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01 juni 2023, Item does not contain fulltext, In 2021, 47,412 HCT (19,806 (42%) allogeneic and 27,606 (58%) autologous) in 43,109 patients were reported by 694 European centers. 3494 patients received advanced cellular therapies, 2524 of which were CAR-T treatments, an additional 3245 received DLI. Changes compared to the previous year were CAR-T treatment (+35%), allogeneic HCT +5.4%, autologous HCT +3.9%, more pronounced in non-malignant disorders. Main indications for allogeneic HCT were myeloid malignancies 10,745 (58%), lymphoid malignancies 5127 (28%) and non-malignant disorders 2501 (13%). Main indications for autologous HCT were lymphoid malignancies 22,129 (90%) and solid tumors 1635 (7%). In allogeneic HCT, use of haploidentical donors decreased by -0.9% while use of unrelated and sibling donors increased by +4.3% and +9%. Cord blood HCT decreased by -5.8%. Pediatric HCT increased overall by +5.6% (+6.9% allogeneic and +1.6% autologous). Increase in the use of CAR-T was mainly restricted to high-income countries. The drop in HCT activity reported in 2020 partially recovered in 2021, the second year of the SARS-CoV-2 pandemic. The transplant community confronted with the pandemic challenge, continued in providing patients access to treatment. This annual EBMT report reflects current activities useful for health care resource planning.

01 juni 2023, Item does not contain fulltext, For hematopoietic cell transplantation (HCT) and cellular therapy (CT), clinical patient care is localized, and practices may differ between countries and from center to center even within the same country. Historically, international guidelines were not always adapted to the changing daily clinical practice and practical topics there were not always addressed. In the absence of well-established guidelines, centers tended to develop local procedures/policies, frequently with limited communication with other centers. To try to harmonize localized clinical practices for malignant and non-malignant hematological disorders within EBMT scope, the practice harmonization and guidelines (PH&G) committee of the EBMT will co-ordinate workshops with topic-specific experts from interested centers. Each workshop will discuss a specific issue and write guidelines/recommendations that practically addresses the topic under review. To provide clear, practical and user-friendly guidelines when international consensus is lacking, the EBMT PH&G committee plans to develop European guidelines by HCT and CT physicians for peers' use. Here, we define how workshops will be conducted and guidelines/recommendations produced, approved and published. Ultimately, there is an aspiration for some topics, where there is sufficient evidence base to be considered for systematic reviews, which are a more robust and future-proofed basis for guidelines/recommendations than consensus opinion.

01 juni 2023, Item does not contain fulltext, From 2016 EBMT and JACIE developed an international risk-adapted benchmarking program of haematopoietic stem cell transplant (HSCT) outcome to provide individual EBMT Centers with a means of quality-assuring the HSCT process and meeting FACT-JACIE accreditation requirements relating to 1-year survival outcomes. Informed by previous experience from Europe, North America and Australasia, the Clinical Outcomes Group (COG) established criteria for patient and Center selection, and a set of key clinical variables within a dedicated statistical model adapted to the capabilities of the EBMT Registry. The first phase of the project was launched in 2019 to test the acceptability of the benchmarking model through assessment of Centers' performance for 1-year data completeness and survival outcomes of autologous and allogeneic HSCT covering 2013-2016. A second phase was delivered in July 2021 covering 2015-2019 and including survival outcomes. Reports of individual Center performance were shared directly with local principal investigators and their responses were assimilated. The experience thus far has supported the feasibility, acceptability and reliability of the system as well as identifying its limitations. We provide a summary of experience and learning so far in this 'work in progress', as well as highlighting future challenges of delivering a modern, robust, data-complete, risk-adapted benchmarking program across new EBMT Registry systems.

