scholarly journals Small-Sized Clone of T Cells in Multiple Myeloma Patient after Auto-SCT: T-LGL Leukemia Type or Clonal T-Cell Aberration?

2013 ◽  
Vol 2013 ◽  
pp. 1-3
Author(s):  
Giuseppe Mele ◽  
Marilena Greco ◽  
Maria Rosaria Coppi ◽  
Giacomo Loseto ◽  
Angela Melpignano ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Cell Expansion ◽  
Peripheral Blood Stem Cell ◽  
Lymphoproliferative Disorders ◽  
Multiple Myeloma Patient ◽  
Blood Stem Cell Transplantation ◽  
Lgl Leukemia ◽  
Lymphocytic Proliferation

Second cancers and particularly postransplant lymphoproliferative disorders (PTLDs) are extremely rare in patients undergoing autologous peripheral blood stem cell transplantation (auto-SCT). We report the case of clonally rearranged T-cell expansion which occurred after auto-SCT for Multiple Myeloma (MM). Does asymptomatic clonal T-cell large granular lymphocytic proliferation, in our experience, represent either a secondary cancer after auto-SCT or clonal T cell aberration or derive from expansion of coexisting undetected small-sized clone of T cells?

scholarly journals Clonally Expanded Bone Marrow T Cells Show Effector Differentiation and Rarely Recognize Disease-Associated Antigens in Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 7-7
Author(s):  
Carlotta Welters ◽  
Meng-Tung Hsu ◽  
Christian Alexander Stein ◽  
Livius Penter ◽  
María Fernanda Lammoglia Cobo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Board Of Directors ◽  
Peripheral Blood ◽  
Cell Expansion ◽  
Advisory Committees ◽  
Myeloma Cells ◽  
T Cell Expansion

Multiple myeloma is a malignancy of monoclonal plasma cells accumulating in the bone marrow. The critical influence of tumor-infiltrating T cells on disease control and therapeutic responses has been shown in a variety of malignancies, however, the role of multiple myeloma bone marrow-infiltrating T cells is incompletely understood. Although it has been shown that multiple myeloma neo-antigen-specific T cells can be expanded in vitro, little is known about functions and specificities of clonally expanded multiple myeloma-infiltrating bone marrow T cells. Here we asked at the single cell level whether clonally expanded T cells i) were detectable in multiple myeloma bone marrow and peripheral blood, ii) showed characteristic immune phenotypes, and iii) recognized antigens selectively presented on multiple myeloma cells. A total of 6,744 single bone marrow T cells from 13 treatment-naïve patients were index-sorted and sequenced using our methodologies for determination of paired T cell receptor (TCR) αβ sequences along with immune phenotype, transcription factor and cytokine expression. Clonal T cell expansion occurred predominantly within the CD8+ compartment. Phenotypes of clonally expanded T cells were distinctive of cytolytic effector differentiation and significantly different from non-expanded CD8+ T cells. Less than 25% of expanded CD8+ T cell clones expressed the immune checkpoint molecules programmed death-1 (PD-1), cytotoxic T lymphocyte antigen-4 (CTLA-4), or T cell immunoglobulin and mucin-domain containing-3 (TIM-3), while B and T lymphocyte attenuator (BTLA) was expressed on more than half of the expanded clones. Clonal T cell expansion did not correlate with neo-antigen load as determined by whole exome and RNA sequencing of purified multiple myeloma cells. Furthermore, peripheral blood TCRβ repertoire sequencing from five selected patients with substantial bone marrow T cell expansion identified 90% of expanded bone marrow T cell clones overlapping with peripheral blood. To determine whether clonally expanded bone marrow T cells recognized antigens selectively presented on multiple myeloma cells, 71 dominant TCRs from five selected patients with substantial clonal T cell expansion were re-expressed in 58α-β- T-hybridoma reporter T cells and co-incubated with CD38-enriched multiple myeloma cells from the same patients. Only one of these TCRs recognized antigens selectively presented on multiple myeloma cells and this TCR was not neo-antigen-specific. Hypothesizing that the target antigen was a non-mutated self-antigen, we could show that this TCR also recognized the plasma cell leukemia cell line U-266 in an HLA-A*02:01-restricted manner. In summary, clonally expanded T cells in multiple myeloma bone marrow of newly diagnosed patients show cytolytic effector differentiation. In the majority of patients, clonally expanded bone marrow T cells do not recognize antigens presented on multiple myeloma cells and are not neo-antigen-specific. Our findings are relevant for the design of future therapeutics and clinical trials. The identified TCR, which recognizes a multiple myeloma antigen shared with U-266 in an HLA-A*02:01-restricted manner, could be a promising candidate for T cell therapy. Disclosures Bullinger: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Hexal: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees.

