussed Hege’s budding research interests and — in a rather unconventional move — Sherwin asked her to spend her 2 research years of fellowship at Cell Genesys re-engineering T cells and hematopoietic stem cells to target HIV and cancer.

“That was a handshake deal between [Sherwin] and the head of our fellowship program,” Hege said. “There was no paperwork. There was no contract. Just an agreement that the company would pay my salary for one of those years and the university would pay my salary for the other year.”

The arrangement — unorthodox at the time — set a precedent that she follows to this day, as Hege continues to see patients as part of her active clinical duties at UCSF despite a full-time job leading early clinical development for a portfolio of investigational therapies at Bristol Myers Squibb.

“I give a lot of credit to Steve Sherwin and the head of our fellowship program for thinking out of the box and allowing me to do something that was very unusual,” Hege said.

Bridging the gap

Sherwin described Hege as someone who seems to be good at everything she tries — whether it be patient care, research or an outdoor adventure with a competitive edge carved out as a member of the women’s varsity soccer team during her undergraduate years at Dartmouth College.

“It was very clear to me from the beginning that she was a standout as a person, as a physician and as a research scientist,” Sherwin told Healio | Cell Therapy Next.

Cell Genesys originally focused on using reengineered cells to treat HIV, and Hege served as one of the most instrumental figures in reapplying the CAR-T approach to blood cancers.

Despite the failure of CAR-T to cure HIV, Hege and her colleagues passed along what they learned conducting these seminal trials, and these insights became crucial in helping to develop the technology, Sherwin added.

For example, their work helped show that retroviral vectors could be used to transduce T cells with high efficiency.

“Kristen saw the potential for the treatment of cancer,” Sherwin said. “She was a pioneer in leading that effort at Cell Genesys and had the vision long before most people to involve herself and put the focus of her time on these pioneering therapies.”

Although the initial HIV CAR-T trials did produce a hint of efficacy, effective antiretroviral therapies emerged and as a result Cell Genesys redirected its efforts toward cancer immunotherapies, including cellular vaccines and oncolytic viruses. In 2009 the company merged with ANI Pharmaceuticals.

In September 2010, Hege accepted a job as head of translational development for

hematology/oncology at Celgene.

Hege contributed to the emerging knowledge base around cellular therapies. She partnered with June — a CAR-T pioneer and professor in immunotherapy in the department of pathology and laboratory medicine at Perelman School of Medicine at University of Pennsylvania — on a 2012 paper published in Science Translation Medicine that showed CAR T cells injected into HIV-positive patients more than 10 years earlier could still be detected in the body and had no long-term toxicities associated with them.

The samples came from Hege’s CAR-T clinical trials at Cell Genesys.

“[It] has become a seminal paper in the field, showing the long-term safety of these genetically modified T-cell approaches,” Hege said.

Few in the cell therapy field have as long and established a track record as Hege, June said. Her experience in both academia and industry has contributed to getting CAR T cells to patients faster than otherwise would have been possible, he added.

Early believers like Hege brought the treatment back into the commercial fold, June said.

“We were operating in a cloud, and the pullout delayed the field by almost a decade,” June said.

Hege — and her more than 2 decades of experience running cell therapy trials — was one of the instrumental figures in helping academia receive the resources from biopharma to move CAR-T forward, June added.

‘Rally from [an] epic descent’

Hege led the early clinical development group at Celgene and partnered with former Cell Genesys colleague Mitchell H. Finer, PhD — then chief science officer of bluebird bio and developer of a retroviral transduction system now used in commercial CAR T cells.

The two met for drinks at ASCO Annual Meeting in 2011 and reminisced about their time developing CAR-T for HIV. They concluded that recent scientific advances — such as the value of T-cell co-stimulation and preconditioning lymphodepletion —had the potential to make the modality viable again, this time for cancer treatment.

“That’s what kicked off the original bluebird bio/Celgene partnership, which then led to picking BCMA as our first target, licensing of a binder from the NCI and building the CAR with a 4-1BB costimulatory domain based on June’s data,” she said.

They followed promising preclinical data with the first-in-human trial of what would become known as ide-cel.

“All of a sudden nearly everybody started to respond,” Hege said. “The results were dramatic.

