Donor Lymphocyte Infusion For Treatment Research Articles

Donor-derived CD19 CAR-T Cells versus Chemotherapy Plus Donor Lymphocyte Infusion for Treatment of Recurrent CD19-positive B-ALL After Allogeneic Hematopoietic Stem Cell Transplantation.

This study aimed to compare the efficacy of anti-CD19 chimeric antigen receptor T cells (CAR-T cells) versus chemotherapy plus donor lymphocyte infusion (chemo-DLI) for treating relapsed CD19-positive B-cell acute lymphoblastic leukemia (B-ALL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Clinical data of 43 patients with B-ALL who relapsed after allo-HSCT were retrospectively analyzed. Twenty-two patients were treated with CAR-T cells (CAR-T group), and 21 with chemotherapy plus DLI (chemo-DLI group). The complete remission (CR) and minimal residual disease (MRD)-negative CR rates, leukemia-free survival (LFS) rate, overall survival (OS) rate, and incidence of acute graft-versus-host disease (aGVHD), cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were compared between the two groups. The CR and MRD-negative CR rates in the CAR-T group (77.3% and 61.5%) were significantly higher than those in the chemo-DLI group (38.1% and 23.8%) (P=0.008 and P=0.003). The 1- and 2-year LFS rates in the CAR-T group were superior to those in the chemo-DLI group: 54.5% and 50.0% vs. 9.5% and 4.8% (P=0.0001 and P=0.00004). The 1- and 2-year OS rates in the CAR-T versus chemo-DLI group were 59.1% and 54.5% vs. 19% and 9.5% (P=0.011 and P=0.003). Six patients (28.6%) with grade 2-4 aGVHD were identified in the chemo-DLI group. Two patients (9.1%) in the CAR-T group developed grade 1-2 aGVHD. Nineteen patients (86.4%) developed CRS in the CAR-T group, comprising grade 1-2 CRS in 13 patients (59.1%) and grade 3 CRS in 6 patients (27.3%). Two patients (9.1%) developed grade 1-2 ICANS. Donor-derived anti-CD19 CAR-T-cell therapy may be better, safer, and more effective than chemo-DLI for B-ALL patients who relapse after allo-HSCT.

Post-Transplant CD34+ Selected Stem Cell “Boost” for Mixed Chimerism after Reduced-Intensity Conditioning Hematopoietic Stem Cell Transplantation in Children and Young Adults with Primary Immune Deficiencies

Mixed chimerism and eventual graft loss occurs in a proportion of children with primary immune deficiencies receiving alemtuzumab, fludarabine, and melphalan reduced-intensity conditioning (RIC) regimens before allogeneic hematopoietic stem cell transplantation (HSCT). We investigated the usefulness of a CD34+ selected stem cell “boost” without conditioning to treat mixed chimerism in children and young adults who received predominantly an alemtuzumab, fludarabine, and melphalan RIC regimen for primary immune deficiencies and reported the outcomes. Patients with a primary immune deficiency disorder who were either enrolled on a prospective CD34+ boost study for treatment of mixed chimerism from 2011 to 2014 (n = 9) or treated with a CD34+ boost on a clinical basis from 2014 to 2016 (n = 3) were included in this analysis. Response to a CD34+ boost was defined as a rise in donor chimerism by ≥15% with donor chimerism of at least 20%, stabilization was defined as a rise in chimerism by <15% with donor chimerism ≥ 20%, and no response was defined as any decline in donor chimerism or need for a second HSCT after a CD34+ boost. Twelve patients received alemtuzumab, fludarabine, and melphalan. Median age was 4.5 years (range, .9 to 20.6), and median whole blood donor chimerism before the boost was 25% (range, 3% to 61%). Three patients (25%) met criteria for response, 1 patient (8%) was considered to have stabilization, and 8 patients (67%) had no response 12 months after the boost. None of the patients developed any complications from a CD34+ boost, including no acute graft-versus-host disease (GVHD). All patients are alive with a median follow-up of 32 months (range, 8 to 79). We conclude that a CD34+ selected stem cell boost can be considered for treatment of mixed chimerism after alemtuzumab, fludarabine, and melphalan RIC HSCT in children and young adults with primary immune deficiencies. Approximately one-third of patients can be expected to benefit from a CD34+ selected stem cell boost and may avoid the need for a second HSCT. Lack of any GVHD or toxicity makes a stem cell boost an attractive option compared with donor lymphocyte infusions for treatment of mixed chimerism.

