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Shyam Bhakta, MD, MBA
Contributing Editor, ISCT Telegraft
United States

Dr. Mary Laughlin grew up in Buffalo, NY, where the Roswell Park Cancer Center and Institute is located and where she also completed an internship while in high school. Dr. Laughlin says that at the time, Roswell Park was just one of three cancer centers nationwide, with Memorial Sloan-Kettering Cancer Center (New York, NY) and Fred Hutchinson Cancer Center (Seattle, WA) being the other two. According to Dr. Laughlin, allogeneic bone marrow transplants were experimental.

When the first such transplant was performed at the Fred Hutchinson Cancer Center, the concept of human leukocyte antigen (HLA) had not yet been discovered. Donors were matched based on mixed lymphocyte antigen. Patients were housed in sterile environments in which clinicians, nurses, and other caregivers wore suits similar to spacesuits designed for astronauts. Patients considered for transplants were also considered refractory to all established therapies. While opportunistic infections posed a great risk, many patients with leukemias refractory to standard therapy were cured with allogeneic bone marrow transplants. These early experiences in high school shaped Mary’s career.

Mary attended college at the University of Rochester and graduated with a degree in nursing, after which she worked as a critical care nurse and then as a nurse anesthetist. She then applied to medical school and entered the State University of New York (SUNY) Buffalo at the age of 30 (she mentioned that at the time, tuition was only $1,200!). She enrolled in an accelerated program and received her medical degree in only three years. She completed her internal medicine residency and hematology-oncology fellowship at Duke University Medical Center (Durham, NC).

During her fellowship training at Duke, she worked with Dr. Clair Bloomfield, who was recruited from the University of Minnesota, as well as with Dr. Jeff Hertzig, who worked on conditioning regimens prior to allogeneic bone marrow transplantation. She also worked with Dr. Michael Caligiuri, who went on to lead the Arthur James Cancer Hospital at Ohio State University (Columbus, OH) as well as to serve as president of the City of Hope Cancer Center in Duarte, CA. 

A Storied Career in Academia and Industry

After completion of her training, Mary joined Duke University, where she served on the faculty for 10 years. Following her tenure, she was recruited to Case Western Reserve University (Cleveland, OH). She received $15 million from two families to establish the Cleveland Cord Blood Center, located in Warrensville Heights, OH. Mary reports that the center donated more than 1,000 cord blood units to 18 different countries, and that umbilical cord blood received approval by the United States Food and Drug Administration (USFDA).

During her tenure at Case Western Reserve University, she served as president of ISCT. Following her tenure at Case, she then joined the faculty at the University of Virginia (Charlottesville, VA), where she established a cell therapy program.

Despite a very decorated, distinguished, and productive career as an academic educator, investigator, and clinician, in 2013 Mary “hung up the pager” and made the transition to industry, joining Novartis in their cell and gene therapy unit in 2013. When asked why she made the transition from academia to industry, she says that while academics allowed her to complete phase 1 and 2 studies, it was difficult to conduct randomized phase 3 studies, and she wanted the experience to take new therapies to the USFDA. Therefore, cell therapy demonstrated equal and promising potential to that of small molecule therapies. During her time with Novartis, Mary worked closely with GamedaCell, which received USFDA approval for its umbilical cord blood-derived CD34+ cell therapy product.

Although Mary had a longstanding proven track record in cell therapy, she wanted more experience in solid-tumor oncology and transitioned from cell and gene therapy to oncology. She devised clinical trials for steroid-refractory graft-versus-host disease (GVHD). The clinical trials were open-label, and treatment of study subjects assigned to the control arm was at the discretion of the investigator. During this time, she demonstrated positive results for a trial involving ruxolitinib (Jakafi), a treatment for GVHD. Following her time at Novartis, Mary was then recruited to Takeda Pharmaceuticals, who had just purchased an immunotherapy drug for treatment of lung cancer. During this time, Mary was involved in a very large initiative between Takeda and MD Anderson Cancer Center (Houston, TX) for natural killer (NK) cell products.

