The immunological phenotype of rituximab-sensitive chronic graft-versus-host disease: a phase II study

Dorp, Suzanne van; Resemann, Henrike K; Boome, Liane te; Pietersma, Floor; Baarle, Debbie van; Gmelig-Meyling, F.H.J.; Weger, Roel de; Petersen, Eefke; Minnema, Monique C.; Lokhorst, Henk M.; Ebeling, Saskia B.; Beijn, Scott J.P.; Knol, Edward F.; Dijk, Marijke van; Meijer, Ellen; Kuball, Jürgen

doi:10.3324/haematol.2011.041814

Cited by 16 publications

(18 citation statements)

References 25 publications

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“…22,23 In brief, target cells were labeled overnight with 100Cu 51 Cr (150Cu for primary cells) and incubated for 5 hours with transduced T cells in 5 effector-to-target ratios (E:T) between 30:1 and 0.3:1. The fold change compared with reactivity of engineered T cells expressing unmutated ␥9␦2TCR was calculated.…”

Section: Functional T-cell Assaysmentioning

confidence: 99%

γ9 and δ2CDR3 domains regulate functional avidity of T cells harboring γ9δ2TCRs

Gründer¹,

Dorp²,

Hol³

et al. 2012

Blood

107

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Immunotherapy with innate immune cells has recently evoked broad interest as a novel treatment option for cancer patients. ␥9␦2T cells in particular are emerging as an innate cell population with high frequency and strong antitumor reactivity, which makes them and their receptors promising candidates for immune interventions. However, clinical trials have so far reported only limited tumor control by adoptively transferred ␥9␦2T cells. As a potential explanation for this lack of efficacy, we found unexpectedly high variability in tumor recognition within the physiologic human ␥9␦2T-cell repertoire, which is substantially regulated by the CDR3 domains of individual ␥9␦2TCRs. In the present study, we demonstrate that the reported molecular requirements of CDR3 domains to interact with target cells shape the physiologic ␥9␦2T-cell repertoire and, most likely, limit the protective and thera- IntroductionImmunotherapy with innate immune cells has become widely used because this approach obviates the need to match a cellular product to a defined HLA haplotype, allowing adoptive immunotherapies to be used in virtually any cancer patient without extensive in vitro selection or manipulation of the cellular product. 1-4 ␥9␦2T cells are promising as an innate cell population for this purpose because they are usually observed at high frequencies in the human peripheral blood and provide a strong antitumor reactivity against various solid and hematologic cancers. 5 However, within ␥9␦2T-cell populations, individual clones display great diversity in the repertoire because of the activating or inhibitory receptors expressed. 6 Selecting innate cell products for certain cell types, such as those with a low level of inhibitory receptors, therefore seems plausible, especially considering the limited efficacy of adoptively transferred innate immune cells in clinical trials. 7,8 An alternative proposal is to engineer cells to express defined activating innate receptors that mediate strong antitumor reactivity, such as a defined ␥9␦2TCR, 9 which could pave the way for readily available and more effective cellular products. However, the molecular details of how a ␥9␦2TCR interacts with its target are not fully understood, making it challenging to select defined ␥9␦2T cells or to engineer T cells with defined ␥9␦2TCRs.In "classic" immunoreceptors such as ␣␤TCRs or Igs, the complementary determining regions (CDRs) determine affinity and specificity for a specific (peptide) epitope. V(D)J recombination allows the creation of a highly variable CDR repertoire ensuring recognition of an immense collection of antigens. ␥9␦2T cells also possess a rearranged TCR that mediates recognition. The phosphoantigen isopentenyl pyrophosphate (IPP) has been suggested to be a key player in ␥9␦2TCR-mediated activation, 5,10,11 but no direct interaction between a ␥9␦2TCR and IPP or any other phosphoantigen has ever been demonstrated. It was previously suggested that positively charged residues within the ␥9␦2TCR are crucial for the response to negatively...

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Section: Functional T-cell Assaysmentioning

confidence: 99%

γ9 and δ2CDR3 domains regulate functional avidity of T cells harboring γ9δ2TCRs

Gründer¹,

Dorp²,

Hol³

et al. 2012

Blood

107

View full text Add to dashboard Cite

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“…If not treated therapeutically, patients were considered to be at high risk for fungal infection and received prophylaxis with voriconazole as the first choice (trough level >1 mg/dL) [23,24]. Concomitant treatments of the adult patients have been described in more detail elsewhere [25,26].…”

Section: Donor Selection and Stem Cell Processingmentioning

confidence: 99%

Sufficient Immunosuppression with Thymoglobulin Is Essential for a Successful Haplo-Myeloid Bridge in Haploidentical-Cord Blood Transplantation