01 september 2023, Contains fulltext : 296498.pdf (Publisher’s version ) (Open Access), BACKGROUND: AUTO1 is a fast off-rate CD19-targeting chimeric antigen receptor (CAR), which has been successfully tested in adult lymphoblastic leukemia. Tscm/Tcm-enriched CAR-T populations confer the best expansion and persistence, but Tscm/Tcm numbers are poor in heavily pretreated adult patients. To improve this, we evaluate the use of AKT inhibitor (VIII) with the aim of uncoupling T-cell expansion from differentiation, to enrich Tscm/Tcm subsets. METHODS: VIII was incorporated into the AUTO1 manufacturing process based on the semiautomated the CliniMACS Prodigy platform at both small and cGMP scale. RESULTS: AUTO1 manufactured with VIII showed Tscm/Tcm enrichment, improved expansion and cytotoxicity in vitro and superior antitumor activity in vivo. Further, VIII induced AUTO1 Th1/Th17 skewing, increased polyfunctionality, and conferred a unique metabolic profile and a novel signature for autophagy to support enhanced expansion and cytotoxicity. We show that VIII-cultured AUTO1 products from B-ALL patients on the ALLCAR19 study possess superior phenotype, metabolism, and function than parallel control products and that VIII-based manufacture is scalable to cGMP. CONCLUSION: Ultimately, AUTO1 generated with VIII may begin to overcome the product specific factors contributing to CD19+relapse.

Contains fulltext : 296528.pdf (Publisher’s version ) (Open Access), Allogeneic natural killer (NK) cell-based immunotherapy is a promising, well-tolerated adjuvant therapeutic approach for acute myeloid leukemia (AML). For reproducible NK cell immunotherapy, a homogenous, pure and scalable NK cell product is preferred. Therefore, we developed a good manufacturing practice (GMP)-compliant, cytokine-based ex vivo manufacturing process for generating NK cells from CD34(+) hematopoietic stem and progenitor cells (HSPC). This manufacturing process combines amongst others IL15 and IL12 and the aryl hydrocarbon receptor antagonist StemRegenin-1 (SR1) to generate a consistent and active NK cell product that fits the requirements for NK cell immunotherapy well. The cell culture protocol was first optimized to generate NK cells with required expansion and differentiation capacity in GMP-compliant closed system cell culture bags. In addition, phenotype, antitumor potency, proliferative and metabolic capacity were evaluated to characterize the HSPC-NK product. Subsequently, seven batches were manufactured for qualification of the process. All seven runs demonstrated consistent results for proliferation, differentiation and antitumor potency, and preliminary specifications for the investigational medicinal product for early clinical phase trials were set. This GMP-compliant manufacturing process for HSPC-NK cells (named RNK001 cells) is used to produce NK cell batches applied in the clinical trial 'Infusion of ex vivo-generated allogeneic natural killer cells in combination with subcutaneous IL2 in patients with acute myeloid leukemia' approved by the Dutch Ethics Committee (EudraCT 2019-001929-27).

01 augustus 2023, Item does not contain fulltext, We previously analyzed trends in incidence and factors associated with lethal complications in ALL/AML/CML patients (causes of deaths; COD-1 study). The objective of this study was the analysis of incidence and specific causes of death after HCT, with focus on infectious deaths in two time periods, 1980-2001 (cohort-1) and 2002-2015 (cohort-2). All patients with HCT for lymphoma, plasma cell disorders, chronic leukemia (except CML), myelodysplastic/myeloproliferative disorders, registered in the EBMT-ProMISe-database were included (n = 232,618) (COD-2 study). Results were compared to those in the ALL/AML/CML COD-1 study. Mortality from bacterial, viral, fungal, and parasitic infections decreased in very early, early and intermediate phases. In the late phase, mortality from bacterial infections increased, while mortality from fungal, viral, or unknown infectious etiology did not change. This pattern was similar for allo- and auto-HCT in COD-1 and COD-2 studies, with a distinct and constant lower incidence of all types of infections at all phases, after auto-HCT. In conclusion, infections were the main cause of death before day +100, followed by relapse. Mortality from infectious deaths significantly decreased, except late phase. Post-transplant mortality has significantly decreased in all phases, from all causes after auto-HCT; it has decreased in all phases after allo-HCT except late phase.

