Donald G. Phinney, PhD
Senior Editor
Department of Molecular Medicine
UF Scripps Biomedical Research
Jupiter, FL, USA
In this issue of Cytotherapy Corner, I want to highlight a manuscript in the June 2023 issue by Garcia-Rosa et al., from the ISCT Stem Cell Engineering Committee that reviews the current state of adoptive cell therapies for Graft-versus-Host Disease (GvHD). While allogeneic hematopoietic stem cell transplantation (HSCT) is curative for various maladies, the associated risk of developing GvHD remains high despite advances in pre-transplant conditioning regimens. For example, the incidences of acute and chronic GvHD are 40% and 50-70%, respectively, for all allogeneic HSCT recipients and the one-year survival rate for patients with severe acute GvHD is ~40%. The manuscript by Garcia-Rosa et al. provides a comprehensive overview of current strategies used to mitigate GvHD including graft manipulation, pharmacological agents, and cellular therapies. While the most effective strategy to reduce GvHD incidence is T-lymphocyte depletion, the authors summarize data describing the capacity of different T cells subsets to induce GvHD and how this information is being exploited to develop improved graft manipulation regimens. Similarly, the authors also briefly describe pharmacological agents in use today and their mechanism of action, which is largely aimed at preventing T cell activation and expansion of antigen activated T cells. The remainder of the paper is devoted to reviewing various cellular therapies under development for treating/preventing GvHD. Since GvHD arises from a cellular therapy, this approach seems counterintuitive. However, transplantation of Regulatory T cells (Tregs) has been shown to suppress immune responses in pre-clinical models of GvHD and other inflammatory and auto-immune diseases, and data exploring direct Treg transplantation in patients and administration of IL2 to induced expansion of Tregs in vivo is discussed. The authors also review existing clinical data on the use of mesenchymal stromal cells (MSCs) to prevent GvHD. The MSC story is an interesting one as one product, Remestemcel-L, yielded a high overall response rate in a phase 3 trail involving pediatric patients but the product has yet to receive FDA approval despite these promising clinical results. Other cellular therapies discussed include us of natural killer (NK) cells, myeloid-derived suppressor cells (MDSCs) and regulatory B cells. While the role of NK cells in preventing GvHD is indeterminate, studies have shown that grafts treated with G-CSF, which contain a higher frequency of MDSCs, result in better GvHD free survival in patients. The manuscript concludes with a discussion about the future challenges in developing cellular therapies for treating/preventing GvHD. Overall, this manuscript represents another excellent contribution from the Stem Cell Engineering Committee that I am sure the readership will find highly informative.
In the July 2023 issue, I want to highlight a paper by Kanner et al., that describes the production and evaluation of gene-edited chimeric antigen receptor (CAR) T cells harboring a PD-1 knockout. The PD-L1/PD-1 axis represents a widely studied immune checkpoint that inhibits the anti-tumor function of T cells, thereby enabling immune escape. Consequently, to facilitate checkpoint interference, the authors generated CAR-T cells expressing a CD19-directed CAR using a CRISPR-based platform consisting of a Cas9 with guides containing both RNA and DNA residues, which provides superior genome integrity following editing. An additional edit was generated by knocking out of the PDCD1 gene. After validation of the engineered CAR-T cells, the authors demonstrated that their administration to mice harboring cell-line derived xenografts of the CD19+ B-ALL tumor cell line NALM-6 engineered to express recombinant human PDL1 resulted in a dose-dependent increase in survival. Additionally, the CAR-T cells also promoted a statistically significant extension in the lifespan of mice harboring patient-derived xenografts of B-non-Hodgkin lymphoma. The authors further showed that their engineered CAR-T cells did not induce Graft-versus-Host disease and were superior with respect to survival compared to CAR KI cells (no PDCD1 KO) when administered to mice harboring xenografts of B cell tumors expressing PD-L1. Lastly, single cell RNA-sequencing based profiling of CAR-T cells isolated from of an orthotopically engrafted CD19+ NALM-6/PD-L1 tumor xenograft model indicated that those harboring the PDCD1 KO displayed lower exhaustion and dysfunction signatures and higher activation signatures compared to those with an intact PDCD1 gene. Together, these studies, which are comprehensive in nature, demonstrate that CD19 CAR-T cells harboring a PDCD1 KO exhibit superior efficacy against metastatic B cell tumors.
Happy reading.
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