Multiple myeloma–reactive T cells recognize an activation-induced minor histocompatibility antigen encoded by the ATP-dependent interferon-responsive (ADIR) gene

Blood ◽  
2007 ◽  
Vol 109 (9) ◽  
pp. 4089-4096 ◽  
Author(s):  
Cornelis A. M. van Bergen ◽  
Michel G. D. Kester ◽  
Inge Jedema ◽  
Mirjam H. M. Heemskerk ◽  
Simone A. P. van Luxemburg-Heijs ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Cell Types ◽  
Donor Lymphocyte Infusion ◽  
Cellular Immunotherapy ◽  
Cell Reactivity ◽  
Cellular Activation ◽  
Minor Histocompatibility Antigens ◽  
Suitable Target ◽  
T Cell Reactivity

Abstract Minor histocompatibility antigens (mHags) play an important role in both graft-versus-tumor effects and graft-versus-host disease (GVHD) after allogeneic stem cell transplantation. We applied biochemical techniques and mass spectrometry to identify the peptide recognized by a dominant tumor-reactive donor T-cell reactivity isolated from a patient with relapsed multiple myeloma who underwent transplantation and entered complete remission after donor lymphocyte infusion. A frequently occurring single nucleotide polymorphism in the human ATP-dependent interferon-responsive (ADIR) gene was found to encode the epitope we designated LB-ADIR-1F. Although gene expression could be found in cells from hematopoietic as well as nonhematopoietic tissues, the patient suffered from only mild acute GVHD despite high percentages of circulating LB-ADIR-1F–specific T cells. Differential recognition of nonhematopoietic cell types and resting hematopoietic cells as compared with activated B cells, T cells, and tumor cells was demonstrated, illustrating variable LB-ADIR-1F expression depending on the cellular activation state. In conclusion, the novel mHag LB-ADIR-1F may be a suitable target for cellular immunotherapy when applied under controlled circumstances.

ATP Dependent Interferon Responsive (ADIR) Gene Encodes an Activation Induced Minor Histocompatibility Antigen Recognized on Multiple Myeloma by CD8+ T Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 549-549
Author(s):  
Cornelis A. Van Bergen ◽  
Michel G. Kester ◽  
Inge Jedema ◽  
Mirjam H. Heemskerk ◽  
Simone A. Van Luxemburg ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Amino Acid ◽  
Cd8 T Cells ◽  
Cell Types ◽  
Donor Lymphocyte Infusion ◽  
Target Cells ◽  
Genomic Polymorphism ◽  
Minor Histocompatibility Antigens ◽  
Stimulatory Capacity

