-
1.
Adoptive therapy with cytomegalovirus-specific cytotoxic T lymphocytes for refractory cytomegalovirus DNAemia and disease after allogeneic haematopoietic stem cell transplantation
Jiang, Z., Fan, Z., Zhang, T., Lin, R., Xu, H., Xu, N., Huang, F., Chi, P., Ou, X., Wang, Z., et al
British journal of haematology. 2024
Abstract
Cytomegalovirus (CMV) DNAemia and disease are common complications in patients undergoing allogeneic haematopoietic stem cell transplantation (allo-HSCT). Few studies have compared the efficacy and safety of the HSCT donor and third-party CMV-specific cytotoxic T lymphocytes (CMV-CTLs) in the treatment of CMV DNAemia and disease. In this study, we retrospectively compared the efficacy and safety of HSCT donor and third-party CMV-CTLs in patients with refractory CMV DNAemia or disease after allo-HSCT at our centre from January 2017 to September 2021. Fifty-three patients who received CMV-CTL therapy were enrolled, including 40 in the donor group and 13 in the third-party group, and they were adults aged 18 years or older. Within 6 weeks of treatment, 26 (65.0%) and 9 (69.2%) patients achieved complete response in the donor and third-party groups (p = 1.000). The 2-year overall survival was 59.6% (95% CI 46.1%-77.1%) and 53.8% (32.6%-89.1%) in the donor and third-party groups (p = 0.860). Four (10.0%) patients in the donor group and two (15.4%) patients in the third-party group developed acute graft-versus-host disease within 3 months after CMV-CTL infusions. In conclusion, our data suggest that donor and third-party CMV-CTLs have comparable efficacy and safety for refractory CMV DNAemia and disease.
-
2.
Prevention of CMV/EBV reactivation by double-specific T cells in patients after allogeneic stem cell transplantation: results from the randomized phase I/IIa MULTIVIR-01 study
Gerbitz, A., Gary, R., Aigner, M., Moosmann, A., Kremer, A., Schmid, C., Hirschbuehl, K., Wagner, E., Hauptrock, B., Teschner, D., et al
Frontiers in immunology. 2023;14:1251593
-
-
-
Free full text
-
Editor's Choice
Abstract
INTRODUCTION Allogeneic stem cell transplantation is used to cure hematologic malignancies or deficiencies of the hematopoietic system. It is associated with severe immunodeficiency of the host early after transplant and therefore early reactivation of latent herpesviruses such as CMV and EBV within the first 100 days are frequent. Small studies and case series indicated that application of herpes virus specific T cells can control and prevent disease in this patient population. METHODS We report the results of a randomized controlled multi centre phase I/IIa study (MULTIVIR-01) using a newly developed T cell product with specificity for CMV and EBV derived from the allogeneic stem cell grafts used for transplantation. The study aimed at prevention and preemptive treatment of both viruses in patients after allogeneic stem cell transplantation targeting first infusion on day +30. Primary endpoints were acute transfusion reaction and acute-graft versus-host-disease after infusion of activated T cells. RESULTS Thirty-three patients were screened and 9 patients were treated with a total of 25 doses of the T cell product. We show that central manufacturing can be achieved successfully under study conditions and the product can be applied without major side effects. Overall survival, transplant related mortality, cumulative incidence of graft versus host disease and number of severe adverse events were not different between treatment and control groups. Expansion of CMV/EBV specific T cells was observed in a fraction of patients, but overall there was no difference in virus reactivation. DISCUSSION Our study results indicate peptide stimulated epitope specific T cells derived from stem cell grafts can be administered safely for prevention and preemptive treatment of reactivation without evidence for induction of acute graft versus host disease. CLINICAL TRIAL REGISTRATION https://clinicaltrials.gov, identifier NCT02227641.
