A PHASE IB STUDY OF IMMUNOTHERAPY WITH EX VIVO PRE-ACTIVATED AND EXPANDED CB-NK CELLS IN COMBINATION WITH CETUXIMAB, IN COLORECTAL CANCER PATIENTS WITH MINIMAL RESIDUAL DISEASE (MRD)
Ontology highlight
ABSTRACT:
DISEASE(S): Neoplasm, Residual,Colon Cancer,Resected Stage
PROVIDER: 2389354 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Background aimsSeveral methods to expand and activate (EA) NK cells ex vivo have been developed for the treatment of relapsed or refractory cancers. Infusion of fresh NK cells is generally preferred to the infusion of cryopreserved/thawed (C/T) NK cells because of concern that cryopreservation diminishes NK cell activity. However, there has been little head-to-head comparison of the functionality of fresh versus C/T NK cell products.MethodsWe evaluated activity of fresh and C/T EA NK cells generated by interleukin (IL)-15, IL-2 and CD137L expansion.ResultsAnalysis of C/T NK cell products demonstrated decreased recovery of viable CD56+ cells, but the proportion of NK cells in the C/T EA NK cell product did not decrease compared with the fresh EA NK cell product. Fresh and C/T EA NK cells demonstrated increased granzyme B compared with NK cells pre-expansion, but only fresh EA NK cells showed increased NKG2D. Compared with fresh EA NK cells, cytotoxic ability of C/T EA NK cells was reduced, but C/T EA NK cells remained potently cytotoxic against tumor cells via both antibody-independent and antibody-dependent mechanisms within 4 h post-thaw. Fresh EA NK cells generated high levels of gamma interferon (IFN-γ), which was abrogated by JAK1/JAK2 inhibition with ruxolitinib, but C/T EA NK cells showed lower IFN-γ unaffected by JAK1/JAK2 inhibition.DiscussionUsage of C/T EA NK cells may be an option to provide serial "boost" NK cell infusions from a single apheresis to maximize NK cell persistence and potentially improve NK-induced responses to refractory cancer.
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Project description:Purpose: Daratumumab and its use in combination with other agents is becoming a new standard of care for the treatment of multiple myeloma. We mechanistically studied how daratumumab acts on natural killer (NK) cells.Experimental Design: Quantities of NK cells in peripheral blood and/or bone marrow of patients with multiple myeloma or healthy donors were examined by flow cytometry. NK-cell apoptosis and the associated mechanism were assessed by flow cytometry and immunoblotting. Patients' NK cells were expanded in vitro using feeder cells. Combination treatment of daratumumab and expanded NK cells was performed using an MM.1S xenograft animal model.Results: CD38-/low NK cells survived, whereas CD38+ NK cells were almost completely eliminated, in peripheral blood and bone marrow of daratumumab-treated multiple myeloma patients. NK-cell depletion occurred due to daratumumab-induced NK-cell fratricide via antibody-dependent cellular cytotoxicity. Consequently, CD38-/low NK cells were more effective for eradicating multiple myeloma cells than were CD38+ NK cells in the presence of daratumumab. Blockade of CD38 with the F(ab)2 fragments of daratumumab inhibited the antibody-mediated NK-cell fratricide. CD38-/low NK cells displayed a significantly better potential for expansion than CD38+ NK cells, and the expanded NK cells derived from the former population were more cytotoxic than those derived from the latter against multiple myeloma cells. Therefore, infusion of ex vivo-expanded autologous NK cells from daratumumab-treated patients may improve the antibody therapy.Conclusions: We unravel a fratricide mechanism for daratumumab-mediated NK-cell depletion and provide a potential therapeutic strategy to overcome this side effect in daratumumab-treated patients with multiple myeloma. Clin Cancer Res; 24(16); 4006-17. ©2018 AACR.
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Project description:The infusion of natural killer (NK) cells is a promising therapy for patients with advanced malignancies. Clinical expanded NK-cell products were compared with freshly isolated NK cells. Autologous peripheral blood mononuclear cells were collected by apheresis from 8 patients. NK cells were isolated by anti-CD3-negative selection followed by anti-CD56-positive selection. They were then expanded by co-culture with interleukin-2 and an irradiated Epstein-Barr virus (EBV)-transformed lymphoblastoid cell line (EBV-TM-LCL) to produce 14 NK-cell products. Molecular changes in the 14 NK-cell products were characterized using gene and microRNA expression microarrays. EBV-TM-LCL feeder cells from 3 lots were also analyzed as they were expanded for over 90 days and each lot was used for multiple NK-cell expansions. The gene expression profiles among the 3 EBV-TM-LCL lots used showed no differences and were not affected by their time in culture. Freshly isolated and expanded NK cells had distinct gene and microRNA expression profiles. Compared with fresh NK cells, expanded NK cells overexpressed 1098 genes and 28 human microRNAs. Genes in the crosstalk between dendritic and NK cells and metabolic pathways were up-regulated in expanded NK cells, whereas genes in a number of immune function pathways were down-regulated. Among all the most up-regulated genes were the NK cell-activating receptor natural cytotoxicity triggering receptor 3, myxovirus restistance 1, lymphotoxin ?, and BCL2-associated X protein. Although some expanded NK-cell product variability was observed, perhaps related to patient factors, further studies on larger numbers of products will be needed to determine the impact of these differences on clinical outcomes.