Abstract Minor histocompatibility antigens (mHag) play an important role in beneficial graft versus tumor (GVT) reactivities but mHag reactive T cells may also cause graft versus host disease (GVHD). A female patient with relapsed multiple myeloma (MM) after allogeneic HLA identical stem cell transplantation (SCT) responded 7 weeks after donor lymphocyte infusion (DLI) by developing transient acute GVHD grade II and complete clearance of the malignant cells resulting in a long lasting complete remission. From blood and bone marrow samples that were taken at the time of the clinical response, a dominant HLA-A2 restricted CD8+ CTL designated RDR2, was isolated that recognized the patients MM cells, PHA-blasts and EBV-LCL, but not resting T cells. To identify the peptide recognized by CTL RDR2, HLA-A2 was isolated from EBV-LCL that were recognized by CTL RDR2, and peptides were separated and fractionated by HPLC techniques applying several different separation conditions. Various HPLC fractions were analyzed by mass spectrometry (MS) and tested for recognition by CTL RDR2 in 51Chromium release assays. Based on the correlation between the presence of specific masses in the MS analyses and the reactivity of the fractions, candidate masses were selected, sequence analysis was performed, and synthetic peptides were generated. An 11-mer peptide was recognized by CTL RDR2 and was found to be identical to amino acid 13–23 of an alternatively translated protein of the ATP dependent interferon responsive (ADIR) gene. ADIR gene constructs forcing translation into the alternative frame displayed higher recognition as compared to constructs resulting in normal translation. Patient but not donor cells contained a known genomic polymorphism in the ADIR gene resulting in an amino acid change from serine (S) to phenylalanine (F) in the alternative frame. When ADIR gene transcripts from a panel of 76 unrelated HLA-A2 positive individuals were sequenced, a 100% correlation was found between the presence of the ADIR polymorphism and lysis of PHA-blasts by CTL RDR2. The polymorphism was present in 43 out of 76 individuals tested. We designated the mHag LB-ADIR-1F. Tetramer staining of patient samples taken after DLI showed at the peak of the response 2.6% LB-ADIR-1F specific CD8+ T cells. Despite the high number of circulating cytotoxic CTL, GVHD was mild, and rapidly disappeared after treatment. Since ADIR gene expression is not restricted to hematopoiesis, we compared recognition of LB-ADIR-1F expressing hematopoietic cell types with recognition of LB-ADIR-1F expressing mesenchymal stem cells and biliary epithelial cells. In both IFNg production assays and in cytotoxicity assays responses to MM cells, other hematological malignancies and activated T and B cells were strong, whereas resting T cells and non hematopoietic cells displayed only minor stimulatory capacity and were poorly lysed by LB-ADIR-1F specific T cells. In conclusion, the ADIR gene encodes a new frequently occurring mHag, and recognition of the antigen by LB-ADIR-1F reactive cells seems to depend on the activation state of the target cells. We therefore hypothesize that administration of LB-ADIR-1F reactive T cells may result in GVT responses, and that concurrent GVHD development may depend on the activation state of GVHD target tissues.

Identification of New Hematopoietic Minor Histocompatibility Antigen UTA2-1; Ready for Application in Antitumor Immunotherapy

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2979-2979
Author(s):  
Rimke Oostvogels ◽  
Monique C. Minnema ◽  
Maureen van Elk ◽  
Robbert M Spaapen ◽  
Debbie van Baarle ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Conflicts Of Interest ◽  
Cytotoxic T Lymphocyte ◽  
Donor Lymphocyte Infusion ◽  
Hematopoietic Tissue ◽  
Minor Histocompatibility Antigens ◽  
Population Frequency ◽  
Number Of Patients ◽  
Specific Tissue

Abstract Abstract 2979 Allogeneic stem cell transplantation (allo-SCT), alone or followed by donor lymphocyte infusion (DLI), is a potentially curative treatment for various hematological malignancies. In an HLA-matched transplantation setting, the therapeutic graft-versus-tumor (GvT) effect is mediated by donor T-cells directed at minor histocompatibility antigens (mHags), which are HLA-bound polymorphic peptides. Since mHags are also involved in the induction of graft-versus-host disease (GvHD), the immunotherapeutic potential of a mHag depends on its hematopoietic tissue restriction. The identification of more relevant mHags, which are presented by frequent HLA molecules and display an equally balanced population frequency, is imperative to enable broad implementation of mHag-based immunotherapy. We now report the discovery of a novel mHag that fulfills all these criteria and thus has evident clinical and immunotherapeutic relevance. The mHag was identified by analysis of a cloned CD8+ cytotoxic T lymphocyte (CTL), isolated from a multiple myeloma (MM) patient at the peak of his clinical response. This response started just after a second DLI following an HLA matched sibling transplantation and resulted in a complete remission that at present persists for over 8 years, without other treatment. The CTL 503A1 was specifically selected for analysis since it displayed strong cytotoxic activity toward a mHag which was presented by the frequent HLA-molecule HLA-A2*0101. Phenotype analyses revealed a phenotype frequency of around 40% in the Caucasoid population, providing a possibility to apply this mHag in immunotherapy in nearly 12% of allo-SCT patients. Using genome wide zygosity-genotype correlation analysis, followed by fine epitope mapping with synthetic peptides, we identified the antigen recognized by this clone as a nonameric peptide encoded by the SNP rs2166807 on the gene C12orf35. This new mHag was designated as UTA2-1. Quantitative PCR experiments confirmed the hematopoietic tissue restriction of gene C12orf35, with high expression on malignant B and T cells. In a detailed analysis exploring the clinical relevancy of UTA2-1, CTL 503A1 lysed not only benign hematopoietic cells but also primary and immortalized multiple myeloma cells without affecting fibroblasts, keratinocytes or stromal cells derived from the original patient. Tetramer analyses executed on original recipient peripheral blood samples taken after allo-SCT and the DLIs, demonstrated significant expansion of UTA2-1 specific T-cells, coinciding with strong clinical responses after allo-SCT and the second DLI. In summary, UTA2-1 has an ideally balanced population frequency, HLA-A2 restriction, hematopoietic-specific tissue distribution, optimal expression on malignant cells and the clinical capacity to evoke effective T-cell responses during an anti-myeloma effect. With these properties, UTA2-1 is the most clinically relevant mHag identified so far, next to the well-studied mHag HA-1, and has potential of expanding mHag-based adoptive immunotherapy for a great number of patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The Levels and Patterns of Cytokines Produced by CD4 T Lymphocytes of BALB/c Mice Infected with Leishmania major by Inoculation into the Ear Dermis Depend on the Infectiousness and Size of the Inoculum