01 augustus 2023, Item does not contain fulltext, BACKGROUND: Adjuvants are key for effective vaccination against cancer and chronic infectious diseases. Saponin-based adjuvants (SBAs) are unique among adjuvants in their ability to induce robust cell-mediated immune responses in addition to antibody responses. Recent preclinical studies revealed that SBAs induced cross-presentation and lipid bodies in otherwise poorly cross-presenting CD11b(+) murine dendritic cells (DCs). METHOD: Here, we investigated the response of human DC subsets to SBAs with RNA sequencing and pathway analyses, lipid body induction visualized by laser scanning microscopy, antigen translocation to the cytosol, and antigen cross-presentation to CD8(+) T cells. RESULTS: RNA sequencing of SBA-treated conventional type 1 DC (cDC1) and type 2 DC (cDC2) subsets uncovered that SBAs upregulated lipid-related pathways in CD11c(+) CD1c(+) cDC2s, especially in the CD5(-) CD163(+) CD14(+) cDC2 subset. Moreover, SBAs induced lipid bodies and enhanced endosomal antigen translocation into the cytosol in this particular cDC2 subset. Finally, SBAs enhanced cross-presentation only in cDC2s, which requires the CD163(+) CD14(+) cDC2 subset. CONCLUSIONS: These data thus identify the CD163(+) CD14(+) cDC2 subset as the main SBA-responsive DC subset in humans and imply new strategies to optimize the application of saponin-based adjuvants in a potent cancer vaccine.

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Contains fulltext : 247647.pdf (Publisher’s version ) (Open Access)

Radboud University, 19 mei 2022, Promotores : Jansen, J.H., Massuger, L.F.A.G. Co-promotores : Dolstra, H., Hobo, W.A., Contains fulltext : 249036.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 251625.pdf (Publisher’s version ) (Open Access)

Item does not contain fulltext, Allogeneic natural killer (NK) cell transfer is a potential immunotherapy to eliminate and control cancer. A promising source are CD34 + hematopoietic progenitor cells (HPCs), since large numbers of cytotoxic NK cells can be generated. Effective boosting of NK cell function can be achieved by interleukin (IL)-15. However, its in vivo half-life is short and potent trans-presentation by IL-15 receptor α (IL-15Rα) is absent. Therefore, ImmunityBio developed IL-15 superagonist N-803, which combines IL-15 with an activating mutation, an IL-15Rα sushi domain for trans-presentation, and IgG1-Fc for increased half-life. Here, we investigated whether and how N-803 improves HPC-NK cell functionality in leukemia and ovarian cancer (OC) models in vitro and in vivo in OC-bearing immunodeficient mice. We used flow cytometry-based assays, enzyme-linked immunosorbent assay, microscopy-based serial killing assays, and bioluminescence imaging, for in vitro and in vivo experiments. N-803 increased HPC-NK cell proliferation and interferon (IFN)γ production. On leukemia cells, co-culture with HPC-NK cells and N-803 increased ICAM-1 expression. Furthermore, N-803 improved HPC-NK cell-mediated (serial) leukemia killing. Treating OC spheroids with HPC-NK cells and N-803 increased IFNγ-induced CXCL10 secretion, and target killing after prolonged exposure. In immunodeficient mice bearing human OC, N-803 supported HPC-NK cell persistence in combination with total human immunoglobulins to prevent Fc-mediated HPC-NK cell depletion. Moreover, this combination treatment decreased tumor growth. In conclusion, N-803 is a promising IL-15-based compound that boosts HPC-NK cell expansion and functionality in vitro and in vivo. Adding N-803 to HPC-NK cell therapy could improve cancer immunotherapy.

Contains fulltext : 235811.pdf (Publisher’s version ) (Open Access)

Item does not contain fulltext, The low 5-year survival rate for patients with acute myeloid leukemia (AML), primarily caused due to disease relapse, emphasizes the need for better therapeutic strategies. Disease relapse is facilitated by leukemic stem cells (LSCs) that are resistant to standard chemotherapy and promote tumor growth. To target AML blasts and LSCs using natural killer (NK) cells, we have developed a trispecific killer engager (TriKE(TM)) molecule containing a humanized anti-CD16 heavy chain camelid single-domain antibody (sdAb) that activates NK cells, an IL-15 molecule that drives NK-cell priming, expansion and survival, and a single-chain variable fragment (scFv) against human CLEC12A (CLEC12A TriKE). CLEC12A is a myeloid lineage antigen that is highly expressed by AML cells and LSCs, but not expressed by normal hematopoietic stem cells (HSCs), thus minimizing off-target toxicity. The CLEC12A TriKE induced robust NK-cell specific proliferation, enhanced NK-cell activation, and killing of both AML cell lines and primary patient-derived AML blasts in vitro while sparing healthy HSCs. Additionally, the CLEC12A TriKE was able to reduce tumor burden in preclinical mouse models. These findings highlight the clinical potential of the CLEC12A TriKE for the effective treatment of AML.