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Project description:Here we present the single cell transcriptomes of human cord blood (CB) long-term hematopoietic stem cells (LT-HSCs) cultured in differentiation promoting medium over a time-course of 0, 6 24 or 72 h. A condition was included for LT-HSCs cultured with the CDK6 inhibitor Palbociclib for durations of 24 or 72 h. Palbociclib causes reversible cell cycle arrest in early G1 in these culture conditions. The objectives of this study were to understand the impact of cell culture on CB LT-HSCs in a time resolved manner and to investigate the role of cell cycle progression in driving this transcriptional change. In the present study we report that 72 h of culture causes extensive rewiring of the CB LT-HSC transcriptome and that changes are dynamically acquired over the time-course. We also report that cell cycle progression is not the main driver of transcriptional change in tested culture conditions.
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Project description:Relapse has emerged as the most important cause of treatment failure after allogeneic hematopoietic stem cell transplantation (HSCT). To test the hypothesis that natural killer (NK) cells can decrease the risk of leukemia relapse, we initiated a phase 1 dose-escalation study of membrane-bound interleukin 21 (mbIL21) expanded donor NK cells infused before and after haploidentical HSCT for high-risk myeloid malignancies. The goals were to determine the safety, feasibility, and maximum tolerated dose. Patients received a melphalan-based reduced-intensity conditioning regimen and posttransplant cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis. NK cells were infused on days -2, +7, and +28 posttransplant. All NK expansions achieved the required cell number, and 11 of 13 patients enrolled received all 3 planned NK-cell doses (1 × 105/kg to 1 × 108/kg per dose). No infusional reactions or dose-limiting toxicities occurred. All patients engrafted with donor cells. Seven patients (54%) developed grade 1-2 acute GVHD (aGVHD), none developed grade 3-4 aGVHD or chronic GVHD, and a low incidence of viral complications was observed. One patient died of nonrelapse mortality; 1 patient relapsed. All others were alive and in remission at last follow-up (median, 14.7 months). NK-cell reconstitution was quantitatively, phenotypically, and functionally superior compared with a similar group of patients not receiving NK cells. In conclusion, this trial demonstrated production feasibility and safety of infusing high doses of ex vivo-expanded NK cells after haploidentical HSCT without adverse effects, increased GVHD, or higher mortality, and was associated with significantly improved NK-cell number and function, lower viral infections, and low relapse rate posttransplant.
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Project description:V?2(neg) ?? T cells, of which V?1+ ?? T cells are by far the largest subset, are important effectors against CMV infection. Malignant gliomas often contain CMV genetic material and proteins, and evidence exists that CMV infection may be associated with initiation and/or progression of glioblastoma multiforme (GBM). We sought to determine if V?1+ ?? T cells were cytotoxic to GBM and the extent to which their cytotoxicity was CMV dependent. We examined the cytotoxic effect of ex vivo expanded/activated V?1+ ?? T cells from healthy CMV seropositive and CMV seronegative donors on unmanipulated and CMV-infected established GBM cell lines and cell lines developed from short- term culture of primary tumors. Expanded/activated V?1+ T cells killed CMV-negative U251, U87, and U373 GBM cell lines and two primary tumor explants regardless of the serologic status of the donor. Experimental CMV infection did not increase V?1+ T cell--mediated cytotoxicity and in some cases the cell lines were more resistant to lysis when infected with CMV. Flow cytometry analysis of CMV-infected cell lines revealed down-regulation of the NKG2D ligands ULBP-2, and ULBP-3 as well as MICA/B in CMV-infected cells. These studies show that ex vivo expanded/activated V?1+ ?? T cells readily recognize and kill established GBM cell lines and primary tumor-derived GBM cells regardless of whether CMV infection is present, however, CMV may enhance the resistance GBM cell lines to innate recognition possibly contributing to the poor immunogenicity of GBM.
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