Cellular immunotherapy in multiple myeloma: Lessons from preclinical models

Binsfeld, Marilène; Fostier, Karel; Muller, Joséphine; Baron, Frédéric; Schots, Rik; Béguin, Yves; Heusschen, Roy; Caers, Jo

doi:10.1016/j.bbcan.2014.08.001

Cited by 17 publications

(17 citation statements)

References 147 publications

(195 reference statements)

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“…[9][10][11] CD38 is ubiquitously expressed on MM cells, 12,13 but is also present on other immune cells, including MDSCs and regulatory B cells (Bregs). 14,15 These CD38-positive (CD38 1 ) immunosuppressive cell populations are associated with decreased immune function and disease progression.…”

Section: Introductionmentioning

confidence: 99%

Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma

Krejcik

Casneuf

Nijhof

et al. 2016

Blood

734

730

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• CD38-expressing immunosuppressive regulatory T and B cells and myeloid-derived suppressor cells were sensitive to daratumumab treatment.• Cytotoxic T-cell number, activation, and clonality increased after daratumumab treatment in heavily pretreated relapsed and refractory MM.Daratumumab targets CD38-expressing myeloma cells through a variety of immunemediated mechanisms (complement-dependent cytotoxicity, antibody-dependent cellmediated cytotoxicity, and antibody-dependent cellular phagocytosis) and direct apoptosis with crosslinking. These mechanisms may also target nonplasma cells that express CD38, which prompted evaluation of daratumumab's effects on CD38-positive immune subpopulations. Peripheral blood (PB) and bone marrow (BM) from patients with relapsed/refractory myeloma from 2 daratumumab monotherapy studies were analyzed before and during therapy and at relapse. Regulatory B cells and myeloid-derived suppressor cells, previously shown to express CD38, were evaluated for immunosuppressive activity and daratumumab sensitivity in the myeloma setting. A novel subpopulation of regulatory T cells (Tregs) expressing CD38 was identified. These Tregs were more immunosuppressive in vitro than CD38-negative Tregs and were reduced in daratumumab-treated patients. In parallel, daratumumab induced robust increases in helper and cytotoxic T-cell absolute counts. In PB and BM, daratumumab induced significant increases in CD8 1 :CD4 1 and CD8 1:Treg ratios, and increased memory T cells while decreasing naïve T cells. The majority of patients demonstrated these broad T-cell changes, although patients with a partial response or better showed greater maximum effector and helper T-cell increases, elevated antiviral and alloreactive functional responses, and significantly greater increases in T-cell clonality as measured by T-cell receptor (TCR) sequencing. Increased TCR clonality positively correlated with increased CD81 PB T-cell counts. Depletion of CD38 1 immunosuppressive cells, which is associated with an increase in T-helper cells, cytotoxic T cells, T-cell functional response, and TCR clonality, represents possible additional mechanisms of action for daratumumab and deserves further exploration. (Blood. 2016;128(3):384-394)

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Section: Introductionmentioning

confidence: 99%

Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma

Krejcik

Casneuf

Nijhof

et al. 2016

Blood

734

730

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“…These alterations are caused in part by the replacement of normal bone marrow with malignant plasma cells, suppressing normal hematopoiesis. Moreover, the immune response is directly suppressed by MM cells and through their interactions with the microenvironment [2]. As the immune response impairment contributes to MM progression, cellular immunotherapy appears to be a promising therapeutic approach.…”

Section: Introductionmentioning

confidence: 99%

“…Mouse models have contributed to the understanding of MM biology and to the introduction of novel agents [12], and are of great interest in the preclinical evaluation of cellular immunotherapy [2]. Currently, only two immunocompetent murine models have been described in which allo-SCT is associated with a GvM effect [13], [14], but these models do not resemble human MM disease [13] or do not use allo-SCT as a curative treatment for established disease [14].…”