Analysis of T-Cell Repertoire before and 21 Days after Autologous Peripheral Blood Stem Cell Transplantation for Systemic Sclerosis.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1648-1648
Author(s):  
Albert D. Donnenberg ◽  
Vera S. Donnenberg ◽  
Thomas A. Medsger ◽  
Diane M. BuchBarker ◽  
Dawn M. Betters ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Systemic Sclerosis ◽  
T Cell ◽  
Peripheral Blood Stem Cell ◽  
Conditioning Regimen ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Autologous Pbsct ◽  
Blood Stem Cell Transplantation

Abstract The goal of autologous peripheral blood stem cell transplantation (PBSCT) in autoimmune diseases is to ablate the clones of autoimmune lymphocytes. We evaluated the T-cell repertoire in 5 patients (pts) with systemic sclerosis (SSc) who received T-depleted (mean T-cell reduction, 5.2 log) autologous PBSCT after a conditioning regimen of cyclophosphamide (200–400 mg/m2/day x 5), fludarabine (25 mg/m2/day x 5), and rabbit anti-thymocyte globulin (2.5 mg/kg/day x 3). One pt has had a recurrence of SSc at 12 months after PBSCT; the other pts are progression-free at 4.9+, 5.1+, 6.5+ and 11.5+ months, respectively, after PBSCT. We used 5-color flow cytometry to assess T-cell receptor V-beta repertoire in CD4+ and CD8+ peripheral T-cells susbsetted into central memory (CM; CD45RA−/CD27+), naïve (N, CD45RA+/CD27+), effector/memory (EM; CD45RA−/CD27−) and effector (E; CD45RA−/CD27−) populations. Pts were studied before and at 21 days after PBSCT. The pt with recurrence of SSc had 2 large expansions in CD4+ T-cells (Vbeta 1 and 14) before PBSCT, which were conserved and amplified at 21 days post PBSCT. These expansions were limited to the EM and E populations before PBSCT but were evident in all except the E subset at 21 days after PBSCT. Of the remaining 4 pts, none had evidence of CD4 expansions, and 3 had multiple CD8 expansions before PBSCT. In all cases, the expansions were limited to the EM and E populations. None of these T-cell restrictions were conserved in the 21-day post-PBSCT sample. These data suggest that EM and E T-cell expansions present before PBSCT in pts with SSc can be ablated by an immunosuppressive conditioning regimen. Although our observations require confirmation in a larger series of pts, the conservation of restrictions at 21 days after PBSCT may be a poor prognostic sign for efficacy of autologous PBSCT in SSc.

Intensive Immunosuppression Plus T-Cell Depleted Autologous Peripheral Blood Stem Cell Transplantation for Systemic Sclerosis.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5205-5205
Author(s):  
Diane BuchBarker ◽  
Albert D. Donnenberg ◽  
Thomas A. Medsger ◽  
Michael P. Carroll ◽  
Deborah L. Griffin ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Systemic Sclerosis ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Peripheral Blood ◽  
Peripheral Blood Stem Cell ◽  
The Mean ◽  
Blood Stem Cell Transplantation