PICO Summary
Population
Adults undergoing allogeneic transplant from a matched donor who was seropositive for cytomegalovirus (CMV) and Epstein-barr virus (EBV) and enrolled in the MULTIVIR-01 study in centres in Germany (n=33)
Intervention
A newly developed T cell product with specificity for CMV and EBV derived from the allogeneic stem cell grafts used for transplantation. (n=16; 9 received full treatment)
Comparison
Control (n=13)
Outcome
Central manufacturing can be achieved successfully under study conditions and the product can be applied without major side effects. Overall survival, transplant related mortality, cumulative incidence of graft versus host disease and number of severe adverse events were not different between treatment and control groups. Expansion of CMV/EBV specific T cells was observed in a fraction of patients, but overall there was no difference in virus reactivation
-
3.
Early antibiotic de-escalation and discontinuation in Patients with Febrile Neutropenia after Cellular Therapy: A Single Center Prospective Unblinded Randomized Trial
Ram, R., Amit, O., Adler, A., Bar-On, Y., Beyar-Katz, O., Avivi, I., Shasha, D., Ben-Ami, R.
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND The optimal duration of empiric antimicrobial therapy of febrile neutropenia in patients after cellular therapy is unclear. Early de-escalation has been suggested by some authorities, however data are lacking for cellular therapy recipients. METHODS we performed a randomized controlled study of cellular therapy recipients with febrile neutropenia to evaluate the safety and non-inferiority of an early de-escalation and discontinuation (EDD) antibiotic strategy versus standard broad spectrum antibiotic treatment until recovery of neutropenia (standard duration arm). The primary outcome was the fraction of antibiotic-free neutropenia days. RESULTS we randomized 110 patients (standard duration arm, n=51, EDD arm, n=59). The fraction of antibiotic-free neutropenia days was higher for patients in the EDD arm compared to standard duration arm (median [IQR], 0.8 [0.62-0.86] versus 0.51 [0.17-0.86], respectively, p=.016). This was true for the per-protocol, allogeneic HCT, autologous HCT, and anti-CD19 CAR-T subgroups. Treatment success rate, subsequent fever, death within 30 days, and other common cellular therapy-related toxicities were all similar between the 2 study arms. CONCLUSIONS An EDD antibiotic strategy in patients after cellular therapy was safe and associated with a substantial reduction in broad-spectrum antibiotic utilization without compromising cellular therapy outcomes.
-
4.
[Effect of Plasmacytoid Dendritic Cell Dose in Grafts on CMV Infection after Allogeneic Hematopoietic Stem Cell Transplantation]
Yao, D., Tian, Y. Y., Lu, J., Xiao, P. F., Ling, J., Zheng, D. F., Gao, J., Fan, L. Y., Zheng, J. J., Li, J., et al
Zhongguo shi yan xue ye xue za zhi. 2023;31(4):1184-1191
Abstract
OBJECTIVE To investigate the correlation between plasmacytoid dendritic cell (pDC) dose in grafts and the occurrence of cytomegalovirus (CMV) infection after allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS The clinical data of 80 children who received allo-HSCT in Children's Hospital of Soochow University from August 20, 2020 to June 11, 2021 were retrospectively analyzed. Proportions of DC subsets and T-cell subsets in grafts were detected by flow cytometry in order to calculate infused cell dose of each cell. Weekly monitoring of CMV-DNA copies in peripheral blood for each child were performed after transplantation. The last follow-up date was December 31, 2021. RESULTS All the children gained hematopoietic reconstitution. CMV infection was observed in 51 children (63.8%±5.4%) within the first 100 days after transplantation, including 2 cases developing CMV disease. Univariate analysis indicated that infused doses of DC and pDC were significantly associated with CMV infection within 100 days after allo-HSCT (P <0.05). Multivariate analysis indicated that a high dose infusion of pDC was an independent protective factor for CMV infection within 100 days after allo-HSCT (P <0.05). By the end of follow-up, 7 children died of transplantation-related complications, including 2 deaths from CMV disease, 2 deaths from extensive chronic graft-versus-host disease, and 3 deaths from capillary leak syndrome. The overall survival rate was 91.2%. CONCLUSION The pDC in grafts may be associated with early infection of CMV after allo-HSCT, while a high infused pDC dose may serve as a protective factor for CMV infection after transplantation.
-
5.
