The role of immune reconstitution in relapse after allogeneic hematopoietic stem cell transplantation.

INTRODUCTION: Leukemia relapse following stem cell transplantation remains a significant barrier to long-term remission. Timely and balanced immune recovery after transplantation is crucial for preventing leukemia relapse. AREAS COVERED: After an extensive literature search of PubMed and Web of Science through October 2023, we provide an overview of the dynamics of immune reconstitution and its role in controlling leukemia relapse. We also discuss strategies to promote immune reconstitution and reduce disease recurrence following allogeneic hematopoietic stem cell transplantation. EXPERT OPINION: Immune reconstitution after transplantation has substantial potential to prevent relapse and might predict disease recurrence and prognosis. High dimensional cytometry, multi-omics, and T cell repertoire analysis allow for a more comprehensive and detailed understanding of the immune system's dynamics post-transplantation, and contribute to the identification of rare immune cell subsets or potential biomarkers associated with successful immune reconstitution or increased risk of complications. Strategies to enhance the immune system, such as adoptive immunotherapy and cytokine-based therapy, have great potential for reducing leukemia relapse after transplantation. Future research directions should focus on refining patient selection for these therapies, implementing appropriate and timely treatment, investigating combination approaches to maximize therapeutic outcomes, and achieving a robust graft-versus-leukemia (GVL) effect while minimizing graft-versus-host disease (GVHD) for optimal results.

Haematopoietic stem-cell transplantation in China in the era of targeted therapies: current advances, challenges, and future directions.

In the era of targeted therapies, haematopoietic stem-cell transplantation (HSCT), both allogeneic and autologous, remains a curative approach for patients with chemosensitive and immunesensitive malignant and non-malignant haematological disease in China. Since 2000, we have seen a substantial increase in the number of HSCTs, especially haploidentical HSCT, in patients with acute leukaemia and severe aplastic anaemia. Haploidentical donors have been the most common allograft donors in China since 2013. Key components of allogeneic HSCT include best donor selection for acute leukaemia, incorporation of target therapy, especially chimeric antigen receptor T cells, allografts for acute leukaemia outcome improvement, total therapy for relapsed or refractory acute leukaemia and haploidentical allografts as upfront therapy for severe aplastic anaemia. Despite many challenges in the HSCT setting in China, such as how to redefine the roadmap for HSCT, improve the health-related quality of life of long-term surviving transplant recipients, and promote national and international collaboration, allogeneic HSCT and autologous HSCT will continue to have an important role in treating diverse diseases between now and 2050. The development of HSCT in China will contribute to the worldwide development of HSCT.

Immune Reconstitution of Patients Who Recovered From Steroid-Refractory Acute Graft-Versus-Host Disease After Basiliximab Treatment.

We aimed to identify the characteristics of immune reconstitution (IR) in patients who recovered from steroid-refractory acute graft-versus-host disease (SR-aGVHD) after basiliximab treatment. A total of 179, 124, 80, and 92 patients were included in the analysis for IR at 3, 6, 9, and 12 months, respectively, after haploidentical donor hematopoietic stem cell transplantation (HID HSCT). We observed that IR was fastest for monocytes and CD8+ T cells, followed by lymphocytes, CD3+ T cells, and CD19+ B cells and slowest for CD4+ T cells. Almost all immune cell subsets recovered comparably between patients receiving <5 doses and ≥5 doses of basiliximab. Most immune cell subsets recovered comparably between SR-aGVHD patients who recovered after basiliximab treatment and event-free HID HSCT recipients. Patients who recovered from SR-aGVHD after basiliximab treatment experienced satisfactory IR, which suggested that basiliximab may not have prolonged the negative impact on IR in these patients.

Adoptive therapy with cytomegalovirus-specific T cells for cytomegalovirus infection after haploidentical stem cell transplantation and factors affecting efficacy.

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) × 103 copies/mL to 3.9 (range, 0-112) × 103 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.

Comparable anti-CMV responses of transplant donor and third-party CMV-specific T cells for treatment of CMV infection after allogeneic stem cell transplantation.

