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by

Jingjing Li, PhD
University of New South Wales
Sydney, Australia

Hematopoietic Stem Cell Transplantation and Stem Cell Engineering

The origins of Hematopoietic Stem Cell (HSC) transplantation can be traced back to the mid-20th century when early explorations were undertaken to unlock the therapeutic potential of bone marrow. Dr. E. Donnall Thomas and his colleagues conducted groundbreaking research in the 1950s and 1960s, laying the groundwork for modern HSC transplantation. Their pioneering work showcased the feasibility of transplanting hematopoietic stem cells from one individual to another, ushering in new hope for treating previously untreatable blood disorders and cancers. Over the decades, enhancements in transplantation techniques, donor compatibility, and supportive care have transformed HSC transplantation into a standard and life-saving medical procedure, evolving from its experimental origins into a foundational pillar of hematological and oncological treatments.

In parallel, stem cell engineering emerged, capitalizing on the innate regenerative capabilities of stem cells and employing engineering principles, including genetic engineering, to craft innovative therapies and tools for an expansive spectrum of diseases. This interdisciplinary field amalgamates state-of-the-art technologies and molecular biology to meticulously manipulate stem cells, affording precise command over their differentiation, expansion, and seamless integration into specific tissues. Consequently, stem cell engineering has ascended as an integral component of the cell and gene therapy arena, reshaping the treatment paradigm for conditions that were once deemed untreatable.

The ISCT Stem Cell Engineering (SCE) Committee perpetuates the legacy of these pioneering visionaries, wholly committed to advancing the field and stretching the boundaries of what engineered stem cells can achieve within the realm of cell and gene therapies.

Overview of Committee and Scope

Established in 2020, the ISCT Stem Cell Engineering Committee was initially formed to promote and disseminate scientific discovery and establish clinical recommendations in the fields of stem and hematopoietic cell transplantation, engineering of stem cells (including gene therapy and graft manipulation such as T cell depletion techniques), and more advanced cell and gene therapy solutions for definitive cure of malignant and non-malignant life-threatening disorders. The scope of the committee continues to encompass all facets of stem cell engineering within the ever-evolving domain of cell and gene therapy. The committee's core mission revolves around furnishing a robust platform for discourse and advancement of the field, and it endeavors to do so through the publication of reviews and position papers in Cytotherapy, ISCT’s peer reviewed academic Journal, and educational sessions at ISCT Annual and Regional Meetings. These activities leverage the translational expertise of delegates to address challenges to capitalizing on recent research developments.

The committee is composed of experts hailing from diverse domains, [WvH1] including allogeneic stem cell transplantation, ex-vivo stem cell (including T cell) genetic reprogramming and gene therapy, care for patients with immune deficiencies and immune dysregulation, and in vitro stem cell (including T cell) manipulation. This multifaceted composition ensures a comprehensive spectrum of perspectives, effectively covering the myriad of aspects of stem cell engineering. Presently, the ISCT SCE committee is under the leadership of Dr. Jaap Jan Boelens (Memorial Sloan Kettering Cancer Center, New York, United States) and Dr. Alice Bertaina (Stanford School of Medicine, Stanford, United States). Its membership spans all career stages and boasts global representation.

Addressing Key Topics within the Field

The committee collaborates closely with the ISCT executive team and other ISCT committees, actively engaged in identifying and championing progress in stem cell research, enabling technologies, and emerging applications of engineered stem cell products. This comprehensive engagement extends to the exploration of diverse stem cell sources for clinical transplantation, the development of innovative engineering strategies, the utilization of emerging techniques for manipulating stem cells, and the practical implementation of stem cell engineering in clinical contexts. Additionally, the committee meticulously considers variables such as agent clearance in conditioning regimens and the immune reconstitution/immune milieu post-transplantation as prognostic factors for outcomes. To achieve these objectives, the Stem Cell Engineering Committee plays an integral role in planning the Roundtable Programs at the ISCT Annual Meeting and ISCT Regional Meetings. Furthermore, the committee actively participates in abstract reviews, conducts thorough evaluations to capture the present state and novel developments in engineered cell therapies, and releases position papers to propel the field forward.

Highlight the Committee’s recent activities and publications that address such topics.

During 2022-2023, the ISCT SCE Committee has published multiple reviews in Cytotherapy, shedding light on the latest advancements and challenges in hematopoietic stem cell transplantation and stem cell engineering.

1.       In the June 2023 issue of Cytotherapy (Vol.25, Issue 6), led by Moises Garcia-Rosa (MD, Memorial Sloan Kettering Cancer Center, United States), the committee examined the current landscape of adoptive cellular therapies, including mesenchymal stromal cells and regulatory T cells, as potential interventions for treatment of graft-versus-host disease (GvHD). The review article highlighted the still incomplete understanding of the biology of these cell populations and their mechanism of action in the treatment of GvHD. Ongoing trials aim to enhance our understanding and broaden the application of these therapies, with the goal of improving GvHD-related outcomes in the near future.  

