scholarly journals Altered T-Lymphocyte Biology Following High-Dose Melphalan and Autologous Stem Cell Transplantation With Implications for Adoptive T-Cell Therapy

2020 ◽  
Vol 10 ◽  
Author(s):  
Thomas Mika ◽  
Swetlana Ladigan-Badura ◽  
Abdelouahid Maghnouj ◽  
Bakr Mustafa ◽  
Susanne Klein-Scory ◽  
...  

In relapsed and refractory multiple myeloma (MM), adoptive cell therapies (ACT) including CAR-T-cells are under clinical investigation. However, relapse due to T-cell exhaustion or limited persistence is an obstacle. Before ACT are considered in MM, high-dose (HD) melphalan followed by autologous stem-cell transplantation (autoSCT) has been administered in most clinical situations. Yet, the impact of HD chemotherapy on T-cells in MM with respect to ACT is unclear. In this study, T-lymphocytes’ phenotypes, expansion properties, lentiviral transduction efficacy, and gene expression were examined with special respect to patients following HD melphalan. Significant impairment of T-cells’ expansion and transduction rates could be demonstrated. Expansion was diminished due to inherent disadvantages of the predominant T-cell phenotype but restored over time. The quantitative fraction of CD27−/CD28− T-cells before expansion was predictive of T-cell yield. Following autoSCT, the transduction efficacy was reduced by disturbed lentiviral genome integration. Moreover, an unfavorable T-cell phenotype after expansion was demonstrated. In initial analyses of CD107a degranulation impaired T-cell cytotoxicity was detected in one patient following melphalan and autoSCT. The findings of our study have potential implications regarding the time point of leukapheresis for CAR-T-cell manufacturing. Our results point to a preferred interval of more than 3 months until patients should undergo cell separation for CAR-T therapy in the specific situation post-HD melphalan/autoSCT. Monitoring of CD27−/CD28− T-cells, has the potential to influence clinical decision making before apheresis in MM.

JCI Insight ◽  
2019 ◽  
Vol 4 (4) ◽  
Author(s):  
Alfred L. Garfall ◽  
Edward A. Stadtmauer ◽  
Wei-Ting Hwang ◽  
Simon F. Lacey ◽  
Jan Joseph Melenhorst ◽  
...  

JCI Insight ◽  
2018 ◽  
Vol 3 (8) ◽  
Author(s):  
Alfred L. Garfall ◽  
Edward A. Stadtmauer ◽  
Wei-Ting Hwang ◽  
Simon F. Lacey ◽  
Jan Joseph Melenhorst ◽  
...  

Blood ◽  
2021 ◽  
Author(s):  
Mariapia A Degli-Esposti ◽  
Geoffrey R Hill

The reactivation of viruses from latency after allogeneic stem cell transplantation (SCT) continues to represent a major clinical challenge requiring sophisticated monitoring strategies in the context of prophylactic and/or pre-emptive antiviral drugs that are associated with significant expense, toxicity, and rates of failure. Accumulating evidence has demonstrated the association of polyfunctional virus-specific T-cells with protection from viral reactivation, affirmed by the ability of adoptively transferred virus-specific T-cells to prevent and treat reactivation and disease. The roles of innate cells (NK cells) in early viral surveillance, and dendritic cells in priming of T-cells have also been delineated. Most recently, a role for strain-specific humoral responses in preventing early cytomegalovirus (CMV) reactivation has been demonstrated in preclinical models. Despite these advances, many unknowns remain: what are the critical innate and adaptive responses over time, is the origin (e.g. recipient versus donor) and localization (e.g. in parenchymal tissue versus lymphoid organs) of these responses important, how does GVHD and the prevention/treatment thereof (e.g. high dose steroids) impact the functionality and relevance of a particular immune axis, do the immune parameters that control latency, reactivation and dissemination differ, and what is the impact of new antiviral drugs on the development of enduring antiviral immunity. Thus, whilst antiviral drugs have provided major improvements over the last two decades, understanding the immunological paradigms underpinning protective antiviral immunity after SCT offers the potential to generate non-toxic immune-based therapeutic approaches for lasting protection from viral reactivation.


Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5431-5431 ◽  
Author(s):  
Peter Reimer ◽  
Thomas Ruediger ◽  
Florian Weissinger ◽  
Hans Konrad Mueller-Hermelink ◽  
Andreas Engert ◽  
...  

Abstract Introduction: Peripheral T-cell lymphomas (PTCL) are rare diseases and optimal treatment strategies still remain to be defined. With the exception of the ALK-positive anaplastic large cell lymphoma (ALCL) that shows a favourable outcome following conventional chemotherapy, PTCL are known for their poorer prognosis compared to aggressive B-cell lymphomas. However, the impact of the different PTCL-subtypes on treatment outcome has not been clearly demonstrated in prospective studies. PTCL unspecified (PTCL-U) and angioimmunoblastic T-cell lymphoma (AIL) represent the most common subtypes of PTCL in Western countries, accounting for approximately 70% of PTCL. We therefore analysed the data of our study on myeloablative radiochemotherapy followed by autologous stem cell transplantation (ASCT) in primary diagnosed PTCL with regard to the main histologic subtypes. Material and Methods: From 06/00 to 06/06 92 patients with confirmed diagnosis of PTCL entered the study. Primary cutaneous PTCL and ALK+ ALCL were excluded from the trial. Main subtypes were PTCL-U (n= 37) and AIL (n= 28) accounting for 65 of the 92 patients (71%). 0f these patients 53 (PTCL, n= 31; AIL, n= 22) were evaluable for the analysis (82%). Results: Median age was 50 years in the PTCL-U and 47.5 years in the AIL group, respectively. The International Prognostic Index (IPI) did not differ in both groups. In the PTCL-U and the AIL group a low/intermediate-low risk was found in 35% and 36%, respectively and a high/intermediate-high risk in 65% and 64%, respectively. There were slightly more patients in stage IV in the AIL group compared to the PTCL-U group (64% versus 53%). In addition, more patients in the AIL group complained of B-symptoms and had bone marrow involvement compared to the PTCL-U group (86% versus 66% and 48% versus 39%, respectively). However, in an intent-to treat analysis only 58% in the PTCL-U group compared to 82% in the AIL group underwent ASCT mainly due to a higher rate of patients with progressive disease in the PTCL-U group. The median overall survival (OS) was 11 months in the PTCL-NOS and 20 months in the AIL group. Regarding only patients undergoing ASCT, the median OS was 13.5 months in the PTCL-U and 25.5 months in the AIL group. Conclusion: Our analysis suggests that patients with AIL, although showing a slightly more unfavourable risk profile at diagnosis, benefit more from upfront autotransplantation than patients with PTCL-U in our study.


2012 ◽  
Vol 4 (1) ◽  
pp. e2012075 ◽  
Author(s):  
Giuseppe Visani ◽  
Paola Picardi ◽  
Patrizia Tosi ◽  
Alessandro Isidori

The role of high-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) in the treatment armamentarium of aggressive B- and T-cell non-Hodgkin lymphoma (NHL) is still a matter of debate. In the pre-Rituximab era, the PARMA study demonstrated the superiority of HDT/ASCT over conventional salvage chemotherapy in chemosensitive, relapsed patients. Subsequently, HDT/ASCT has become a standard approach for relapsed NHL. With the advent of Rituximab in the landscape of NHL, transplantation as part of first-line therapy has been challenged. However, no benefit in terms of disease-free or overall survival of HDT/ASCT over standard therapy was shown when Rituximab was added to both arms. Moreover, the superiority of HDT/ASCT over conventional salvage therapy in patients relapsing from first-line therapy including Rituximab was not confirmed. From these disappointing results, novel strategies, which can enhance the anti-lymphoma effect, at the same time reducing toxicity have been developed, with the aim of improving the outcome of HDT/ASCT in aggressive NHL.In T-cell lymphoma, few publications demonstrated that consolidation of complete remission with HDT/ASCT is safe and feasible. However, up to one-third of patients may never receive transplant, mostly due to progressive disease, and relapse still remains a major concern even after transplant.


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