Posoleucel, an Allogeneic, Off-the-Shelf Multivirus-Specific T-Cell Therapy, for the Treatment of Refractory Viral Infections in the Post-HCT Setting
Pfeiffer, T., Tzannou, I., Wu, M., Ramos, C., Sasa, G., Martinez, C., Lulla, P., Krance, R. A., Scherer, L., Ruderfer, D., et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2023;:Of1-of7
-
-
-
Free full text
-
Full text
-
Editor's Choice
Abstract
PURPOSE Viral infections are a major cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (allo-HCT). In the absence of safe and effective antiviral treatments, virus-specific T cells have emerged as a promising therapeutic option. Posoleucel is a multivirus-specific T-cell therapy for off-the-shelf use against six viral infections that commonly occur in allo-HCT recipients: adenovirus, BK virus (BKV), cytomegalovirus, Epstein-Barr virus, human herpes virus-6, and JC virus. PATIENTS AND METHODS We conducted an open-label, phase II trial to determine the feasibility and safety of posoleucel in allo-HCT recipients infected with one or more of these viruses. Infections were either unresponsive to or patients were unable to tolerate standard antiviral therapies. Fifty-eight adult and pediatric patients were enrolled and treated. RESULTS Posoleucel was well tolerated, with no cytokine release syndrome or other infusion-related toxicities; two patients (3.4%) developed Grade 2 and one patient (1.7%) Grade 3 GvHD during the trial. The overall response rate 6 weeks after the first posoleucel infusion was 95%, with a median plasma viral load reduction of 97%. Of the 12 patients who had two or more target viral infections identified at study entry, 10 (83%) had a clinical response for all evaluable viruses. Of the 23 patients treated for refractory BKV-associated hemorrhagic cystitis, 74% had resolution of symptoms and macroscopic hematuria by 6 weeks post-infusion. CONCLUSIONS In this open-label trial, treatment of refractory viral infections/disease in allo-HCT recipients with posoleucel was feasible, safe, and effective.
PICO Summary
Population
Adult and pediatric allogeneic HSCT recipients infected with one or more of adenovirus, BK virus (BKV), cytomegalovirus, Epstein-Barr virus, human herpes virus-6, and JC virus (n=58)
Intervention
Single intravenous infusion of 2 × 107/m2 of posoleucel with the option to receive a second infusion after four weeks and additional infusions at biweekly intervals thereafter.
Comparison
None
Outcome
Posoleucel was well tolerated, with no cytokine release syndrome or other infusion-related toxicities; two patients (3.4%) developed Grade 2 and one patient (1.7%) Grade 3 GvHD during the trial. The overall response rate 6 weeks after the first posoleucel infusion was 95%, with a median plasma viral load reduction of 97%. Of the 12 patients who had two or more target viral infections identified at study entry, 10 (83%) had a clinical response for all evaluable viruses. Of the 23 patients treated for refractory BKV-associated hemorrhagic cystitis, 74% had resolution of symptoms and macroscopic hematuria by 6 weeks post-infusion.
-
6.
Adoptive therapy with cytomegalovirus-specific T cells for cytomegalovirus infection after haploidentical stem cell transplantation and factors affecting efficacy
Pei, X. Y., Zhao, X. Y., Liu, X. F., Mo, X. D., Lv, M., Xu, L. P., Wang, Y., Chang, Y. J., Zhang, X. H., Liu, K. Y., et al
American journal of hematology. 2022;97(6):762-769
Abstract
Adoptive therapy with cytomegalovirus (CMV)-specific cytotoxic T lymphocytes (CMV-CTLs) has emerged as an effective method for CMV infection. However, the efficacy reportedly ranges from 50% to 90%, and factors affecting anti-CMV efficacy have not been established. We investigated the safety and efficacy of adoptive therapy with CMV-CTLs for CMV infection in 190 patients after haploidentical stem cell transplantation (haplo-SCT), and importantly, we analyzed the main factors affecting antiviral efficacy. The CMV peak titer decreased from 19 (range, 1.0-503.0) × 10(3) copies/mL to 3.9 (range, 0-112) × 10(3) copies/mL after CMV-CTL infusion. The cumulative complete response (CR) rates in the first, fourth, and sixth weeks after the first CMV-CTL infusion were 37.9% (95% CI 35.0-40.8), 76.8% (95% CI 70.7-82.9), and 89.5% (95% CI 85.2-93.8), respectively. In multivariate analysis, persistent CMV infection prior to CMV-CTL infusion (hazard ratio [HR] 2.29, 95% CI 1.29-4.06, p = .005) and basiliximab treatment within 2 weeks of CMV-CTL infusion (HR 1.87, 95% CI 1.06-3.81, p = .031) were independent predictors of poor antiviral efficacy of CMV-CTL therapy. Our data showed that adoptive therapy with CMV-CTLs is a safe and effective treatment for CMV infection after haplo-SCT. Persistent CMV infection and basiliximab treatment are correlated with poor anti-CMV efficacy of CMV-CTL therapy.
