Reverse TCR repertoire evolution toward dominant low-affinity clones during chronic CMV infection.

Adaptive evolution is a key feature of T cell immunity. During acute immune responses, T cells harboring high-affinity T cell antigen receptors (TCRs) are preferentially expanded, but whether affinity maturation by clonal selection continues through the course of chronic infections remains unresolved. Here we investigated the evolution of the TCR repertoire and its affinity during the course of infection with cytomegalovirus, which elicits large T cell populations in humans and mice. Using single-cell and bulk TCR sequencing and structural affinity analyses of cytomegalovirus-specific T cells, and through the generation and in vivo monitoring of defined TCR repertoires, we found that the immunodominance of high-affinity T cell clones declined during the chronic infection phase, likely due to cellular senescence. These data showed that under conditions of chronic antigen exposure, low-affinity TCRs preferentially expanded within the TCR repertoire, with implications for immunotherapeutic strategies.

Global koff -rates of polyclonal T-cell populations merge subclonal avidities and predict functionality.

The avidity of TCRs for peptide-major histocompatibility complexes (pMHCs) is a governing factor in how T cells respond to antigen. TCR avidity is generally linked to T-cell functionality and there is growing evidence for distinct roles of low and high avidity T cells in different phases of immune responses. While physiological immune responses and many therapeutic T-cell products targeting infections or cancers consist of polyclonal T-cell populations with a wide range of individual avidities, the role of T-cell avidity is usually investigated only in monoclonal experimental settings. In this report, we induced polyclonal T-cell responses with a wide range of avidities toward a model epitope by altered peptide ligands, and benchmarked global avidity of physiological polyclonal populations by investigation of TCR-pMHC koff -rates. We then investigated how varying sizes and avidities of monoclonal subpopulations translate into global koff -rates. Global koff -rates integrate subclonal avidities in a predictably weighted manner and robustly correlate with the functionality of murine polyclonal T-cell populations in vitro and in vivo. Surveying the full avidity spectrum is essential to accurately assess polyclonal immune responses and inform the design of polyclonal T-cell therapeutics.

Characterization and outcome of post-transplant lymphoproliferative disorders within a collaborative study.

Background: Post-transplant lymphoproliferative disorders (PTLD) are heterogeneous lymphoid disorders ranging from indolent polyclonal proliferations to aggressive lymphomas that can arise after solid organ transplantation (SOT) and allogeneic hematopoietic transplantation (allo-HSCT). Methods: In this multi-center retrospective study, we compare patient characteristics, therapies, and outcomes of PTLD after allo-HSCT and SOT. Twenty-five patients (15 after allo-HSCT and 10 after SOT) were identified who developed PTLD between 2008 and 2022. Results: Median age (57 years; range, 29-74 years) and baseline characteristics were comparable between the two groups (allo-HSCT vs SOT), but median onset of PTLD was markedly shorter after allo-HSCT (2 months vs. 99 months, P<0.001). Treatment regimens were heterogeneous, with reduction of immunosuppression in combination with rituximab being the most common first-line treatment strategy in both cohorts (allo-HSCT: 66%; SOT: 80%). The overall response rate was lower in the allo-HSCT (67%) as compared to the SOT group (100%). Consequently, the overall survival (OS) trended towards a worse outcome for the allo-HSCT group (1-year OS: 54% vs. 78%; P=0.58). We identified PTLD onset ≤150 days in the allo-HSCT (P=0.046) and ECOG >2 in the SOT group (P=0.03) as prognostic factors for lower OS. Conclusion: PTLD cases present heterogeneously and pose unique challenges after both types of allogeneic transplantation.

Allogeneic Stem-Cell Transplantation in Patients With Myelodysplastic Syndromes and Prevention of Relapse.

Myelodysplastic syndromes (MDS) mainly affect the elderly population, which implies that the majority of patients cannot tolerate intensive therapeutic approaches, including allogeneic hematopoietic stem-cell transplantation (allo-HSCT). The underlying impaired stem-cell function leads to peripheral cytopenia, including a propensity to progress to acute myeloid leukemia. Allo-HSCT is considered the only potentially curable therapy. Reduced-intensity conditioning regimens have shown to improve early tolerability of the procedure, but late effects like graft-versus-host disease and relapse remain major challenges in the care of these patients. Therefore, special attention should be paid to posttransplantation care in terms of graft-versus-host disease management, measurable residual disease monitoring, and prevention of relapse. In fact, recent advances in the field have shown that minimal residual disease measurement and preemptive therapies may be a promising approach to prevent or at least delay relapse. This review briefly discusses indication and selection of patients for allo-HSCT in MDS, pretransplantation evaluation and choice of conditioning regimens, and prophylactic and preemptive approaches to prevent relapse after allo-HSCT.

Production and Application of CAR T Cells: Current and Future Role of Europe.

Rapid developments in the field of CAR T cells offer important new opportunities while at the same time increasing numbers of patients pose major challenges. This review is summarizing on the one hand the state of the art in CAR T cell trials with a unique perspective on the role that Europe is playing. On the other hand, an overview of reproducible processing techniques is presented, from manual or semi-automated up to fully automated manufacturing of clinical-grade CAR T cells. Besides regulatory requirements, an outlook is given in the direction of digitally controlled automated manufacturing in order to lower cost and complexity and to address CAR T cell products for a greater number of patients and a variety of malignant diseases.