Abstract Autologous peripheral blood stem cell transplantation (PBSCT) may be therapeutic in patients (pts) with severe autoimmune disorders. A pre-PBSCT regimen that optimizes immunosuppression without excessive myelotoxicity would potentially have favorable safety and efficacy profiles in these pts. To test this hypothesis we are conducting a phase I trial of cyclophosphamide (CY) dose escalation (initial CY dose 200 mg/m2/day x 5, days −7 to −3) plus fludarabine (25 mg/m2/day x 5, days −7 to −3) and rabbit anti-thymocyte globulin (ATG; 2.5 mg/kg/day x 3, days −5 to −3) followed by T-cell depleted (TCD) autologous PBSCT in adults with systemic sclerosis (SSc). To date, 5 pts (2 male, 3 female; median age, 44 yr; range, 39–59 yr) have undergone TCD PBSCT. Each pt had satisfactory PBSC collection with one 4-hr large-volume leukapheresis (LVL) after mobilization with CY (2.0 g/m2) plus G-CSF. Mean yields of CD34+ and CD3+ cells by LVL were 18.8 (range, 10.5–33.0) x 106/kg and 1.23 (range, 0.37–2.45) x 108/kg, respectively. To deplete T cells in the PBSC product we used a combination of CD34+ selection (Isolex 300i v 2.5; Baxter Oncology) and ex vivo incubation with anti-CD3 antibody (OKT3; Ortho Biotech), which resulted in a mean 5.2-log reduction of T cells (range, 4.7–6.3 log). The final PBSC products contained a mean of 9.94 (range, 4.8–13.0) x 106 CD34+ cells/kg and 1.34 (range, 0.06–4.54) x 103 CD3+ cells/kg. The daily dose of CY was 200 mg/m2 in the first 3 pts and 400 mg/m2 in the next 2 pts. Using rare-event flow cytometry, we found that the mean half-life (t 1/2) of CD3+ cells in these pts was biphasic; t 1/2 was 0.8 days from day −7 to −5 and 0.2 days from −5 to −3 days, correlating with ATG administration. In contrast, the mean t1/2 of CD3+ cells was 2.5 days in pts with hematologic malignancies receiving a myeloablative preparative regimen of CY, busulfan and etoposide. After PBSCT, the median nadir of WBC, neutrophil and platelet levels were 1.2 (range, 0.4–2.0), 0.9 (range, 0.1–1.7) and 135 (range, 114–185) x 109/L, respectively. One pt at the second CY dose level developed pericardial effusion and tamponade at day +5 and required surgical intervention. No pts developed opportunistic infections. All pts are alive at a median of 6.5+ months (range, 4.9+–15.5+ months) after PBSCT. Compared with pre-PBSCT levels, Rodnan total skin score (TSS) decreased by 10, 11 and 15 points, respectively, in 3 pts and increased by 5 and 8 points in 2 pts. One pt with worsening TSS at 12 months after PBSCT developed SSc renal crisis and requires hemodialysis. Of 3 pts with improved TSS, 1 has worsening polymyositis and 1 has recurrence of palpable tendon friction rubs. Even at the lowest CY dose, this immunosuppressive regimen provides significantly greater and more rapid T-cell kill than a conventional myeloablative regimen. The efficacy of this regimen and TCD-PBSCT in SSc is encouraging but requires longer followup and experience with a larger number of pts.

Association Of Large Granular Lymphocytic Leukemia (LGL) With B-Cell Lymphoproliferative Disorders

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1387-1387 ◽  
Author(s):  
Alan P. Z. Skarbnik ◽  
Craig A. Portell ◽  
Jaroslaw P. Maciejewski ◽  
Ramon V. Tiu ◽  
Brad Pohlman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
B Cell ◽  
Median Time ◽  
Monoclonal Gammopathy ◽  
Cell Lymphoma ◽  
Lymphoproliferative Disorders ◽  
Additional Patient ◽  
Cell Disorder ◽  
Lgl Leukemia

Abstract Introduction Large granular lymphocytic (LGL) leukemia is an uncommon disease, characterized by a clonal proliferation of mature, post-thymic T-cells, typically CD3+, CD4-, CD8+, CD16+, CD57+ phenotype, representing constitutively active T-cells Less commonly, LGL leukemia is derived from CD3-, CD56+ natural killer (NK) cells. Clonal T-LGLs escape apoptosis by failure to respond to the Fas/Fas ligand (FasL) pathway. Activating mutations in the STAT3gene occur frequently in LGL leukemia, and may play a role in pathogenesis. Autoimmune disorders are frequently associated with LGL leukemia (∼1/3 present with rheumatoid arthritis). The association between LGL leukemia and B-cell lymphoproliferative disorders has been reported, often with low-grade histologies, but is deemed uncommon and the pathogenesis is not well established. We have analyzed a series of patients (pts) diagnosed with both LGL leukemia or expansion and clonal B-cell disorders. Patients and methods Pts with NK or T-LGL leukemia or expansion who were evaluated at Fox Chase Cancer Center or the Cleveland Clinic Taussig Cancer Institute were reviewed, after Institutional Review Board approval. Inclusion criteria were age ≥ 18 yrs and diagnosis of both LGL and B-cell lymphoproliferative disorder. Results One hundred and twenty six pts with a diagnosis of T-LGL leukemia, NK-LGL leukemia or T-LGL expansion were identified. Of these, 44 (34.9%) pts were diagnosed with a clonal B-cell disorder. Twenty-six pts (20.6%) were diagnosed with a clonal B-cell disorder concomitantly with or shortly after the LGL diagnosis, 15 of whom presented with monoclonal gammopathy of unknown significance (MGUS) as their B-cell disorder, 9 with monoclonal B-cell lymphocytosis (MBL), 5 of whom also had monoclonal gammopathy. Eighteen pts (14.2%) had a previous diagnosis of clonal B-cell disorder, including diffuse large B cell lymphoma (DLBCL) (N= 6), CLL (N = 3), mantle cell lymphoma (N=3), multiple myeloma (N = 2), Hodgkin lymphoma (N = 2), Burkitt lymphoma (N = 1) and hairy cell leukemia (N = 1). Fifteen pts (11.9%) received treatment prior to the diagnosis of LGL, 10 of them (7.9%) with regimens including rituximab. The median time from completion of last treatment with rituximab to diagnosis of LGL disorder was 33 months. An additional patient with prior DLBCL was diagnosed with LGL shortly after receiving an oral SYK inhibitor. Two illustrative patients had unexpectedly prolonged remissions of their B cell disorder. A 66 years old man with multiple myeloma who achieved complete remission (CR) after 8 months of bortezomib therapy was then diagnosed with T-LGL, and his myeloma is in ongoing remission now 5 years after T-LGL diagnosis without further therapy. A 66 years old woman with relapsed DLBCL treated with 2ndline immunochemotherapy (R-ICE) for 3 cycles developed lymphocytosis and was diagnosed with T-LGL. With no further therapy, DLBCL is in ongoing remission now 5 years after diagnosis of T-LGL. Discussion We report a large series of patients with both clonal B-cell disorders and LGL. Where diagnosis of B-cell disorder and LGL are concurrent, we hypothesize an underlying immune dysregulation leading to both B-cell and T-cell proliferations. Where B-cell disorder precedes LGL, we hypothesize that the underlying disease and/or its treatment creates the environment for LGL, either directly allowing LGL expansion or permitting persistence of antigens that drive LGL expansion. Most pts with antecedent B lymphoma received rituximab (R), with a median time from R-treatment to LGL diagnosis of 33 months. Late onset neutropenia (LON) has been linked to bone marrow expansion of LGL in patients treated with rituximab, suggesting a possible pathogenetic role in our cases as well. Further, in some pts primary B-cell malignancies unexpectedly entered prolonged remission after T-LGL developed, suggesting a possible anti-B cell immune component of LGL. Further studies are warranted. Disclosures: No relevant conflicts of interest to declare.