Contains fulltext : 238646.pdf (Publisher’s version ) (Open Access)

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Contains fulltext : 237287.pdf (Publisher’s version ) (Open Access)

QC 20220927

Allogeneic natural killer (NK) cell transfer is a potential immunotherapy to eliminate and control cancer. A promising source are CD34 + hematopoietic progenitor cells (HPCs), since large numbers of cytotoxic NK cells can be generated. Effective boosting of NK cell function can be achieved by interleukin (IL)-15. However, its in vivo half-life is short and potent trans-presentation by IL-15 receptor α (IL-15Rα) is absent. Therefore, ImmunityBio developed IL-15 superagonist N-803, which combines IL-15 with an activating mutation, an IL-15Rα sushi domain for trans-presentation, and IgG1-Fc for increased half-life. Here, we investigated whether and how N-803 improves HPC-NK cell functionality in leukemia and ovarian cancer (OC) models in vitro and in vivo in OC-bearing immunodeficient mice. We used flow cytometry-based assays, enzyme-linked immunosorbent assay, microscopy-based serial killing assays, and bioluminescence imaging, for in vitro and in vivo experiments. N-803 increased HPC-NK cell proliferation and interferon (IFN)γ production. On leukemia cells, co-culture with HPC-NK cells and N-803 increased ICAM-1 expression. Furthermore, N-803 improved HPC-NK cell-mediated (serial) leukemia killing. Treating OC spheroids with HPC-NK cells and N-803 increased IFNγ-induced CXCL10 secretion, and target killing after prolonged exposure. In immunodeficient mice bearing human OC, N-803 supported HPC-NK cell persistence in combination with total human immunoglobulins to prevent Fc-mediated HPC-NK cell depletion. Moreover, this combination treatment decreased tumor growth. In conclusion, N-803 is a promising IL-15-based compound that boosts HPC-NK cell expansion and functionality in vitro and in vivo. Adding N-803 to HPC-NK cell therapy could improve cancer immunotherapy., QC 20210308

Contains fulltext : 229284.pdf (Publisher’s version ) (Closed access), Acute myeloid leukemia (AML) is an immune-susceptible malignancy, as demonstrated by its responsiveness to allogeneic stem cell transplantation (alloSCT). However, by employing inhibitory signaling pathways, including PD-1/PD-L1, leukemia cells suppress T cell-mediated immune attack. Notably, impressive clinical efficacy has been obtained with PD-1/PD-L1 blocking antibodies in cancer patients. Yet, these systemic treatments are often accompanied by severe toxicity, especially after alloSCT. Here, we investigated RNA interference technology as an alternative strategy to locally interfere with PD-1/PD-L1 signaling in AML. We demonstrated efficient siRNA-mediated PD-L1 silencing in HL-60 and patients' AML cells. Importantly, WT1-antigen T cell receptor(+) PD-1(+) 2D3 cells showed increased activation toward PD-L1 silenced WT1(+) AML. Moreover, PD-L1 silenced AML cells significantly enhanced the activation, degranulation, and IFN-γ production of minor histocompatibility antigen-specific CD8(+) T cells. Notably, PD-L1 silencing was equally effective as PD-1 antibody blockade. Together, our study demonstrates that PD-L1 silencing may be an effective strategy to augment AML immune-susceptibility. This provides rationale for further development of targeted approaches to locally interfere with immune escape mechanisms in AML, thereby minimizing severe toxicity. In combination with alloSCT and/or adoptive T cell transfer, this strategy could be very appealing to boost graft-versus-leukemia immunity and improve outcome in AML patients.