During the COVID19 pandemic, Mary was recruited to Bristol-Myers Squibb for her expertise in cell therapy. She then went on to Regeneron, where she served as Global Vice President for Solid Tumor Oncology and worked on therapies for ovarian cancer as well as gamma-delta T-cells for hepatocellular carcinoma. She also worked on a 400-patient phase 3 trial comparing standard chemotherapy to an anti-CD19 therapeutic antibody for treatment of diffuse large cell lymphoma, as well as another trial combining this therapy with a product from Roche. Currently, Mary is Vice President at Iovance Biotherapeutics where her focus is on treating small cell lung cancer. 

Her Proudest Achievements

When asked about her proudest contributions to CGT, Mary says that her work on "umbilical cord blood as a cell therapy product" comes to mind. She describes cord blood as a “once-upon-a-time throw-away product” that was taken through the FDA approval process and has been developed into a lifesaving therapy. Her work on this seminal topic led to first-author manuscripts in the New England Journal of Medicine (1, 2). Mary claims that cord blood is an important armamentarium for patients who lack a related sibling donor. Prior attempts used haploidentical grafts. While these therapies had early success and were less expensive, challenges and problems arose five to ten years following initial treatment. She finds that immunology is the common thread throughout her career and that cord blood banks are very rewarding as potentially lifesaving therapy from a product that is donated at birth. Lastly, she concludes that the people with whom she worked in this field have been the most rewarding aspect of her career.

If Mary could share a few words of advice with someone starting out in their career, she would emphasize that “persistence is important.” When developing an innovative therapy, researchers often become targets of criticism, as skeptics may challenge their ideas and search for deficiencies in their work. Her advice is that if the science behind someone’s work is solid and sound, they should remain persistent. For example, a colleague at another major pharmaceutical company worked on a small-molecule therapy for T-cells. Although the company was initially reluctant to move the program forward, her colleague’s patience and persistence ultimately contributed to the development of a major class of therapeutics. She also stresses the importance of “the denominator” — ensuring that study populations are large enough for results observed in small initial trials to be replicated in larger patient cohorts. She spoke in detail about the limitations of generalizing findings from small- and large-animal models to humans. Lastly, Mary also encourages young investigators to adopt a strong team-based mentality, given the increasing importance of collaboration and cooperation in clinical research.

During her tenure as ISCT president, Mary recalls a particularly memorable moment involving a last‑minute trip to the annual meeting in Berlin. Her luggage failed to arrive on time, leaving her with nothing but her “comfortable travel attire” of sweatpants and a sweatshirt. Thanks to the generosity of local Germans she met upon arrival, she was able to track down a suit and other professional clothing just in time for her induction ceremony.

Tackling the Challenges Ahead

Mary anticipates that one of the biggest challenges for the field of cell and gene therapy (CGT) is increasing — the burdensome oversight and regulation of CGT is stifling innovation in cancer therapeutics. For example, the common practice of centralized (“core laboratory”) analysis of radiographic imaging by radiologists blinded to study design, treatment assignment, and other baseline characteristics. However, she also pointed out that such practice has not had an impact on mortality or survival of study subjects. She also talks about how open-label studies lead to dropout of subjects assigned to placebo, or standard therapy, or less aggressive therapy, a process that may lead to reporting of exaggerated benefit of new therapies even in peer-reviewed publications. Further, Mary says that common practice of requiring studies in small- and large-animal models that may not be applicable to how therapies behave in humans and how such practice only adds time, delay, and expense to the development of emerging cancer therapeutics. 

Finally, on a positive note, Mary shares that the development of tumor-infiltrating lymphocytes (TILs) is very promising because such lymphocytes target up to 20 known tumor-associated antigens. 

references

1. Laughlin MJ et al.  Hematopoietic engraftment and survival in adult recipients of umbilical-cord blood from unrelated donors.  N Engl J Med, 2001; 344(24): 1815 – 22.
2. Laughlin MJ et al.  Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia.  N Engl J Med, 2004; 351(22): 2265 – 75.