-
7.
Voriconazole in hematopoietic stem cell transplantation and cellular therapies: Real-world usage and therapeutic level attainment at a major transplant center
Lindsay, J., Krantz, E. M., Morris, J., Sweet, A., Tverdek, F., Joshi, A., Yeh, R., Hill, J. A., Greenwood, M., Chen, S. C., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Voriconazole (VCZ) was one of the first mold-active triazoles available; however, its current use among high-risk hematology populations is unknown as the uptake of posaconazole (PCZ) and isavuconazole (ISZ) increases. OBJECTIVES We evaluated the usage and therapeutic level attainment of VCZ in hematopoietic cell transplant (HCT) and chimeric antigen receptor T cell (CAR-T) therapy patients at our cancer center. STUDY DESIGN Electronic medical records for all adult HCT or CAR-T patients with an order for VCZ, PCZ or ISV between January 1, 2018, and June 30, 2020 were extracted. Clinical characteristics, VCZ indication, trough VCZ levels, and frequency of VCZ initiation from 6 months pre- to 6 months post HCT/CAR-T infusion in consecutive HCT/CAR-T recipients within the study period (infusion between July 1, 2018, and January 1, 2020) were assessed. The association between relevant clinical characteristics and the attainment of sub- or supratherapeutic levels was also evaluated. RESULTS Of 468 patients prescribed mold-active triazoles, 256 (54.7%) were prescribed VCZ, 324 (69.2%) PCZ, and 60 (12.8%) ISZ; 152/468 (32.5%) treatment regimens were sequentially modified to alternate mold-active triazoles. Among consecutive HCT and CAR-T recipients at our center, evaluated 6 months pre- or post- HCT/ CAR-T, VCZ was commonly initiated pre- or post-allogeneic HCT (102/381, 26.8%), with most use in the first 30 days post stem cell infusion (40/381, 10.5%); VCZ use was less common in autologous HCT (13/276, 4.7%) and CAR-T (10/153, 6.5%). Of 223 VCZ orders that met inclusion for analysis, indications included empiric treatment in 108/223 (48.4%), directed therapy in 25/223 (11.2%), primary prophylaxis in 69/223 (30.9%) and secondary prophylaxis in 21/223 (9.4%). Of 223 eligible VCZ patients, 144 (64.6%) had at least one VCZ level measured during the study period; 75/144 (52.1%) had a therapeutic VCZ level (1.0-5.5mg/L) at the first measurement (median 2.8mg/L [range 0.1 - 13.5]) at a median of 6 days of therapy, with 26.4% subtherapeutic and 21.5% supratherapeutic; 46/88 (52.3%) were therapeutic at the second measurement (2.1mg/L [0.1 - 9.9]) at a median of 17 days of therapy; and 33/48 (68.8%) at the third (2.3mg/L [0.1 - 7.7]) at a median of 29 days. In multivariable analysis of factors associated with sub- or supratherapeutic levels (body mass index ≥30, concurrent omeprazole use, concurrent letermovir use, indication for VCZ, history/timeframe of HCT), the only significant association was lower odds of a supratherapeutic VCZ level among those undergoing HCT within the previous 30 days compared to those without a history of HCT. CONCLUSIONS VCZ continues to remain an important option in the treatment and prevention of invasive fungal infections in an era when alternative oral mold-active triazoles are available. In spite of long-standing experience with VCZ prescribing, therapeutic level attainment remains a challenge.
