Donald G. Phinney, PhD
Senior Editor, Cytotherapy
The Scripps Research Institute-Scripps Florida
Jupiter, FL, USA
In this issue of Cytotherapy Corner, I want to highlight a paper in the April 2022 issue contributed by the ISCT Stem Cell Engineering Committee that provides a perspective on how immune reconstitution milestones may be used to assess the recovery status and overall survival (OS) of allogeneic hematopoietic stem cell transplantation (HCT) patients. This paper by Bertaina et al., has broad appeal to the transplant community and the ISCT since bone marrow transplantation has been a stalwart of cell therapy for many decades. The authors begin by providing a succinct description of how allogeneic HCT compromises innate and adaptive immunity, the time frame for immune reconstitution, and variables that impact recovery of immune competence. The importance of reconstitution of T cell immunity and the factors that modulate this process are also described. The authors then delve into a detailed discussion focused on how implementation of well-defined immune reconstitution milestones may be used for risk-based stratification of complications, which can then guide management of such complications to improve patient outcomes. These milestones include response to vaccination, absolute lymphocyte counts and NK or CD4 T cell counts. In the latter case, an overview of how CD4 counts evolved from a marker of opportunistic infections in HIV patients to one used in combination with CD34 dose to predict overall survival and non-relapse mortality (NRM) is provided. Retrospective studies that correlate CD4 reconstitution thresholds with patient outcomes of interest are also highlighted along with a description of current and emerging tools to measure T cell diversity and thymic output in patients. Lastly, the authors argue that the milestone of early immune reconstitution of 50 CD4 T cells/µL by day 100 post-transplant is predictive of outcomes of interest in both pediatric and adult HCT recipients. They then discuss the impacts of pre-conditioning regimens and transplant platforms on immune reconstitution and how these may be modulated to minimize the number of at risk patients for poor outcomes. The paper is expertly written, highly informative, and makes a solid case for implementation and further validation of early CD4 T cell counts as a simple but predictable maker of risks/outcomes in HCT patients.
In the May 2022 issue, I found the paper by Srinivasan et al. of particular interest, as it describes strategies to reduce the heterogeneity and enhance the immune modulatory activity of MSCs during large-scale manufacturing. This topic is of keen interest to my lab and a problem we have been working on for several years. The manuscript provides an in-depth review of the current state of MSC therapeutics and discusses several strategies to improve MSC potency and reduce heterogeneity including the implementation of donor screening, something that is often ignored or dismissed as inconsequential. The authors describe a catalog of markers that have been shown to correlate with CFU-F activity, differentiation potential, and immune modulation, which have been largely based on enrichment or gain/loss-of-function studies. However, it is unclear if any of these markers have been shown to be differentially expressed across a large cohort of MSC donors, which is key to implementing them as screening tools. The authors go on to describe biophysical and genomic markers that may be useful in identifying MSCs that are most amenable to large scale expansion and discuss the use of media bio-additives that have been used to enhance MSC scalability. They also provide a comprehensive review on methods that have been employed to prime MSCs to augment secretion of specific paracrine factors. The section includes bio-active factors as well as use of biophysical priming methods. Notably, the authors also discuss challenges associated with priming, which is some cases may result in unintended or detrimental consequences including reduced growth or viability or increased immunogenicity. Other topics covered in detail include genetic modification and formulation of MSC-based products. Lastly, the authors describe best practices used as release criteria to assess the viability, sterility, and potency of manufactured MSC products. Overall, the article is highly informative and highlights advances made in the field and the many challenges that remain.
Happy reading and keep those submissions coming.