Section: Introductionmentioning

confidence: 99%

Establishment of a Murine Graft-versus-Myeloma Model Using Allogeneic Stem Cell Transplantation

et al. 2014

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BackgroundMultiple myeloma (MM) is a malignant plasma cell disorder with poor long-term survival and high recurrence rates. Despite evidence of graft-versus-myeloma (GvM) effects, the use of allogeneic hematopoietic stem cell transplantation (allo-SCT) remains controversial in MM. In the current study, we investigated the anti-myeloma effects of allo-SCT from B10.D2 mice into MHC-matched myeloma-bearing Balb/cJ mice, with concomitant development of chronic graft-versus-host disease (GvHD).Methods and resultsBalb/cJ mice were injected intravenously with luciferase-transfected MOPC315.BM cells, and received an allogeneic (B10.D2 donor) or autologous (Balb/cJ donor) transplant 30 days later. We observed a GvM effect in 94% of the allogeneic transplanted mice, as the luciferase signal completely disappeared after transplantation, whereas all the autologous transplanted mice showed myeloma progression. Lower serum paraprotein levels and lower myeloma infiltration in bone marrow and spleen in the allogeneic setting confirmed the observed GvM effect. In addition, the treated mice also displayed chronic GvHD symptoms. In vivo and in vitro data suggested the involvement of effector memory CD4 and CD8 T cells associated with the GvM response. The essential role of CD8 T cells was demonstrated in vivo where CD8 T-cell depletion of the graft resulted in reduced GvM effects. Finally, TCR Vβ spectratyping analysis identified Vβ families within CD4 and CD8 T cells, which were associated with both GvM effects and GvHD, whereas other Vβ families within CD4 T cells were associated exclusively with either GvM or GvHD responses.ConclusionsWe successfully established an immunocompetent murine model of graft-versus-myeloma. This is the first murine GvM model using immunocompetent mice that develop MM which closely resembles human MM disease and that are treated after disease establishment with an allo-SCT. Importantly, using TCR Vβ spectratyping, we also demonstrated the presence of GvM unique responses potentially associated with the curative capacity of this immunotherapeutic approach.

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“…Indeed, cell transfer therapy for cancer has been recognized as the fourth anticancer modality following the operation, chemotherapy and radiotherapy (Qian et al, 2014). However, the use of several immune cell types has been hampered by serious drawbacks including the poor efficacy and/or the complexity of cell propagation (Binsfeld et al, 2014;Kelderman et al, 2014;Weber et al, 2014). Interestingly, these shortcomings can be overcome through infusion of a large number of EAAL cells, as demonstrated in HCC (Takayama et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Adoptive Immunotherapy for Small Cell Lung Cancer by Expanded Activated Autologous Lymphocytes: a Retrospective Clinical Analysis

Zhang

Li²,

Sun³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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Background: To investigate the clinical efficacy of expanded activated autologous lymphocytes (EAAL) in patients with small cell lung cancer (SCLC). Materials and Methods: A total of 32 SCLC patients were selected and randomly divided into EAAL treatment and control groups, 16 cases in each. EAAL were obtained by proliferation of peripheral blood mononuclear cells (PBMCs) of patients followed by phenotype determination. Clinical data of all patients were recorded. Patients of both groups were followed up and the overall survival (OS) were compared retrospectively. Results: After culture and proliferation in vitro, the percentages of CD3 + , CD3 + CD8 + , CD45RO + , CD28 + , CD29 + , CD8 + CD28 + and CD3+CD16+/CD56+ cells increased markedly (p<0.05). The OS of the EAAL treatment group was longer than that of control group, but the difference was not statistically significant (p=0.060, HR=0.487, 95%CI 0.228~1.037). 1-to 3-year survival rates in EAAL treatment group were longer than those in control group, but there was still no significant difference (p>0.05). COX multivariate regression analysis showed that the number of chemotherapy cycles and the application of EAAL immunotherapy were independent prognostic factors for SCLC patients. The OS in females and chemotherapy≤6 cycles were obviously prolonged after EAAL immunotherapy. Conclusions: In vitro induction and proliferation of EAAL is easy and biologically safe. Generally, EAAL adoptive immunotherapy can evidently prolong the OS of SCLC patients.

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Cellular immunotherapy in multiple myeloma: Lessons from preclinical models

Cited by 17 publications

References 147 publications

Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma

Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma

Establishment of a Murine Graft-versus-Myeloma Model Using Allogeneic Stem Cell Transplantation

Adoptive Immunotherapy for Small Cell Lung Cancer by Expanded Activated Autologous Lymphocytes: a Retrospective Clinical Analysis

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