Adoptive transfer of cytomegalovirus (CMV)-specific cytotoxic T lymphocytes (CMV-CTLs) from original transplant donors or third-party donors was effective for the treatment of CMV infection after allogenic stem cell transplantation (allo-SCT), but the antiviral activity of CMV-CTL types has not been compared. To determine whether third-party CMV-CTLs provide comparable long-term antiviral efficacy to transplant donor CMV-CTLs, we first compared the antiviral abilities of transplant donors and third-party CMV-CTLs for treatment of CMV infection in two mouse models, compared the in vivo recovery of CMV-specific immunity, and analyzed the underlying mechanisms driving sustained antiviral immunity. The results showed that both donor and third-party CMV-CTLs effectively combated systemic CMV infection by reducing CMV pathology and tumor burden 28 days postinfusion. The in vivo recovery of CMV-specific immunity after CMV-CTL infusion was comparable in both groups. A detailed analysis of the source of recovered CMV-CTLs showed the proliferation and expansion of graft-derived endogenous CMV-CTLs in both groups. Our clinical study, which enrolled 31 patients who received third-party CMV-CTLs and 62 matched pairs of individuals who received transplant donor CMV-CTLs for refractory CMV infection, further showed that adoptive therapy with donor or third-party CMV-CTLs had comparable clinical responses without significant therapy-related toxicity. We observed strong expansion of CD8+ tetramer+ T cells and proliferation of recipient endogenous CMV-CTLs after CMV-CTL infusion, which were associated with a reduced or cleared viral load. Our data confirmed that adoptive therapy with third-party or transplant donor CMV-CTLs triggered comparable antiviral responses to CMV infection that might be mediated by restoration of endogenous CMV-specific immunity.

Donor NKG2C homozygosity contributes to CMV clearance after haploidentical transplantation.

CMV infection remains an important cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Several investigators have reported that adaptive NKG2C+ NK cells persistently expand during CMV reactivation. In our study, 2 cohorts were enrolled to explore the relationships among the NKG2C genotype, NKG2C+ NK cell reconstitution, and CMV infection. Multivariate analysis showed that donor NKG2C gene deletion was an independent prognostic factor for CMV reactivation and refractory CMV reactivation. Furthermore, adaptive NKG2C+ NK cells' quantitative and qualitative reconstitution, along with their anti-CMV function after transplantation, was significantly lower in patients grafted with NKG2Cwt/del donor cells than in those grafted with NKG2Cwt/wt donor cells. At day 30 after transplantation, quantitative reconstitution of NKG2C+ NK cells was significantly lower in patients with treatment-refractory CMV reactivation than in patients without CMV reactivation and those with nonrefractory CMV reactivation. In humanized CMV-infected mice, we found that, compared with those from NKG2Cwt/del donors, adaptive NKG2C+ NK cells from NKG2Cwt/wt donors induced earlier and stronger expansion of NKG2C+ NK cells as well as earlier and stronger CMV clearance in vivo. In conclusion, donor NKG2C homozygosity contributes to CMV clearance by promoting the quantitative and qualitative reconstruction of adaptive NKG2C+ NK cells after haploidentical allo-HSCT.

First-line Therapy With Donor-derived Human Cytomegalovirus (HCMV)-specific T Cells Reduces Persistent HCMV Infection by Promoting Antiviral Immunity After Allogenic Stem Cell Transplantation.

BACKGROUND: Human cytomegalovirus (HCMV) infection, especially persistent HCMV infection, is an important cause of morbidity and mortality after allogenic stem cell transplantation (allo-SCT). Antiviral agents remain the first-line therapy but are limited by side effects and acquired resistance. METHODS: We evaluated the safety and efficacy of donor-derived HCMV-specific cytotoxic T cells (CTLs) as a first-line therapy for HCMV infection after allo-SCT and investigated the underlying mechanisms. RESULTS: In humanized HCMV-infected mice, first-line therapy with CTLs effectively combated systemic HCMV infection by promoting the restoration of graft-derived endogenous HCMV-specific immunity in vivo. In a clinical trial, compared with the pair-matched, high-risk control cohort, first-line therapy with CTLs significantly reduced the rate of persistent (2.9% vs 20.0%, P = .018) and late (5.7% vs 20.0%, P = .01) HCMV infection and cumulative incidence of persistent HCMV infection (hazard ratio [HR], 0.13; 95% confidence interval [CI], 0.10-0.82; P = .02), lowered 1-year treatment-related mortality (HR, 0.15. 95% CI, 0.11-0.90. P = .03), and improved 1-year overall survival (HR, 6.35; 95% CI, 1.05-9.00; P = .04). Moreover, first-line therapy with CTLs promoted the quantitative and functional recovery of CTLs in patients, which was associated with HCMV clearance. CONCLUSIONS: We provide robust support for the benefits of CTLs combined with antiviral drugs as a first-line therapy for treating HCMV infection and suggest that adoptively infused CTLs may stimulate the recovery of endogenous HCMV-specific immunity. CLINICAL TRIALS REGISTRATION: NCT02985775.