Toll-Like Receptor 2 and 4 Are Expressed on Transplanted T-Cell Subsets and Influence Outcome after Allogeneic Unrelated Peripheral Blood Stem Cell Transplantation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1066-1066
Author(s):  
Uwe Platzbecker ◽  
Jan Stoehlmacher ◽  
Eray Goekkurt ◽  
Caroline Pabst ◽  
Christian Thiede ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Peripheral Blood Stem Cell ◽  
Toll Like Receptor ◽  
Clinical Endpoints ◽  
Blood Stem Cell Transplantation

Abstract Introduction: Recently, Toll-like receptor (TLR) 2 and 4 have been identified as the most important receptors for LPS, which is contained in the cell wall of gram-negative bacteria and is known to be a main inducer of graft versus host disease (GVHD). The role of TLR expressing T-cells within the graft for the induction of GVHD in patients after unrelated peripheral blood stem cell transplantation (PBSCT) is unknown. Methods and patients: We therefore determined by flow cytometry expression of TLR 2 and 4 on T-cells within the graft of 63 patients receiving unrelated PBSCT after intensive conditioning followed by cyclosporine A and methotrexate as GVHD prophylaxis. Additionally, donor specific single nucleotide polymorphisms (SNP) for TLR2 (R753Q), TLR4 (D299G) and TLR4 (Y135A) were determined. The data were finally correlated with clinical endpoints. Results: As expected, TLRs were not expressed on T-cells in peripheral blood of healthy donors (TLR 2: <1.0%, TLR4 <0.5% of T-cells, n=6). In contrast we detected a distinct up-regulation of these receptors on T-cells within the grafts. TLR2 and TLR4 expression on CD4+ T-cells ranged from 1.2%–12.3% (median 3.1%) for TLR2 and from 1.2%–12.0% (median 3.7%) for TLR4. Among the CD8+ T-cells 0.9%–16.1% (median 3.3%) expressed TLR2 and 0.7%–13.3% (median 3.5%) expressed TLR4. The SNP for TLR2 (R753Q) and TLR4 (D299G) was found in 8.6% and 10.3% of the allogeneic donors, respectively but did neither correlate with the expression levels of TLR on T-cells nor with clinical endpoints. Treatment-related mortality from infections was observed in 10 patients (16%). Interestingly, higher expression of TLR2 and 4 on CD4+ but not CD8+ T-cells was significantly associated with an increased cumulative incidence of fatal infections (38% vs. 8% p=0.03 for TLR2 and 37% vs. 9% p=0.007 for TLR4). Neither the overall CD3+, CD4+ and CD8+ cell dose nor the expression of TLR2 and 4 on CD4+ and CD8+ T-cells showed a significant association with the incidence of acute or chronic GVHD or relapse. Conclusion: These data suggest a previously unrecognised up-regulation of TLR, on CD4+ and CD8+ T-cells contained in G-CSF mobilized apheresis products. Whether these phenotypic changes impact on T cell function or patient outcome warrants further investigation.

Sign in / Sign up

Export Citation Format

Share Document