2.       In the May 2023 issue of Cytotherapy (Vol.25, Issue 5), led by Orly R. Klein (MD, Stanford School of Medicine Stanford, United States), the committee reviewed transplant considerations, transplant goals, conditioning regimens, donor choice, and graft manipulation strategies for patients with non-malignant disorders undergoing HSC transplantation. This review suggested that strategies like targeted conditioning regimens, alternative donors, and graft manipulation techniques have expanded accessibility globally, but additional large trials are needed for optimal transplant design. Exciting developments, including post-transplant cyclophosphamide (PTCy), have broadened the applicability of HSC transplantation, particularly for minority patients, though it is highlighted that ongoing monitoring is crucial to understanding potential late effects, and multi-center trials are essential for refining regimens and improving outcomes in non-malignant disorders.

3.       In the June 2022 issue of Cytotherapy (Vol.24, Issue 6), led by Susan Prockop (MD, Boston Children's Hospital Boston, United States), the committee reviewed the viral infections in hematopoietic stem cell transplantation. The review highlights the challenges associated with allogeneic hematopoietic stem cell transplant (HSCT), emphasizing the morbidity and mortality risks arising from impaired T-cell reconstitution, particularly in the context of viral infections. Timely immune recovery, especially T-cell reconstitution, is crucial for reducing infections and disease relapse in HSCT recipients. The conclusion underscores the ongoing issues with viral infections despite recent HSCT advances, advocates for risk stratification based on immune reconstitution milestones, and discusses the potential of adoptive cell therapy, specifically virus-specific T cells, as a promising strategy to address these challenges, emphasizing the need to overcome manufacturing and clinical obstacles for broader application.

4.       In the April 2022 issue of Cytotherapy (Vol24, Issue 4), led by Susan Prockop (MD, Boston Children's Hospital Boston, United States), the committee developed a position statement on immune reconstitution post hematopoietic stem cell transplantation. The review commented on the fact that despite substantial advances since the 1970s and improved access with HLA incompatible or alternative donors, the success of transplantation is hindered by morbidity and mortality from toxicity and disease control issues. The article focuses on the emerging understanding of how the reconstitution of effective immunity after allogeneic transplant can mitigate these challenges and enhance outcomes, highlighting measurable and modifiable milestones in immune reconstitution.

5.       In the March 2022 issue of Cytotherapy (Vol.24, Issue 4), led by Annalisa Ruggeri (MD, PhD

San Raffaele Hospital Milan, Italy) and Allistair Abraham (MD, Children's National Hospital Washington, United States), the committee reviewed current outcomes in allogeneic and autologous HSCT for transfusion-dependent thalassemia and sickle cell disease and provided perspectives on issues surrounding accessibility and costs as barriers to offering curative therapy to patients with hereditary hemoglobinopathies.

Moreover, the ISCT SCE Committee organized roundtable discussions and concurrent sessions during the ISCT 2023 annual meeting in Paris. Moderated by SCE committee members Christal Louis (MD, MPH, Zentalis Pharmaceuticals) and Susan Prockop (MD, Boston Children’s Hospital, USA), the roundtable session featured invited panelists, including Yona Geffen (PhD, Gamida Cell, IL), Marina Cavazzana (MD, PhD, Necker Hospital, Paris Cité University, FR), Michael Schuster (MS, MBA, Mesoblast Inc., US), and Kevin Bosse (PhD, RAC-US, CABP(H), Nationwide Children’s Hospital, US). The committee guided a stimulating discussion on assessing the timing of expanding novel therapies into pediatric cohorts.  The discussion covered topics like the current FDA and EMA guidance for integrating pediatric subjects into early phase trials of novel cellular therapies (PIP requirements). The conversation explored how factors such as the underlying disease, patient numbers, and the presence or absence of alternative therapies impact both the design of registration trials and the hurdles for approval, underscoring the importance of acknowledging the burden of long-term follow-up in pediatrics. Additionally, the committee hosted a science and innovation concurrent session titled “Novel genome editors and their application in human disease,” chaired by committee co-chair Alice Bertaina (MD, PhD, Associate Professor of Pediatrics, Stanford School of Medicine, USA). The session featured speakers, including Benjamin Kleinstiver (PhD, Assistant Professor, Mass General Hospital & Harvard Medical School, USA) and Shengdar Tsai (PhD, Associate Member, St. Jude Children's Research Hospital, USA), focusing on discussing approaches to develop novel nucleases, base and prime editors, and methods to detect off-target activities of the CRISPR/Cas and related nucleases. The speakers delved into clinical applications, novel assays in development, and how these advancements are pushing the boundaries of genetic treatments, aiming for commercial availability soon.

Beyond these accomplishments, the ISCT SCE Committee is currently spearheading several other initiatives. The committee is actively championing workforce development initiatives at all levels, including contributing members to the ISCT Early-Stage Professional (ESP) Mentoring and Leadership Program. These endeavors are aimed at nurturing the next generation of leaders in the field and enhancing the competence of the emerging workforce to effectively address the evolving challenges unique to stem cell and gene therapies. Furthermore, ISCT SCE Committee members play a crucial role in the evaluation process for abstracts submitted to the annual meeting in the “hematopoietic stem cell and engineering” category, ensuring a diverse and high-quality scientific program.

In an ever-evolving landscape of cell and gene therapy, the ISCT Stem Cell Engineering Committee remains committed to advancing the clinical engagement in cell- and gene-based therapies on a global scale. Our future endeavors will continue to foster collaboration with diverse scientific, clinical, and professional organizations, as well as regulatory bodies, to address issues around hematopoietic stem cell transplant and engineered cell therapies. We provide educational resources, such as peer-reviewed articles, while also intensifying our outreach to clinicians and transplant units and centers.