New approaches in allogenic transplantation in AML.

Acute myeloid leukemia (AML) is a heterogeneous disorder with high morbidity and mortality. Allogeneic stem cell transplantation (allo-SCT) is an effective, and sometimes the only, curative postremission therapy for AML patients. Based on genetic risk classification, the published data have suggested that allo-SCT be recommended for high- and most intermediate-risk AML but not for low-risk AML in first complete remission (CR1). Recently, the role of allo-SCT in low-risk AML in CR1 is being established with the development of a risk-directed, minimal residual disease-based strategy. Though human leukocyte antigen-matched sibling transplantation remains the preferred therapeutic option for AML, modern approaches and developments pre-, peri- and post-transplant have facilitated other transplant modalities, especially haploidentical SCT, as promising valid alternative choices. In this paper, we review recent advances in allo-SCT for AML, weigh the benefits of allo-SCT for high-, intermediate-, and even low-risk AML in CR1, discuss the best choice of allo-SCT donor for the treatment of AML, and summarize new approaches for refractory and relapsed AML pre- or post-allo-SCT.

Impact of HLA allele mismatch at HLA-A, -B, -C, -DRB1, and -DQB1 on outcomes in haploidentical stem cell transplantation.

The impact of human leukocyte antigen (HLA) allele mismatch on transplant outcomes in haploidentical stem cell transplantation (haplo-SCT) has not been established. We retrospectively studied 595 patients with hematologic malignancy who received haplo-SCT. The impact of multiple HLA allele mismatches (HLA-A, -B, -C, -DRB1, and -DQB1) and each HLA allele mismatch on transplant outcomes was analyzed. Greater number of HLA allele disparity does not appear worsen outcome. As for each HLA locus, HLA-A mismatch correlated with decreased rate of platelet engraftment (HR 0.740, P = .003); HLA-B mismatch independently correlated with decreased relapse rate (HR 0.494, P = .032) and improved disease-free survival and overall survival (HR 0.514, P = .003; HR 0.494, P = .002, respectively); HLA-C mismatch appeared to be protective for transplant-related mortality (TRM) (HR 0.567, P = .039); HLA-DRB1 mismatch was associated with increased cumulative incidence of grade II-IV acute graft-vs.-host disease (GVHD) (HR 1.942, P = .002). No associations of any HLA mismatch with delayed neutrophil engraftment or increased cumulative incidence of chronic GVHD were observed. Our data indicated that high degree of HLA allele mismatches did not adversely affect transplant outcomes in haplo-SCT and each HLA allele mismatch had different effect.

Comparison of reference values for immune recovery between event-free patients receiving haploidentical allografts and those receiving human leukocyte antigen-matched sibling donor allografts.

To establish optimal reference values for recovered immune cell subsets, we prospectively investigated post-transplant immune reconstitution (IR) in 144 patients who received allogeneic stem cell transplantation (allo- SCT) and without showing any of the following events: poor graft function, grades II‒IV acute graft-versus-host disease (GVHD), serious chronic GVHD, serious bacterial infection, invasive fungal infection, or relapse or death in the first year after transplantation. IR was rapid in monocytes, intermediate in lymphocytes, CD3+ Tcells, CD8+ T cells, and CD19+ B cells, and very slow in CD4+ T cells in the entire patient cohort. Immune recovery was generally faster under HLA-matched sibling donor transplantation than under haploidentical transplantation. Results suggest that patients with an IR comparable to the reference values display superior survival, and the levels of recovery in immune cells need not reach those in healthy donor in the first year after transplantation.We suggest that data from this recipient cohort should be used as reference values for post-transplant immune cell counts in patients receiving HSCT.

Cytomegalovirus-Specific T-Cell Transfer for Refractory Cytomegalovirus Infection After Haploidentical Stem Cell Transplantation: The Quantitative and Qualitative Immune Recovery for Cytomegalovirus.