2003 ◽  
Vol 71 (5) ◽  
pp. 2674-2683 ◽  
Author(s):  
Thierry Lang ◽  
Nathalie Courret ◽  
Jean-Hervé Colle ◽  
Geneviève Milon ◽  
Jean-Claude Antoine
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Leishmania Major ◽  
Interleukin 4 ◽  
High Dose ◽  
Cutaneous Lesions ◽  
Cell Reactivity ◽  
Ifn Γ ◽  
T Cell Reactivity ◽  
Parasite Populations

ABSTRACT The production of cytokines by CD4 lymph node T lymphocytes derived from BALB/c mice recently infected in the ear dermis with high (106 parasites) or low (103 parasites) doses of Leishmania major metacyclic promastigotes (MP) was examined over a 3-week period following inoculation. Results were compared with those obtained when mice were injected with less infectious parasite populations, namely, stationary-phase or log-phase promastigotes (LP). Cells were purified 16 h and 3, 8, and 19 days after inoculation, and the amounts of gamma interferon (IFN-γ) and interleukin-4 (IL-4) released in response to LACK (Leishmania homolog of receptors for activated C kinase) or total L. major antigens were assessed. We found that LACK-reactive T cells from mice inoculated with a high dose of parasites first produced IFN-γ and later on IL-4; the level of IFN-γ produced early by these cells was dependent upon the stage of the promastigotes inoculated, the highest level being reached with cells recovered from mice inoculated with the least infectious parasites, LP; sequential production of IFN-γ and then of IL-4 also characterized L. major antigen-reactive CD4 T cells, suggesting that the early production of IFN-γ does not impede the subsequent rise of IL-4 and finally the expansion of the parasites; after low-dose inoculation of MP, cutaneous lesions developed with kinetics similar to that of lesions induced after inoculation of 106 LP, but in this case CD4 T lymphocytes did not release IFN-γ or IL-4 in the presence of LACK and neither cytokine was produced in response to L. major antigens before the onset of lesion signs. These results suggest the existence of a discreet phase in terms of CD4 T-cell reactivity for at least the first 8 days following inoculation, a time period during which parasites are able to grow moderately. In conclusion, the levels and profiles of cytokines produced by Leishmania-specific CD4 T lymphocytes clearly depend on both the stage of differentiation and number of parasites used for inoculation.

scholarly journals Cytomegalovirus-specific T-cell reactivity in biliary atresia at the time of diagnosis is associated with deficits in regulatory T cells