Reduction in CMV and Adenovirus Viremia after Haploidentical Donor Transplantation Utilizing CD45RA Depletion and NK Cell Infusion

Background. T-cell depletion is often used to reduce graft-vs-host disease in haploidentical donor hematopoietic cell transplantation (HCT). However, the absence of adoptively transferred T-cells may increase graft failure, relapse, and infection. Novel methods have been developed to more selectively deplete naïve T cells and preserve memory T cells. Depletion of CD45RA+ cells can provide robust early recovery of diverse memory T-cell populations in haploidentical donor transplantation, and may provide increased immunity against viral infections. Likewise, the provision of additional donor NK cells may reduce viral complications.Patients and Methods. Sixty-seven patients received initial allogeneic HCT on 3 consecutive IRB approved haploidentical donor HCT trials at St. Jude Children's Research Hospital from 2005 to 2015. CD3-depletion was used in 41 recipients, and CD45RA-depletion was used in 26. All patients received similar preparative doses of fludarabine, thiotepa, and melphalan. Patients with CD3-depleted grafts received OKT3 (n=20) or Campath (n=21), and all 41 received rituximab on Day 0 as EBV prophylaxis. Patients with CD45RA-depleted grafts (n=26) did not receive antibody therapy, but instead received total lymphoid irradiation and a dose of cyclophosphamide added to the preparative backbone. Donor NK cells were given Day +6.Peripheral blood was tested for CMV, EBV, and adenovirus using quantitative PCR at least weekly until day +100, and then as indicated. The first 180 days post-HCT were evaluated. Fisher's exact test was used to compare two proportions.Results. Patients with CD3-depletion received a median 0.04 (range: 0.01 - 0.15) x 106 CD3+ cells/kg, and patients with CD45RA-depletion received a median 80.07 (range: 16.08 - 528.52) x 106 CD3+ cells/kg.CMV reactivation occurred in 23 of 41 patients (56.1%) with CD3-depletion and 5 of 26 patients (19.2%) with CD45RA-depletion (p=0.005). Differences occurred predominantly in those CMV seropositive recipients who received grafts from CMV seropositive donors, as CMV was detected in 22 of 24 (91.7%) +/+ patients with CD3-depletion and 4 of 11 (36.4%) +/+ patients with CD45RA-depletion (p=0.001). Of the 23 patients with CMV after CD3-depletion, the peak viral load was a median 4.49 log10 copies/mL blood (range: <2.7 - 6.87). Of the 5 patients with CMV after CD45RA-depletion, the peak viral load was a median 3.81 log10 copies/mL blood (range: <2.7 - 4.38). Of the 23 patients that experienced CMV following CD3-depleted HCT, 18 (78.3%) received antiviral therapy, 8 (34.8%) received donor lymphocyte infusions (DLI) for treatment. Of the 5 patients that reactivated CMV following CD45RA-depleted HCT, 4 (80%) received antiviral therapy, none received DLI for treatment.EBV was detected in 7 of 41 (17.1%) patients with CD3-depletion and 5 of 26 patients (19.2%) with CD45RA-depletion (p=1). Of the 7 patients with EBV in the CD3-depletion group, 3 received rituximab, and 1 received rituximab, chemotherapy, and DLI. Overall 4 of 41 patients (9.8%) with CD3-depletion received EBV-directed therapy, compared to 0 of 26 patients with CD45RA-depletion (p=0.15).Adenovirus viremia was detected in 11 of 41 patients (26.8%) with CD3-depletion and 1 of 26 patients (3.8%) with CD45RA-depletion (p=0.02). Of the 11 patients with CD3-depletion, the median peak viral load was 3.14 log10 copies/mL DNA (range: 2.03 - 4.11). The patient with adenovirus following CD45RA-depleted transplant had a peak viral load that was below the threshold of quantification (2 log10 copies/mL DNA). Of the 11 patients with adenovirus after CD3-depletion, 9 (81.8%) were given cidofovir, 4 (36.4%) were given DLI for treatment. The patient with adenovirus after CD45RA-depletion received cidofovir.Conclusion. CD45RA-depletion has been shown to effectively deplete naïve T cells while providing substantial memory T-cell populations in the early post-HCT period. The significant reduction in CMV and adenovirus detection in the blood of patients with CD45RA-depletion suggests that adoptive transfer of memory T cells provides protection against these viruses in the early post-HCT period. The incidence of EBV was not significantly different - indicating that in vivo B-cell depletion by rituximab in CD3-depletion recipients and use of CD45RA-depletion may have similar efficacy in minimizing EBV reactivation. DisclosuresNo relevant conflicts of interest to declare.