01 april 2020, Contains fulltext : 220877.pdf (Publisher’s version ) (Open Access), In many healthcare settings, benchmarking for complex procedures has become a mandatory requirement by competent authorities, regulators, payers and patients to assure clinical performance, cost-effectiveness and safe care of patients. In several countries inside and outside Europe, benchmarking systems have been established for haematopoietic stem cell transplantation (HSCT), but access is not universal. As benchmarking is now integrated into the FACT-JACIE standards, the EBMT and JACIE established a Clinical Outcomes Group (COG) to develop and introduce a universal system accessible across EBMT members. Established systems from seven European countries (United Kingdom, Italy, Belgium, France, Germany, Spain, Switzerland), USA and Australia were appraised, revealing similarities in process, but wide variations in selection criteria and statistical methods. In tandem, the COG developed the first phase of a bespoke risk-adapted international benchmarking model for one-year survival following allogeneic and autologous HSCT based on current capabilities within the EBMT registry core dataset. Data completeness, which has a critical impact on validity of centre comparisons, is also assessed. Ongoing development will include further scientific validation of the model, incorporation of further variables (when appropriate) alongside implementation of systems for clinically meaningful interpretation and governance aiming to maximise acceptance to centres, clinicians, payers and patients across EBMT.

Radboud University, 25 september 2020, Promotores : Jansen, J.H., Massuger, L.F.A.G. Co-promotores : Dolstra, H., Bekkers, R.L.M., Contains fulltext : 220308.pdf (publisher's version ) (Open Access)

Contains fulltext : 227447.pdf (publisher's version ) (Open Access)

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Contains fulltext : 229379.pdf (Publisher’s version ) (Open Access), AKT-inhibition is a promising approach to improve T cell therapies; however, its effect on CD4(+) T cells is insufficiently explored. Previously, we and others showed that AKT-inhibition during ex vivo CD8(+) T cell expansion facilitates the generation of polyfunctional T cells with stem cell memory-like traits. However, most therapeutic T cell products are generated from lymphocytes, containing CD4(+) T cells that can affect CD8(+) T cells dependent on the Th-subset. Here, we investigated the effect of AKT-inhibition on CD4(+) T cells, during separate as well as total T cell expansions. Interestingly, ex vivo AKT-inhibition preserved the early memory phenotype of CD4(+) T cells based on higher CD62L, CXCR4 and CCR7 expression. However, in the presence of AKT-inhibition, Th-differentiation was skewed toward more Th2-associated at the expense of Th1-associated cells. Importantly, the favorable effect of AKT-inhibition on the functionality of CD8(+) T cells drastically diminished in the presence of CD4(+) T cells. Moreover, also the expansion method influenced the effect of AKT-inhibition on CD8(+) T cells. These findings indicate that the effect of AKT-inhibition on CD8(+) T cells is dependent on cell composition and expansion strategy, where presence of CD4(+) T cells as well as polyclonal stimulation impede the favorable effect of AKT-inhibition.

01 juli 2020, Contains fulltext : 220591.pdf (Publisher’s version ) (Open Access), BACKGROUND AIMS: Recent technical and clinical advances with cell-based therapies (CBTs) hold great promise in the treatment of patients with rare diseases and those with high unmet medical need. Currently the majority of CBTs are developed and manufactured in specialized academic facilities. Due to small scale, unique characteristics and specific supply chain, CBT manufacturing is considered costly compared to more conventional medicinal products. As a result, biomedical researchers and clinicians are increasingly faced with cost considerations in CBT development. The objective of this research was to develop a costing framework and methodology for academic and other small-scale facilities that manufacture cell-based therapies. METHODS: We conducted an international multi-center costing study in four facilities in Europe using eight CBTs as case studies. This study includes costs from cell or tissue procurement to release of final product for clinical use. First, via interviews with research scientists, clinicians, biomedical scientists, pharmacists and technicians, we designed a high-level costing framework. Next, we developed a more detailed uniform methodology to allocate cost items. Costs were divided into steps (tissue procurement, manufacturing and fill-finish). The steps were each subdivided into cost categories (materials, equipment, personnel and facility), and each category was broken down into facility running (fixed) costs and operational (variable) costs. The methodology was tested via the case studies and validated in developer interviews. Costs are expressed in 2018 euros (€). RESULTS: The framework and methodology were applicable across facilities and proved sensitive to differences in product and facility characteristics. Case study cost estimates ranged between €23 033 and €190 799 Euros per batch, with batch yield varying between 1 and 88 doses. The cost estimations revealed hidden costs to developers and provided insights into cost drivers to he