Hepatology ◽  
2012 ◽  
Vol 55 (4) ◽  
pp. 1130-1138 ◽  
Author(s):  
Stephen M. Brindley ◽  
Allison M. Lanham ◽  
Frederick M. Karrer ◽  
Rebecca M. Tucker ◽  
Andrew P. Fontenot ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Biliary Atresia ◽  
Cell Reactivity ◽  
T Cell Reactivity

Retroviral Gene Transfer of T Cell Receptors (TCR) Specific for Minor Histocompatibility Antigens to Virus-Specific T Cells as Cellular Immunotherapy of Patients with Relapsed Hematological Malignancies after Allogeneic Stem Cell Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5529-5529
Author(s):  
Marieke Griffioen ◽  
H.M. Esther van Egmond ◽  
Menno A.W.G. van der Hoorn ◽  
Renate S. Hagedoorn ◽  
Michel Kester ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Hematological Malignancies ◽  
Surface Expression ◽  
Retroviral Vector ◽  
Cellular Immunotherapy ◽  
Minor Histocompatibility Antigens ◽  
Vector Coding

Abstract Patients with hematological malignancies can be successfully treated by T cell-depleted allogeneic stem cell transplantation (alloSCT) followed by donor lymphocyte infusion (DLI). Failure of some relapsed hematological malignancies to respond to DLI is probably due to immune tolerance induced by regulatory and/or anergic T cells. We previously showed that functional T cells with redirected anti-leukemic reactivity can be generated by transfer of TCRs specific for minor histocompatibility antigens (mHags) to total peripheral blood mononuclear cells (PBMC) as well as CMV-specific T cells. By introducing TCRs into CMV or EBV specific T cells, T cells with proper memory/effector phenotypes are targeted, and due to virus persistence these T cells may show prolonged survival in vivo. The purpose of this study is to develop an efficient method for the isolation, retroviral transduction and expansion of TCR-transduced CMV- and EBV-specific T cells for cellular immunotherapy of patients with relapsed hematological malignancies after alloSCT. For clinical application, construction of single retroviral vectors coding for the α as well as β chains of mHag-specific TCRs is required. We used the MP71 retroviral vector for TCR gene transfer, since this vector contains Myeloproliferative Sarcoma Virus LTR sequences and a Mouse Embryonic Stem Cell Virus leader, which has been optimized for use in the clinic. The MP71 vector also contained a Woodchuck Hepatitis Response Element (WPRE). The WPRE, which is used as an element enhancing transgene expression at the post-transcriptional level, has recently been described to encode 60 amino acids of a protein with potential oncogenic activity. Therefore, we reconstructed the MP71 vector by introduction of a multiple cloning site (MCS) and, for safety issues, deleted the WPRE. The TCR α and β genes specific for the hematopoietic-restricted mHag HA-2 were linked by a 50-bp sequence encoding a “self-cleaving” 2A-like peptide and introduced into the MCS of the MP71 vector. Linkage of the TCR α and β genes by the 2A-like sequence allowed additional linkage of the low affinity nerve growth factor receptor (LNGFR) or human CD20 selection marker genes by an IRES sequence. The advantage of the human CD20 gene is that it can also function as suicide gene, allowing elimination of transduced cells in vivo if undesired side effects occur. Introduction of the single MP71 retroviral vector coding for the HA-2 TCR α and β chains as well as LNGFR into a TCR α- and β-deficient Jurkat T cell line led to high levels of TCR surface expression correlating with LNGFR marker gene expression. These data indicate proper cleavage and assembly of the transduced TCR α and β chains. Moreover, removal of the WPRE did not affect the surface expression level of the transduced TCR. Furthermore, CMV- and EBV-specific T cells were isolated from human individuals by the IFN-γ capture assay and subsequently transduced with a single retroviral vector coding for the HA-2-TCR α and β chains as well as LNGFR. CMV- and EBV-specific T cells from different human individuals could be successfully isolated to 60–90% purity and the TCR-transduced CMV- and EBV-specific T cells were shown to be fully functional, recognizing the viral peptides as well as the endogenously-processed HA-2 mHag.