-
8.
Tracking the Progeny of Virus-specific T-cell Products in Patients Post-Transplant using TCR-Sequencing
Huisman, W., Roex, M. C. J., Hageman, L., Koster, E. A. S., Veld, S. A. J., Hoogstraten, C., van Balen, P., van Egmond, H. M. E., Van Bergen, C. A. M., Einsele, H., et al
Blood advances. 2022
Abstract
Adoptive cellular therapies with T cells are increasingly used to treat a variety of conditions. For instance, in a recent phase I/II trial, we prophylactically administered multi-virus-specific T-cell products to protect recipients of T-cell depleted allogeneic stem-cell grafts against viral reactivations. To establish treatment efficacy, it is important to determine the fate of the individual transferred T-cell populations. However, it is difficult to unequivocally distinguish progeny of the transferred T-cell products from recipient- or stem-cell graft-derived T cells that survived T-cell depletion during conditioning or stem-cell graft manipulation. Using mRNA sequencing of the TCRβ-chains of the individual virus-specific T-cell populations within these T-cell products, we were now able to track the multiple clonal virus-specific subpopulations in peripheral blood and distinguish recipient- and stem-cell graft-derived virus-specific T cells from the progeny of the infused T-cell products. We observed in vivo expansion of virus-specific T cells that were exclusively derived from the T-cell products with similar kinetics as the expansion of virus-specific T cells that could also be detected before the T-cell product infusion. Additionally, we demonstrated persistence of virus-specific T cells derived from the T-cell products in most patients who did not show viral reactivations. This study demonstrates that virus-specific T cells from prophylactically infused multi-antigen-specific T-cell products can expand in response to antigen encounter in vivo and even persist in the absence of early viral reactivations.
-
9.
Adoptive therapy with CMV-specific cytotoxic T lymphocytes depends on baseline CD4+ immunity to mediate durable responses
Fabrizio, V. A., Rodriguez-Sanchez, M. I., Mauguen, A., Dahi, P. B., Doubrovina, E., O'Reilly, R. J., Prockop, S. E.
Blood advances. 2021;5(2):496-503
-
-
Free full text
-
Abstract
Adoptive cell therapy using cytomegalovirus (CMV)-specific cytotoxic T lymphocytes (CMV-CTLs) has demonstrated efficacy posttransplant. Despite the predicted limited engraftment of CMV-CTLs derived from third-party donors, partially matched third-party donor-derived CMV-CTLs have demonstrated similar response rates to those derived from primary hematopoietic cell transplantation donors. Little is known about the mechanisms through which adoptive cellular therapies mediate durable responses. We performed a retrospective analysis of patients receiving CMV-CTLs for treatment of CMV viremia and/or disease after allogeneic transplant between September of 2009 and January of 2018. We evaluated whether response to adoptively transferred CMV-CTLs correlated with immune reconstitution (IR), using validated CD4+ IR milestones of 50 × 106/L and 200 × 106/L. In this analysis, a cohort of 104 patients received CMV-CTLs derived from a primary transplant donor (n = 25), a third-party donor (n = 76), or both (n = 3). Response to therapy did not increase the likelihood of achieving CD4+ IR milestones at 1 (P = .53 and P > .99) or 2 months (P = .12 and P = .33). The origin of CMV-CTLs did not impact subsequent CD4+ IR. CMV-CTLs appeared to interact with host immunity in mediating responses. Recipients with a baseline CD4 >50 × 106/L had higher response to therapy (P = .02), improved overall survival (P < .001), and protection from CMV-related death (P = .002). Baseline endogenous immunity appears to improve CMV-related and overall survival in this cohort and can be an important marker at the initiation of therapy.
-
10.