“All told, [it] has been the most rewarding program I’ve worked on in my career, especially because I started my career in this field,” she added. “I lived through the failure of a biotech company and had to lay myself and my entire team off during the economic recession in 2008. To rally from that epic descent and come back and see the successes of the cell therapy field has been very gratifying.”

Removing barriers

Hege attributes much of what she has achieved to the lessons from mentors and efforts of her collaborators over the years.

She also feels a responsibility to help foster the careers of the next generation of hematologists/oncologists, particularly women from underrepresented groups who wouldn’t typically consider careers in science or medicine.

Along with one of her former interns, Hege began organizing a summer program where she takes a group of young women from the Bristol Myers Squibb college summer internship program on a 4-day wilderness backpacking experience in the High Sierras.

“We all just need to spend more time helping the next generation of women advance and remove any and all barriers that are impeding their progress,” Hege said.

One such program is Society for Immunotherapy of Cancer’s Women in Cancer Immunotherapy Network (WIN), designed to promote and elevate women in the cancer immunotherapy field.

Hege is one of the program organizers for this women’s leadership conference, which she said is not about science.

“It’s about advancing your career, how to say no, how to negotiate, how to achieve work-life balance and how to navigate different career paths,” Hege said.

Women need mentorship programs, beginning in elementary school and continuing through to their professional lives, she said.

“Programs like WIN and others that have received just enough financial support have proven to be extremely impactful on the young women and students of color who participate,” Hege said.

“We haven’t made as much progress as a society in my lifetime as I would have hoped, especially if you look at an organization’s C-suite,” she added. “At most academic medical centers, the leadership team is still dominated by men, so we need to do whatever we can do to move forward faster for the next generation.”

More to come?

Hege is continuing her quest to bring more effective cancer treatments faster and to more patients as she manages early clinical development of Bristol Myers Squibb’s line of investigational cancer therapies.

“I’m excited about BMS’ entire pipeline,” she said.

However, she acknowledged she still has a special place in her heart for development of novel cell therapies and how new approaches have the potential to treat a wider array of diseases more effectively — including the potential use of the modality to treat solid tumors.

“It won’t happen instantly, and we will need some perseverance and resilience to get there,” Hege said. “But I believe it’s possible to treat solid tumors with cellular therapy, that we have the tools to do it, and that the pace of progress will be faster than in the early days of CAR-Ts.”

June’s decades-long collaboration with Hege has been one of most significant of his career, he said. Despite being best known for leading an impactful CAR-T through regulatory approval, June said, Hege’s story of achievement may have some chapters left to be written.

“I don’t think she’s done yet,” June told Healio | Cell Therapy Next. “I think [Hege will] continue to make advances in clinical developments that will have a lasting impact on a field that is in its infancy.”

Looking back at her career thus far, Hege has few regrets. Nevertheless, moving forward, she hopes some aspects of her work will become streamlined to help more people in their time of need.

“The industry needs to figure out how to do what we do faster, more efficiently and with a higher probability of success,” she told Healio | Cell Therapy Next. “There’s a lot of external pressure on our industry, but I feel like maybe that’s what it will take to help us catapult forward and bring more drugs to more patients faster.”

Timing has played a significant role in Hege’s life, both personally and professionally. This includes being in the right place at the right time from a professional development standpoint, and the fact her brother’s death occurred about a year before the FDA approved the first protease inhibitors, which transformed HIV from a deadly disease to a chronic one when treated properly.

“A year later, young men with AIDS were no longer dying, and many of them are still alive today,” she said. “That’s the difference a year makes.”

A year also may have made the difference for one of her close friends, a young mother of two who died of treatment-refractory acute lymphoblastic leukemia just a year before the first breakthrough results using CD19-directed CAR-T for patients with advanced ALL.

“These things remind me that we need to figure out a way to break down barriers and get more drugs to more patients faster,” she said. “Those are powerful motivators and, as an industry, I believe we can rise to the occasion and get more creative.”

Reference:

Scholler J, et al. Sci Transl Med. 2012;doi:10.1126/scitranslmed.3003761.

For more information:

Kristen M. Hege, MD, can be reached at kristen.hege@bms.com.

Carl H. June, MD, can be reached at cjune@upenn.edu.

Steve Sherwin, MD, can be reached at stephen.sherwin@sasbiomed.com.