ADCC can improve graft vs leukemia effect after T- and B-cell depleted haploidentical stem cell transplantation in pediatric B-lineage ALL

Schlegel, Patrick; Jung, Gundram; Lang, Annemarie; Döring, Michaela; Schulte, Johannes H.; Ebinger, Martin; Holzer, Ursula; Heubach, Florian; Seitz, Christian; Lang, Barbara; Hundsdörfer, Patrick; Eggert, Angelika; Eichholz, Thomas; Kreyenberg, Hermann; Lang, Peter; Handgretinger, Rupert

doi:10.1038/s41409-019-0606-1

Cited by 5 publications

(4 citation statements)

References 17 publications

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“…In line with the scientific rationale for this combinatorial approach, haplo HSCT led to a rapid and robust establishment of a functional cellular immune system in this cohort of heavily pretreated patients. Especially NK-cell recovery, a prerequisite for ADCC, was seen early after haplo HSCT, with a peak at approximately day +14 and a significant increase in cell numbers throughout the six cycles of dinutuximab beta therapy, which is consistent with our previous findings in haplo HSCT (14,(29)(30)(31). The long-term consolidation treatment with dinutuximab was dosed in the range of regimens with proven objective response rates in high-risk and refractory neuroblastoma patients (9, 32) who continuously showed relevant dinutuximab serum levels over the course of treatment.…”

Section: Discussionsupporting

confidence: 91%

Immunomonitoring of Stage IV Relapsed Neuroblastoma Patients Undergoing Haploidentical Hematopoietic Stem Cell Transplantation and Subsequent GD2 (ch14.18/CHO) Antibody Treatment

et al. 2021

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Haploidentical stem cell transplantation (haplo SCT) in Stage IV neuroblastoma relapsed patients has been proven efficacious, while immunotherapy utilizing the anti-GD2 antibody dinutuximab beta has become a standard treatment for neuroblastoma. The combinatorial therapy of haplo SCT and dinutuximab may potentiate the efficacy of the immunotherapy. To gain further understanding of the synergistic effects, functional immunomonitoring was assessed during the clinical trial CH14.18 1021 Antibody and IL2 After haplo SCT in Children with Relapsed Neuroblastoma (NCT02258815). Rapid immune reconstitution of the lymphoid compartment was confirmed, with clinically relevant dinutuximab serum levels found in all patients over the course of treatment. Only one patient developed human anti-chimeric antibodies (HACAs). In-patient monitoring revealed highly functional NK cell posttransplant capable of antibody-dependent cellular cytotoxicity (ADCC). Degranulation of NK cell subsets revealed a significant response increased by dinutuximab. This was irrespective of the KIR receptor–ligand constellation within the NK subsets, defined by the major KIR receptors CD158a, CD158b, and CD158e. Moreover, complement-dependent cytotoxicity (CDC) was shown to be an extremely potent effector-cell independent mechanism of tumor cell lysis, with a clear positive correlation to GD2 expression on the cancer cells as well as to the dinutuximab concentrations. The ex vivo testing of patient-derived effector cells and the sera collected during dinutuximab therapy demonstrated both high functionality of the newly established lymphoid immune compartment and provided confidence that the antibody dosing regimen was sufficient over the duration of the dinutuximab therapy (up to nine cycles in a 9-month period). During the course of the dinutuximab therapy, proinflammatory cytokines and markers (sIL2R, TNFa, IL6, and C reactive protein) were significantly elevated indicating a strong anti-GD2 immune response. No impact of FcGR polymorphism on event-free and overall survival was found. Collectively, this study has shown that in-patient functional immunomonitoring is feasible and valuable in contributing to the understanding of anti-cancer combinatorial treatments such as haplo SCT and antibody immunotherapy.

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Section: Discussionsupporting

confidence: 91%

Immunomonitoring of Stage IV Relapsed Neuroblastoma Patients Undergoing Haploidentical Hematopoietic Stem Cell Transplantation and Subsequent GD2 (ch14.18/CHO) Antibody Treatment

et al. 2021

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“…13 It has been shown that ADCC can augment post-transplant antitumor activity of donor-derived effector cells. 27,28 Since DB improves outcomes after autologous SCT during first-line treatment, 5,29 administration of DB may also augment graft-versus-neuroblastoma effects after haplo-SCT through early expanding and persisting donor-derived NK cells . 30…”

Section: Discussionmentioning

confidence: 99%

“…13 It has been shown that ADCC can augment posttransplant antitumor activity of donor-derived effector cells. 27,28 Since DB improves outcomes after autologous SCT during first-line treatment, 5,29 administration of DB may also augment graft-versus-neuroblastoma effects after haplo-SCT through early expanding and persisting donorderived NK cells . 30 Previously, we reported 5-year EFS and OS of 19% and 23%, respectively, in patients with rHR-NB receiving haplo-SCT without antibody treatment, whereas the current trial exhibits 5-year EFS and OS rates of 43% and 53%, respectively.…”

Section: Discussionmentioning

confidence: 99%

Anti-GD2 Antibody Dinutuximab Beta and Low-Dose Interleukin 2 After Haploidentical Stem-Cell Transplantation in Patients With Relapsed Neuroblastoma: A Multicenter, Phase I/II Trial

