Adaeze Ekwe, PhD
Junior Associate Editor, ISCT Telegraft
Queensland University of Technology (QUT)
Australia

A Cell Therapy Pioneer and Mentor

Dr. Malcolm Brenner has been a cornerstone in bringing gene and cell therapies from aspiration to routine clinical practice. Grounded in rigorous science and patient-centered priorities, he helped define how we develop, regulate, and deliver engineered immune cells and gene-modified grafts to patients. I had the opportunity to speak to Dr. Brenner on his distinguished career spanning conventional medicine, immunology, hematology, and the burgeoning fields of cell and gene therapy, including his pivotal roles in the leadership of the scientific society and his enduring commitment to mentorship.

From Immune Deficiency Syndromes to Cell and Gene Therapy

Dr. Brenner, originally from the UK, began his training as a physician, pursuing specialist training and then obtaining a PhD in immunology. He acknowledges the inherent challenge of the MD/PhD route: being a part-time physician and a part-time scientist, which risks compromising the quality of the work. To circumvent this, he prioritized research where patients were an integrated part of the investigation and the research findings could directly influence patient treatment.

His early research focus in immunology in the 1970s stemmed from studying immune deficiency syndromes. The emergence of HIV, an unknown entity at the time although the epidemiology strongly suggested it was viral in nature, led him to anticipate the development of antiviral agents. Seeking another major area where immunology presented a significant problem, Dr. Brenner then shifted his focus to bone marrow transplantation (BMT), a field then in its nascent stages. BMT was plagued by immunological issues: a poor immune system in the recipient and the risk of the donor immune system attacking the host, causing Graft-versus-Host Disease (GvHD).

In his early thirties, Dr. Brenner switched careers, transitioning into hematology, while maintaining his deep focus on immunology. This immunological lens led to a crucial insight during his work at the Royal Free Hospital. Here, T-cell depletion was being used to halt GvHD, but it resulted in unexpected vulnerability in recipients, not only to infection but also to the relapse of leukemia. This observation demonstrated that the donor marrow did more than just replace damaged bone marrow; it was actively responsible for eliminating the malignancy. Recognizing BMT as a type of cell therapy, Dr. Brenner reasoned that if the body could naturally eliminate leukemia via this pathway, “why can’t you do it with other things”? Around the same time, researchers were starting to put new genes into cells to modify their behavior. He identified hematopoietic stem cells as an ideal target because they can repopulate a patient, last lifelong, and thus provide lifelong therapeutic benefits. This realization marked the beginning of his combined interest in cell and gene therapy.

The decision to focus simultaneously on both cell and gene therapy was considered "quite unusual" at that time as most people were focusing on cell or gene therapy. Since pursuing this combined interest proved difficult in the UK, Dr. Brenner moved to the United States. He worked first at St. Jude Children’s Hospital, where together with his long-term colleagues Drs Helen Heslop and Cliona Rooney they pioneered early gene transfer into marrow and demonstrated that Epstein-Barr virus-specific T-cells could be transferred to produce benefits in both infection and malignancy. The team subsequently moved to Baylor College of Medicine where Dr. Brenner remains a Professor at the Center for Cell and Gene Therapy.

Shaping the Landscape of Cell Therapy Societies

In the early 1990s, Dr. Brenner became deeply involved with the International Society of Cell Therapy (ISCT). Dr. Brenner recalls that Adrian Gee played an instrumental role in launching the society and its journal, which were initially known as the International Society of Hematotherapy and Graft Engineering and the Journal of Hematotherapy respectively. Early discussions centered on naming the organization the International Society of Cell and Gene Therapy, but a prevailing sentiment insisted on keeping the two fields distinct. At the time there was already an American Society of Gene Therapy which Dr. Brenner served as president from 2002 to 2003.

The early days of ISCT saw a much smaller organization, compared to its current size, still international but characterized by a highly non-commercial and academic focus. Companies were reluctant to engage with cell therapy, aside from those manufacturing basic components like bags or fluids. The core mission was training people entering cell therapy, with a strong emphasis on technical components and research.

Dr. Brenner felt inspired to take on leadership roles because when a field and its societies are developing, individuals can exert much greater influence. He believed setting standards and teaching was crucial to ensure good results and prevent disparate outcomes, which would otherwise obscure the reality of science. During his one-year presidency, he focused on team efforts and maintaining the society’s core ethos. He emphasized his reluctance for ISCT to become commercially driven despite how financially tempting it was.