Impact of SARS-CoV-2 in Hematopoietic Stem Cell Transplantation and Chimeric Antigen Receptor T Cell Therapy Recipients
Mushtaq, M. U., Shahzad, M., Chaudhary, S. G., Luder, M., Ahmed, N., Abdelhakim, H., Bansal, R., Balusu, R., DeJarnette, S., Divine, C., et al
Transplantation and cellular therapy. 2021
Abstract
Coronavirus disease 2019 (COVID-19), a respiratory illness caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a pandemic in March 2020, and has caused more than 600,000 deaths in the United States at the time of this report. Hematopoietic stem cell transplantation (HCT) or chimeric antigen receptor T cell (CAR-T) therapy recipients have a higher risk of mortality with COVID-19 owing to profound immune dysregulation. In this study, we investigated the impact of SARS-CoV-2 in HCT/CAR-T therapy recipients. This single-center prospective study included all (n?=?58) adult HCT/CAR-T recipients who were diagnosed with COVID-19 at the University of Kansas Medical Center between March 2020 and May 2021. Baseline and disease-related characteristics were ascertained from medical records. Data were analyzed using SPSS version 21 (IBM, Armonk, NY). Bivariate analyses, using the chi-square and t-test, and logistic regression analyses were conducted. The study included 58 HCT/CAR-T patients who acquired SARS-CoV-2 infection, including recipients of allogeneic HCT (n?=?32), autologous HCT (n?=?23), and CAR-T therapy (n?=?3). The median patient age was 58 years (range, 24 to 77 years), and 64% were males. The median time from HCT/CAR-T therapy to SARS-CoV-2 infection was 17.7 months (range, 0.2 to 201.9 months), and 22% of the patients acquired SARS-CoV-2 within the first 100 days post-HCT/CAR-T therapy. The primary hematologic disorders were plasma cell (36%), myeloid (38%), and lymphoid (26%) malignancies. Myeloablative conditioning was performed in 62% of patients. Donors were autologous (45%), matched sibling (15%), matched unrelated (21%), and haploidentical (19%). Prior history of grade II-IV acute graft-versus-host disease (GVHD), active GVHD, and current immunosuppressive therapy (IST) was noted in 22%, 31%, and 36% of patients, respectively. Concurrent infections were observed in 19%. Lymphopenia (P?=?.049) and high serum ferritin concentration (P?=?.020) were associated with mortality. COVID-19 severity was mild in 50% of the patients, moderate in 22%, and severe in 28%. Clinical findings included pneumonia or abnormal chest imaging (in 50%), hypoxia (28%), intensive care unit admission (19%), and mechanical ventilation (10%). Therapies included remdesivir (in 41%), convalescent plasma (35%), dexamethasone (22%), monoclonal antibodies (19%), and tocilizumab (3%). The median duration of viral shedding (positive SARS-CoV-2 PCR) was 7.7 weeks (range, 2 to 18.7 weeks), and 2 patients had a persistent infection for >5 months post-CAR-T therapy. After a median follow-up of 6.1 months (range, 0.5-13.6 months), the mortality rate was 16% in all patients and 28% in allogeneic HCT recipients. Among 9 patients who died, the median survival after SARS-CoV-2 infection was 23 days (range, 14 to 140 days). In survivors with moderate-severe COVID-19, the median time to recovery was 4.2 weeks (range, 1.1 to 24.7 weeks). Among allogeneic HCT recipients, 5 (16%) developed subsequent pulmonary chronic GVHD necessitating systemic steroids and additional IST. Significant predictors of COVID-19 severity included allogeneic HCT (odds ratio [OR], 3.6, 95% confidence interval [CI], 1.2 to 10.8; P?=?.020), history of grade II-IV acute GVHD (OR, 4.6; 95% CI, 1.10 to 18.86; P?=?.036) and concurrent IST (OR, 5.9; 95% CI, 1.8 to 19.8; P?=?.004). HCT and CAR-T cell therapy recipients are at an increased risk of moderate-severe COVID-19 pneumonia and higher mortality with SARS-CoV-2 infection. Our findings confirm the need for continuing vigilance with social distancing and masks, vaccination prioritization, close monitoring, and aggressive treatment of HCT/CAR-T therapy recipients.