scholarly journals The RIG-I Agonist 3pRNA Synergizes with Checkpoint Blockade in Cancer Immunotherapy

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3436-3436 ◽  
Author(s):  
Simon Heidegger ◽  
Diana Kreppel ◽  
Michael Bscheider ◽  
Alexander Wintges ◽  
Sarah Bek ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Immunity ◽  
Conflicts Of Interest ◽  
Cytotoxic T Cells ◽  
Type I ◽  
Therapeutic Success ◽  
Cell Reactivity ◽  
T Cell Reactivity ◽  
Systemic Antibiotics

Abstract Antibody-mediated targeting of regulatory T cell receptors such as CTLA-4 has been shown to enhance anti-tumor immune responses against several cancer entities including malignant melanoma. Yet, therapeutic success in patients remains variable underscoring the need for novel combinatorial approaches. Here we established a vaccination protocol that combines selective engagement of the nucleic acid-sensing pattern recognition receptor RIG-I, antigen and CTLA-4-blockade. We found that vaccination together with RIG-I ligation strongly synergized with CTLA-4 blockade to induce expansion and activation of antigen-specific CD8+ T cells and potent anti-tumor immunity. Cross-priming of cytotoxic T cells as well as anti-tumor immunity required the adapter protein MAVS and type I interferon (IFN) signaling and were mediated by dendritic cells. In addition, the benefit of the combined immunization with anti-CTLA-4 was reduced by systemic antibiotics pointing to the requisite of an intact commensal microbiota in this context. Together, our findings describe a novel combinatorial strategy that may form the basis for the design of new type I IFN-based regimens that enhance antigen-specific T cell reactivity against cancer. Disclosures No relevant conflicts of interest to declare.

scholarly journals Efficacy and Safety of CAR-T Therapy with Safety Switch Targeting Bcma for Patients with Relapsed/Refractory Multiple Myeloma in a Phase 1 Clinical Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3154-3154 ◽  
Author(s):  
Weijun Fu ◽  
Juan Du ◽  
Hua Jiang ◽  
Zhi CHENG ◽  
Runhong Wei ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Conflicts Of Interest ◽  
Phase 1 ◽  
Cellular Immunotherapy ◽  
Infusion Therapy ◽  
Cell Product ◽  
Car T Cell ◽  
Car T

Background: Encouraging results are seen from several early phase clinical trials on the cellular immunotherapy based on chimeric antigen receptor (CAR)-engineered T (CAR-T) targeting B cell maturation antigen (BCMA) for the treatment of relapsed/refractory (RR) multiple myeloma (MM). We developed an anti-BCMA CAR-T cell product manufactured via gamma-retrovirus-mediated transduction of activated T cells to express a second-generation CAR with the 4-1BB costimulatory domain along with a truncated epidermal growth factor receptor (tEGFR) as a safety switch. The preclinical study confirmed its high reactivity against MM cells. Methods: A phase 1 clinical trial (NCT03093168) has been launched to evaluate the safety and feasibility of this BCMA CAR-T cell product for treating RRMM. The enrolled RRMM patients had received at least 2 prior treatment regimens, including a proteasome inhibitor and an immunomodulatory agent, or are double-refractory, and have over 5% BCMA expression on plasma cells (Nine patient with extramedullary plasmacytoma does not express BCMA). Patients were subjected to a lymphodepleting regimen with Cy (300 mg/m2, d-5 to d-3) and Flu daily for 3 days (25 mg/m2, d-5 to d-3) prior to the CAR-T infusion (d0) at a dose of 9×106CAR+ cells/kg. The efficacy was assessed by the International Uniform Response Criteria for Multiple Myeloma, and the toxicity is graded by CTCAE 4.03. Results: As of March 1th, 2019, 46 patients had been infused with this intended dose of the autologous BCMA CAR-T cells, and 44 patients had reached at least 1 month of follow-up. As of this data cut-off, the overall response rate (ORR) for the 44 evaluable patients was 79.6%, including 2sCRs, 16CRs, 8VGPRs and 8PRs, and 16 patients reached MRD-negative response. The CAR-T cell expansion and persistence were consistently observed throughout these patients. The medianPFS is 15mon, and the median OS result has not been reached (49.16% progression-free survival, and 53.95% overall survival at 24 months). Among the 44 infused patients, 22.7% had grade 1-2 Cytokine release syndrome (CRS ) and 6.8% (3 patients) had grade 3 CRS. No grade 4 CRS reactions developed and all toxicities were fully reversible. Conclusions: Our result demonstrates the high potential of this single CAR-T infusion therapy for RRMM, including 2sCRs, 16CRs and ongoing clinical responses for more than 26 months, with manageable CRS to date. These initial data provide strong evidence to support the further development of this anti-myeloma cellular immunotherapy. Disclosures No relevant conflicts of interest to declare.