Lindemans

Boome

Admiraal

et al. 2015

Biology of Blood and Marrow Transplantation

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In haploidentical (haplo)-cord blood (CB) transplantations, early haplo donor engraftment serves as a myeloid bridge to sustainable CB engraftment and is associated with early neutrophil recovery. The conditioning regimens as published for haplo-cord protocols usually contain serotherapy, such as rabbit antithymocyte globulin (ATG) (Thymoglobulin, Genzyme, Cambridge, MA). However, reducing or omitting serotherapy is an important strategy to improve early immune reconstitution after transplantation. The need for serotherapy in successful haplo-cord transplantation, defined as having a haplo-derived myeloid bridge to CB engraftment, has not been investigated before. Two consecutive cohorts of patients underwent transplantation with haplo-CB. The first group underwent transplantation with haplo-CB for active infection and/or an underlying condition with expected difficult engraftment without a conventional donor available. They received a single unit (s) CB and haplo donor cells (CD34(+) selected, 5 × 10(6) CD34(+)/kg). The second cohort included patients with poor-risk malignancies, not eligible for other treatment protocols. They received a sCB and haplo donor cells (CD19/αβTCR-depleted; 5 × 10(6) CD34(+)/kg). Retrospectively in both cohorts, active ATG (Thymoglobulin) levels were measured and post-hematopoietic cell transplantation area under the curve (AUC) was calculated. The influence of ATG exposure for having a successful haplo-myeloid bridge (early haplo donor engraftment before CB engraftment and no secondary neutropenia) and transplantation-related mortality (TRM) were analyzed as primary endpoints. Twenty patients were included (16 in the first cohort and 4 in the second cohort). In 58% of evaluable patients, there was no successful haplo-derived myeloid bridge to CB engraftment, for which a low post-transplantation ATG exposure appeared to be a predictor (P <.001). TRM in the unsuccessful haplo-bridge group was 70% ± 16% versus 12% ± 12% in the successful haplo-bridge group (P = .012). In conclusion, sufficient in vivo T depletion with ATG is required for a successful haplo-myeloid bridge to CB engraftment.

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“…132 Correspondingly, several small trials showed clinical effectiveness of rituximab in cGVHD. GVHD of the skin responded better than cGVHD of the visceral organs, 133 but successful treatment of cGVHD of inner organs has been reported anecdotally. 134 As CD20 is a promising target not only in malignant disease several alternative, humanized or human antibodies such as ocrelizumab, GA101 and ofatumumab are currently being tested and should also be investigated in GVHD.…”

Section: B-cell Targetingmentioning

confidence: 99%

Novel treatment concepts for graft-versus-host disease

Wolf

Lilienfeld‐Toal

Wolf

et al. 2012

Blood

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Acute and chronic graft-versus-host disease (GVHD) are potentially lethal complications after stem cell transplantation (SCT). Steroids are the appropriate firstline treatment for both. However, if patients do not adequately benefit from steroid therapy, mortality is high and standardized treatment algorithms are lacking. This is mainly because of limited data from prospective, randomized clinical trials. In addition, most of the available treatment options only induce clinical benefits in a limited proportion of patients. Thus, there is an urgent clinical need to develop more potent immunosuppressive treatment strategies for patients suffering from acute or chronic steroidrefractory GVHD while maintaining the graft versus tumor effect to avoid a potential rise in relapse-related mortality. The increasing knowledge about host-as well as donor-derived variables favoring GVHD development and the increasing armamentarium of immune-modulatory agents entering preclinical and clinical research will probably allow more effective treatment of GVHD in the future. This review describes novel developments in the treatment of steroid-refractory GVHD, with a special focus on the rationale behind promising pharmacologic compounds or up-coming cellular therapies. (Blood. 2012;119(1):16-25) IntroductionIn 1957, E. D. Thomas and colleagues first described the infusion of bone marrow cells into patients after prior radio-or chemotherapy in their seminal New England Journal of Medicine paper. 1 This work initiated 5 decades of basic and clinical research in the field of stem cell transplantation (SCT) and nowadays SCT is the treatment of choice for many malignant and benign hematopoietic diseases. It was known before 1957 from preclinical animals studies that tranplantation of splenocytes from noncongenic donor strains, while facilitating hematopoietic recovery, induced a severe illness, characterized by progressive weight loss, hunched posture, and diarrhea. 2 In the following years it has become clear that this was not primarily because of the conditioning therapy, but that it was an immune-mediated syndrome, which is now referred to as graft versus host disease (GVHD). GVHD nowadays remains not only a major cause of non-relapse mortality, but also induces substantial morbidity, which can severely affect quality of life. GVHD is a very complex immunologic disorder characterized by a plethora of clinical presentations. 3 Importantly, the predominant use of peripheral blood stem cells (PBSC) rather than bone marrow (BM) and the increasing proportion of reduced intensity conditioning (RIC) regimens has made multifacetted chronic GVHD (cGVHD) more and more clinically relevant. 4,5 The incidence of GVHD thus depends on several variables, including the donor type (related versus unrelated, matched versus mismatched or haploidentical), the type of conditioning (total boby irradiation [TBI] versus nonTBI), the donor's sex (female or male, versus all other sex combinations) and the stem cell source (PBSC versus BM). 6 Despite the inc...

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The immunological phenotype of rituximab-sensitive chronic graft-versus-host disease: a phase II study

Cited by 16 publications

References 25 publications

γ9 and δ2CDR3 domains regulate functional avidity of T cells harboring γ9δ2TCRs

γ9 and δ2CDR3 domains regulate functional avidity of T cells harboring γ9δ2TCRs

Sufficient Immunosuppression with Thymoglobulin Is Essential for a Successful Haplo-Myeloid Bridge in Haploidentical-Cord Blood Transplantation

Novel treatment concepts for graft-versus-host disease

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