Background: The efficiency and mechanisms of adoptive transfer of cytomegalovirus (CMV)specific T cells for refractory CMV infection after haploidentical stem cell transplantation (haplo-SCT) remain largely unknown. Methods: Thirty-two patients with refractory CMV infection who accepted treatment with adoptive CMV-specific T-cell infusion following haplo-SCT were prospectively enrolled. Another 32 patients with nonrefractory CMV infection after haplo-SCT were selected as control subjects. The phenotypical and functional characteristics of CMV-specific T cells were analyzed before and after cellular therapy in the refractory cohort, as well as in the nonrefractory cohort. Results: In the refractory cohort, 27 of the 32 treated patients exhibited CMV clearance within 4 weeks after adoptive T-cell transfer without recurrence. The in vivo expansion of CMV-specific T cells and improvements in the cytokine production and proliferation ability of the CMV-specific T cells were observed after cellular therapy. Moreover, a reduced expression of programmed death-1 (PD-1) on CMV-specific T cells was observed. However, in the remaining 5 patients who showed CMV recurrence 4 weeks after transfer, neither the quantity nor the function of CMV-specific T cells was restored. Conclusions: The adoptive transfer of CMV-specific T cells promotes quantitative and functional recovery of CMV-specific T cells to guard against refractory CMV infection after haplo-SCT.

Donor-Specific Anti-Human Leukocyte Antigen Antibodies Predict Prolonged Isolated Thrombocytopenia and Inferior Outcomes of Haploidentical Hematopoietic Stem Cell Transplantation.

Prolonged isolated thrombocytopenia (PT) after allogeneic stem cell transplantation (allo-SCT) has a great impact on transplant outcome. In this study, we performed a retrospective analysis to investigate the association of donor-specific anti-human leukocyte antigen (HLA) antibodies (DSAs) with PT in 394 patients who underwent unmanipulated haploidentical blood and marrow transplantation (HBMT). For HLA antibody positive samples with a median fluorescent intensity (MFI) > 500, DSAs were further examined. A total of 390 patients (99.0%) achieved sustained myeloid engraftment. Of the 394 cases tested, 45 (11.4%) were DSA positive. The cumulative incidence of PT in this cohort of patients was 9.9 ± 1.5%. The incidence of PT was higher in patients with a MFI ≥ 1000 compared with those with a MFI < 1000 (16.8 ± 6.4% versus 7.4 ± 1.4%, P = 0.05). Multivariate analysis showed that the presence of DSAs (MFI ≥ 1000) was correlated to PT (hazard ratio (HR) 3.262; 95% confidence interval (CI), 1.339-7.946; P = 0.009) and transplant-related mortality (HR 2.320; 95% CI, 1.169-4.426; P = 0.044). Our results, for the first time, suggest an association of DSAs with PT after unmanipulated HBMT. It would help screen out the suitable donor and guide intervention. This indicated that DSAs should be incorporated in the algorithm for unmanipulated HBMT.

Invasive fungal infection in allogeneic hematopoietic stem cell transplant recipients: single center experiences of 12 years.

Invasive fungal infection (IFI) is a growing cause of morbidity and mortality among patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We retrospectively reviewed the records of 408 patients undergoing allo-HSCTs during the period November 1998 to December 2009, analyzed the incidence and risk factors of IFI, and examined the impact of IFI on overall survival. A total of 92 (22.5%) episodes suffered proven or probable IFI (4 patients were proven, 88 patients were probable). Candida was the most common pathogen for early IFI, and mold was the most frequent causative organism for late IFI. A prior history of IFI, human leukocyte antigen (HLA) mismatch, long-time neutropenia, and acute graft-versus-host-disease (GVHD) were risk factors for early IFI. A prior history of IFI, corticosteroid therapy, cytomegalovirus (CMV) disease, and chronic GVHD were risk factors for late IFI. IFI-related mortality was 53.26%. The 12-year overall survival (OS) rate for IFI was significantly lower than that of patients without IFI (41.9% vs. 63.6%, P<0.01).

[Protective effects of carnosine against closed head injury in mice].

OBJECTIVE: To investigate the protective effects of carnosine against experimental closed head injury (CHI) in mice. METHODS: The CHI model was established by free-falling weight-drop. Carnosine (250 mg/kg or 500 mg/kg) was administered intraperitoneally 30 min before brain trauma, then q.d for 7 d; while normal saline was administrated for control group. The neurological defect was evaluated by neurological severity score (NSS) within 7 d; the survival rate and the histological alternations were observed. RESULTS: Carnosine prevented the body weight loss of mice at dose of 500 mg/kg; significantly increased the survival rate, and reduced the neurological defect and histological damage at dose of 250 and 500 mg/kg. CONCLUSION: Carnosine can attenuate closed head injury in mice.