Outcomes of Donor Lymphocyte Infusion for Treatment of Mixed Donor Chimerism after a Reduced-Intensity Preparative Regimen for Pediatric Patients with Nonmalignant Diseases

Mixed donor chimerism is increasingly common in the pediatric hematopoietic stem cell transplantation (HSCT) setting because of the increased use of reduced-intensity preparative regimens for nonmalignant diseases. Donor lymphocyte infusion (DLI) is potentially useful in the treatment of mixed donor chimerism, but little are data available on the use of DLI in this setting. We conducted a retrospective review of 27 pediatric patients who received DLI for mixed donor chimerism between January 2006 and December 2010 after receiving a preparative regimen of alemtuzumab, fludarabine, and melphalan. Twenty-one patients (78%) were alive at a median of 35 months post-transplant. Seven patients (26%) sustained full donor chimerism after DLI only at a median of 35 months post-HSCT. Nine patients (33%) continued with mixed donor chimerism (median, 38% [range, 18% to 70%]) at a median of 37 months after DLI only. Five patients underwent unconditioned stem cell boosts or second conditioned transplants after no improvement in donor chimerism was seen following DLI. Donor source appeared to contribute to outcomes after DLI; patients with mismatched unrelated donors had earlier first decline in chimerism and timing of first DLI, a higher response rate to DLI, and an increased rate of graft-versus-host disease (GVHD). There was no response to DLI in patients with matched sibling donors. Ten patients, all with improvement in chimerism after DLI, developed acute GVHD after DLI, with 3 having grade III GVHD. Three patients developed chronic GVHD after DLI. These data illustrate the potential efficacy of DLI in the treatment of mixed donor chimerism after a reduced-intensity preparative regimen.

CD4 + CD25 + Regulatory T Cell Depletion Improves the Graft-Versus-Tumor Effect of Donor Lymphocytes After Allogeneic Hematopoietic Stem Cell Transplantation

Donor T cells play a pivotal role in the graft-versus-tumor effect after allogeneic hematopoietic stem cell transplantation. Regulatory T cells (T(reg)s) may reduce alloreactivity, the major component of the graft-versus-tumor effect. In the setting of donor lymphocyte infusion after hematopoietic stem cell transplantation, we postulated that T(reg) depletion could improve alloreactivity and likewise the graft-versus-tumor effect of donor T cells. The safety and efficacy of T(reg)-depleted donor lymphocyte infusion was studied in 17 adult patients with malignancy relapse after hematopoietic stem cell transplantation. All but one had previously failed to respond to at least one standard donor lymphocyte infusion, and none had experienced graft-versus-host disease. Two of the 17 patients developed graft-versus-host disease after their first T(reg)-depleted donor lymphocyte infusion and experienced a long-term remission of their malignancy. Four of the 15 patients who did not respond after a first T(reg)-depleted donor lymphocyte infusion received a second T(reg)-depleted donor lymphocyte infusion combined with lymphodepleting chemotherapy aimed to also eliminate recipient T(reg)s. All four developed acute-like graft-versus-host disease that was associated with a partial or complete and durable remission. In the whole cohort, graft-versus-host disease induction through T(reg) depletion was associated with improved survival. These results suggest that T(reg)-depleted donor lymphocyte infusion is a safe, feasible approach that induces graft-versus-host or graft-versus-tumor effects in alloreactivity-resistant patients. In patients not responding to this approach, the combination of chemotherapy-induced lymphodepletion of the recipient synergizes with the effect of T(reg)-depleted donor lymphocyte infusion. These findings offer a rational therapeutic approach for cancer cellular immunotherapy.