Flaadt

Ladenstein

Ebinger

et al. 2023

JCO

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PURPOSE Patients with relapsed high-risk neuroblastoma (rHR-NB) have a poor prognosis. We hypothesized that graft-versus-neuroblastoma effects could be elicited by transplantation of haploidentical stem cells (haplo-SCT) exploiting cytotoxic functions of natural killer cells and their activation by the anti-GD2 antibody dinutuximab beta (DB). This phase I/II trial assessed safety, feasibility, and outcomes of immunotherapy with DB plus subcutaneous interleukin-2 (scIL2) after haplo-SCT in patients with rHR-NB. METHODS Patients age 1-21 years underwent T-/B-cell–depleted haplo-SCT followed by DB and scIL2. The primary end point ‘success of treatment’ encompassed patients receiving six cycles, being alive 180 days after end of trial treatment without progressive disease, unacceptable toxicity, acute graft-versus-host-disease (GvHD) ≥grade 3, or extensive chronic GvHD. RESULTS Seventy patients were screened, and 68 were eligible for immunotherapy. Median number of DB cycles was 6 (range, 1-9). Median number of scIL2 cycles was 3 (1−6). The primary end point was met by 37 patients (54.4%). Median observation time was 7.8 years. Five-year event-free survival (EFS) and overall survival from start of trial treatment were 43% (95% CI, 31 to 55) and 53% (95% CI, 41 to 65), respectively. Five-year EFS among patients in complete remission (CR; 52%; 95% CI, 31 to 69) or partial remission (44%; 95% CI, 27 to 60) before immunotherapy were significantly better compared with patients with nonresponse/mixed response/progressive disease (13%; 95% CI, 1 to 42; P = .026). Overall response rate in 43 patients with evidence of disease after haplo-SCT was 51% (22 patients), with 15 achieving CR (35%). Two patients developed GvHD grade 2 and 3 each. No unexpected adverse events occurred. CONCLUSION DB therapy after haplo-SCT in patients with rHR-NB is feasible, with low risk of inducing GvHD, and results in long-term remissions likely attributable to increased antineuroblastoma activity by donor-derived effector cells.

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“…Changes in post-HCT immunosuppression guided by RQ-PCR chimerism have led to improved survival rates and/or reversion of MC in single-center studies of adult patients with leukemia (34,40,41). The rapid development of novel targeted or immunomodulatory therapies may provide much-needed alternatives, in some cases as a bridge to a second HCT (85). In B-cell precursor ALL (pre B-ALL) this development has been particularly impressive and CD19-targeted strategies including blinatumomab, Fc-optimized CD19 antibodies (86) and most recently CAR-T therapy have been added to the repertoire (87).…”

Section: B Amentioning

confidence: 99%

Highly-sensitive chimerism analysis in blood after allogeneic hematopoietic cell transplantation in childhood leukemia: Results from the Nordic Microchimerism Study

Haugaard

Madsen²,

Masmas³

et al. 2023

Front. Hematol.

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Analysis of chimerism in blood post‐HCT using STR‐PCR is routinely applied in parallel with quantification of MRD to predict relapse of leukemia. Real time quantitative PCR (RQ-PCR) chimerism is 10‐ to 100‐fold more sensitive, but clinical studies in children are sparse. In a prospective multicenter study, we analyzed increasing mixed chimerism (IMC) in blood samples following transplantation for leukemia in 64 children. IMC was defined as a minimum increase of either 0.1% or 0.05% recipient DNA between two samples or a ≥10-fold increase. Samples closer than 30 days to diagnosis of relapse were omitted. The risk of relapse was higher in children with IMC of both 0.1% and 0.05% compared to children without IMC (27.8 (95% CI 4.4-175.8; P<.001), and 18.4 (95% CI 2.8-120.5; P=0.002), respectively). From the date of IMC, the 3-year CI of relapse or MRD-positivity was 26.7% (CI 9.4-47.0) and 18.5% (6.4-35.3) for IMC ≥ 0.1% (n=27) and ≥ 0.05% (n= 40), respectively. In the subset of children without an IMC ≥ 0.1% or ≥ 0.05%, CI of relapse or molecular relapse were 16.7% (5.0 -34.1) and 10.8% (3.4 -23.3), respectively. In all cases with a relapse undetectable by IMC, MRD remained undetectable prior to relapse and standard chimerism negative. In a landmark analysis, neither an IMC ≥ 0.1% nor ≥ 0.05% prior to 90 days post‐HCT was significantly associated with an increased relapse incidence. These results indicate that the serial monitoring of RQ‐PCR chimerism in peripheral blood post-HCT may be a valuable supplement to the minimal residual disease analysis for an early detection of relapse in acute childhood leukemia.

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ADCC can improve graft vs leukemia effect after T- and B-cell depleted haploidentical stem cell transplantation in pediatric B-lineage ALL

Cited by 5 publications

References 17 publications

Immunomonitoring of Stage IV Relapsed Neuroblastoma Patients Undergoing Haploidentical Hematopoietic Stem Cell Transplantation and Subsequent GD2 (ch14.18/CHO) Antibody Treatment

Immunomonitoring of Stage IV Relapsed Neuroblastoma Patients Undergoing Haploidentical Hematopoietic Stem Cell Transplantation and Subsequent GD2 (ch14.18/CHO) Antibody Treatment

Anti-GD2 Antibody Dinutuximab Beta and Low-Dose Interleukin 2 After Haploidentical Stem-Cell Transplantation in Patients With Relapsed Neuroblastoma: A Multicenter, Phase I/II Trial

Highly-sensitive chimerism analysis in blood after allogeneic hematopoietic cell transplantation in childhood leukemia: Results from the Nordic Microchimerism Study

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