scholarly journals Impact of pre-existing T cell immunity to SARS-CoV-2 in uninfected individuals with COVID-19 mortality in different countries

2020 ◽  
Author(s):  
Gennadi V. Glinsky
Keyword(s):  
T Cells ◽  
T Cell ◽  
Herd Immunity ◽  
Inverse Correlation ◽  
Mortality Rates ◽  
Virus Spread ◽  
Cell Reactivity ◽  
Cell Immunity ◽  
Potential Impact ◽  
T Cell Reactivity

AbstractSeveral recent studies identified SARS-CoV-2 reactive T cells in people without exposure to the virus. However, pathophysiological implications of these findings remain unknown. Here, the potential impact of pre-existing T cell reactivity against SARS-CoV-2 in uninfected individuals on markedly different COVID-19 mortality levels in different countries has been investigated. The inverse correlation is documented between the prevalence of pre-existing SARS-CoV-2 reactive T cells in people without exposure to the virus and COVID-19 mortality rates in different countries. In countries with similar levels of pre-existing SARS-CoV-2 cross-reactive T cells in uninfected individuals, differences in COVID-19 mortality appear linked with the extend and consistency of implementations of social measures designed to limit the transmission of SARS-CoV-2 (lockdown; physical distancing; mask wearing). Collectively, these observations support the model that the level of pre-existing SARS-CoV-2 reactive T cells is one of the important determinants of the innate herd immunity against COVID-19. Together with the consistent social measures directed to limit the virus spread, high levels of pre-existing SARS-CoV-2 reactive T cells appear significant determinants diminishing the COVID-19 mortality. Observations reported in this contribution should have significant impact on definitions of the herd immunity threshold required to effectively stop the pandemic in different countries across the globe.

scholarly journals Regulation of cytotoxic T-cell reactivity to syngeneic tumors by the thymus.

1978 ◽  
Vol 148 (2) ◽  
pp. 619-623 ◽  
Author(s):  
C L Reinisch ◽  
S L Andrew
Keyword(s):  
T Cells ◽  
Tumor Cells ◽  
Cytotoxic T Cell ◽  
Target Cells ◽  
Cell Reactivity ◽  
Syngeneic Tumor ◽  
T Cell Reactivity ◽  
Syngeneic Tumors ◽  
Thymectomized Mice

Adult thymectomy has been shown to result in the enhanced capacity of splenic T cells to respond to and lyse syngeneic tumor cells in vitro. In addition, T cells from thymectomized mice which kill syngeneic tumor cells do not lyse either normal lymphoid or mitogen-stimulated syngeneic lymphoblast target cells. These findings indicate that the thymus exports a subpopulation of T cells sensitive to adult thymectomy which regulates the generation of cytolytic T cells directed against syngeneic tumor cells.

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