However, he acknowledges that the field is currently evolving in a non-unidirectional manner. While some work remains purely academic, industry plays a necessary role in making components, and high-volume therapeutic approaches will likely require industry involvement. He views cell and gene therapy as evolving into a complex clinical practice, akin to bone marrow transplant or cardiovascular surgery, involving a close combination of industry and clinical expertise.

Scientific Insights and Future Trajectories

Looking back, Dr. Brenner anticipated several key advancements in the field such as better, faster methods for cell separation that would minimize operator error and increased ease of gene transfer. Looking ahead, he believes the "biggest change that's going to be coming" is the movement of cell therapy from ex vivo to in vivo methods. Despite the growth of in vivo gene therapy/transfer, he clarifies that cells will always remain the biological targets, as genes and mRNA require a cellular environment to function.

Dr. Brenner is still very active in research and trains post-doctoral scientists. His current research focuses on combinatorial approaches that essentially aim to make a tumor appear like a viral infection to the immune system. His work with Dr. Masataka Suzuki and others uses binary oncolytic and helper-dependent viruses delivered directly into the tumor to produce a range of cytokines and chemokines. This technique drastically alters the environment, resulting in various mechanisms of cell death and the recruitment of diverse effector cells. Early clinical results for these combinatorial approaches have been very promising.

The Central Role of Face-to-Face Interaction, Collaboration and Mentorship

A recurring theme in our conversation was the importance of personal, direct interaction in both leadership and scientific development. Dr. Brenner insists that leading people necessitates working with them. He expresses serious concern that modern communication and networking tools (social media, hybrid conferences) accentuated by COVID create too many filters, resulting in "degraded interaction" that lacks the crucial social cues evolved over human history.

Dr. Brenner highlights mentorship as the single most important element lost when face-to-face interaction is absent. His understanding of its value solidified after experiencing both an outstanding and a terrible mentor. He made it a career goal to ensure good mentorship was provided and that those mentored were trained to become mentors themselves. Mentorship is demanding of time but yields high rewards by witnessing the success of others. While he prefers in-house mentorship, he emphasizes the necessity of being collaborative in cell and gene therapy due to the field’s need for diverse skill sets.

To navigate the pervasive issue of bad mentorship in science, Dr. Brenner advises prevention: researchers should seek personal recommendations and scrutinize the lab environment before accepting a position. Signs to avoid include huge labs lacking individualized mentorship or small labs with visibly unhappy personnel. He specifically cautions against mentors who deliberately stall publication by withholding input, or those who maliciously pit two researchers against each other on the same project. For immigrant researchers whose visa status hinges on their position, he recommends choosing larger programs that permit program changes if the mentor-mentee relationship proves ineffective.

Advice for Early-Stage Professionals (ESPs)

For ESPs and people new to the field, Dr. Brenner insists that there is no universal answer as entry into the field is diverse, welcoming experts from areas like RNA chemistry, nanoparticle design, or 3D printing etc. He advises focusing on the research: "What is an important question, and can I help answer it?"

On aspiring to leadership, he says: “if they want to lead people, they have to know how to talk to people”. This means prioritizing physical contact and "FaceTime, not the application” but face-to-face interactions. Attend meetings, approach people and take interest in their research. He views hybrid conference attendance as a low-fidelity experience, comparing it to heavily compressed sound versus a live band.

Dr. Brenner’s final advice for ESPs is to "do your best," cultivate a supportive network of friends for difficult times, and remember "don't be too hard on yourself."

Legacy

Dr. Brenner's career narrative acts as a powerful analogue for the development of the field itself: starting with conventional, segmented practices, transitioning through critical discoveries, and ultimately synthesizing distinct disciplines to solve complex problems through strategic, collaborative approaches. His emphasis on mentorship and personal interaction underscores the idea that, much like gene transfer requires the living environment of a cell to function, scientific progress and leadership require the robust, high-fidelity environment of human connection.

His legacy is less about any single paper than the infrastructure and habits he instilled: a continual desire to merge clinical practice with research, ensuring that patient care directly informs scientific inquiry. The lives changed by virus specific T cells and gene modified therapies testify to the power of that approach. More importantly, the institutions and people he trained continue to deliver new therapies. In a field that can be captivated by novelty, Dr. Brenner reminds us that real progress is built carefully, ethically, and together until it’s reliable enough to belong to every patient who needs it.

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