Changing landscape of invasive aspergillosis in allogeneic stem cell transplant recipients

Invasive aspergillosis (IA) is an important infectious complication in allogeneic stem cell transplant (SCT) recipients. Diagnosis of IA has been difficult and often delayed and treatment outcome has been poor, with mortality rates up to 80%. This review summarizes recent developments in this field. There are indications that the incidence of IA may be decreasing due to multiple factors including better understanding of pathogenesis of IA, earlier diagnosis, and various prophylactic and preventive strategies. Recently posaconazole has shown to be effective in reducing the risk of IA in patients treated for graft-versus-host disease (GVHD). Early use of high-resolution thoracic computed tomography assisted with complimentary methods including bronchoalveolar lavage and serum galactomannan determinations are useful in early diagnosis. Our treatment armamentarium against IA has broadened significantly during the last years and there are some indications of improved outcome more recently. On the other hand, increasing use of blood progenitor grafts instead of marrow with higher risk of chronic GVHD, increasing age of SCT recipients, and wide use of donor lymphocyte infusions for treatment of minimal residual disease or relapse may affect to the opposite direction. Despite some promises and improvements, IA will continue to remain a challenge in the upcoming years.

Human CD8 + cytotoxic T cell responses to adenovirus capsid proteins

Adenoviruses (Ads) cause fatal disease in allogeneic stem cell transplant recipients, but there is no established therapy. Ad-specific CD8 + T cells were detected in PBMC from healthy adults at a mean frequency of 77 per 10 5 CD8 + T cells (range 8–260) by interferon-γ ELISPOT and cytokine flow cytometry assays. CD8 + T cell lines from 7 of 7 donors exhibited MHC-class-I-restricted killing of targets expressing the capsid protein hexon. In contrast, cytotoxicity against the capsid proteins fiber and penton base was weaker or not detected. Two HLA-A2-restricted hexon epitopes and one HLA-B-restricted epitope were identified, all of which are adjacent to or overlap an HLA-DP4-restricted epitope in the highly conserved C-terminus. Thus, hexon is the immunodominant T cell target among capsid proteins and contains multiple C-terminal epitopes conserved among serotypes. These data support evaluation of donor lymphocyte infusions for treatment of Ad disease post-transplant.

Donor Lymphocyte Infusion for the Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation

The results of donor lymphocyte infusion (DLI) for treatment of relapse after bone marrow transplantation (BMT) are reviewed. Durable complete remission can be achieved at the molecular level for a majority (more than 70%) of patients with CML, when treated at early relapse. Results are less favourable for acute leukemias, although useful responses have been reported. Data are scarce though promising for myelodysplastic syndromes and multiple myeloma. Major treatment-associated toxicities are GVHD and bone marrow aplasia. The latter complication can be predicted by evaluating the level of residual donor-derived hematopoiesis. Modification of infused cells (CD8 negative selection or transduction with a suicide gene), addition of peripheral blood stem cells, and early implementation of escalating doses may counteract the complications and increase the response rate. Response rate is variably influenced by the presence of chronic GVHD after initial BMT, T-cell depleted BMT, underlying disease and stage at relapse, and the level of mixed chimerism. DLI is a direct demonstration of the graft-versus-leukemia effect (GVL). Because GVL after BMT is sometimes the predominant cause of cure, it may be advisable in such situations to redirect the conditioning regimens for BMT towards engraftment and less immediate cytotoxicity.

Donor lymphocyte infusions

Donor lymphocyte infusions for treatment of relapse after allogeneic bone marrow or stem cell transplantation is being used with increasing frequency. Study of this form of adoptive immunotherapy will shed light on different aspects of cell-mediated cytotoxicity such as antigen presentation, processing, immune recognition, lymphocyte subsets involved, and mechanism of cell death. Donor lymphocyte infusions are extremely effective for cytogenetic relapses or chronic-phase relapses of chronic myelogenous leukemia, but are less effective in acute leukemias or other disorders. Donor lymphocyte infusions are associated with a significant risk of morbidity and mortality due to graft-versus-host disease and pancytopenia. Lower cell doses, earlier infusions, and selective depletion of CD8+ lymphocytes have been proposed as methods of diminishing these toxicities. Current research is focusing on methods of making donor lymphocyte infusions more effective in the nonchronic myelogenous leukemia setting, and decreasing their toxicity without losing their clinical efficacy in the treatment of relapsed chronic myelogenous leukemia.