Constitutive Chemokine Receptor Expression in B-Cell Non-Hodgkin’s Lymphoma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3590-3590
Author(s):  
Michelle S. Bryson ◽  
Ruth F. Jarrett ◽  
Lesley Sheild ◽  
Gerard J. Graham
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Hodgkin’S Lymphoma ◽  
Memory T Cells ◽  
Cell Lymphoma ◽  
Hodgkin's Lymphoma ◽  
Mantle Cell

Abstract Chemokines are small peptides (∼8-14KDa) that play an essential role in both the innate and adaptive immune system. Chemokines are primarily involved in leukocyte trafficking, but are also involved in a number of cellular mechanisms. They elicit their effect through G-protein coupled receptors, the chemokine receptors (CKR). Functionally chemokines and their receptors are classified as inflammatory or constitutive. Constitutive CKRs and their ligands have a role in numerous diseases including malignancy, chronic inflammation and HIV infection. This study aimed to examine constitutive CKR expression in sub-types of B-cell NHL, of which there are limited studies so far. Lymph node preparations from patients with NHL were examined by flow cytometry using antibodies to CD20, CCR4, CCR6, CCR7, CCR9, CCR10, CXCR4 and CXCR5. The percentage of CD20 positive cells expressing the CKR under investigation was then calculated. The following cases were examined; follicular lymphoma (FL), n=11, Diffuse large B-cell lymphoma (DLBCL), n=11, mantle cell lymphoma (MCL) n=17, Burkitt’s lymphoma (BL), n=9 and MALT lymphoma, n=10. A number of differences between NHL sub-types were detected. FL cases generally had a lower expression of all the CKRs. CXCR5 and CXCR4 expression was high in all sub-types (>84% of B-cells) with no significant differences found, this would be expected as these CKRs are widely expressed in all B-cells. CCR10 expression was low or absent, with no significant differences detected. CCR6 and CCR9 show highest expression in MALT lymphomas, consistent with previous studies, but in comparison with other sub-types the differences was not significant. The most significant results were found with CCR7 and CCR4. CCR7 is expressed on naive T-cells, memory T-cells, B-cells and dendritic cells and is involved in the homing of lymphocytes to lymph nodes. CCR7 is currently the second most commonly reported CKR to be upregulated in malignancy, after CXCR4 and is related. We found very high levels of CCR7 in Mantle cell lymphoma (>90% of B-cells) as compared to other sub-types (p=0.005). CCR4 is expressed on Th2 and Treg lymphocytes, memory T cells and in a small subset of mature B-cells. CCR4 expression in T-cells has been correlated with an adverse prognosis in T-cell NHL and Hodgkin’s lymphoma, yet no systematic studies looking at CCR4 expression in B-cell neoplasms has been reported. These results showed a significant increase in CCR4 expression (>50% of B-cells) in DLBCL, MCL, MALT and BL as compared to FL (p<0.0001). We showed that there are differences in constitutive CKR expression in the different B-cell NHL types, with CCR4 expression being the most interesting finding. How CCR4 expression relates to prognosis in these lymphomas is as yet unknown but is under investigation. Targeting of the chemokine system using anti-CCR4 is already being used in clinical trials for T-cell neoplasms, and may be of potential benefit in selected B-cell neoplasms. Furthermore, the development of anti-CCR7 strategies may prove to be of benefit in the traditionally poor prognosis MCL patients.

scholarly journals The B-cell tumor–associated antigen ROR1 can be targeted with T cells modified to express a ROR1-specific chimeric antigen receptor

Blood ◽  
2010 ◽  
Vol 116 (22) ◽  
pp. 4532-4541 ◽  
Author(s):  
Michael Hudecek ◽  
Thomas M. Schmitt ◽  
Sivasubramanian Baskar ◽  
Maria Teresa Lupo-Stanghellini ◽  
Tetsuya Nishida ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Chimeric Antigen Receptor ◽  
Cell Lymphoma ◽  
Embryonic Stem ◽  
Antigen Receptor ◽  
Orphan Receptor ◽  
Mantle Cell

Monoclonal antibodies and T cells modified to express chimeric antigen receptors specific for B-cell lineage surface molecules such as CD20 exert antitumor activity in B-cell malignancies, but deplete normal B cells. The receptor tyrosine kinase-like orphan receptor 1 (ROR1) was identified as a highly expressed gene in B-cell chronic lymphocytic leukemia (B-CLL), but not normal B cells, suggesting it may serve as a tumor-specific target for therapy. We analyzed ROR1-expression in normal nonhematopoietic and hematopoietic cells including B-cell precursors, and in hematopoietic malignancies. ROR1 has characteristics of an oncofetal gene and is expressed in undifferentiated embryonic stem cells, B-CLL and mantle cell lymphoma, but not in major adult tissues apart from low levels in adipose tissue and at an early stage of B-cell development. We constructed a ROR1-specific chimeric antigen receptor that when expressed in T cells from healthy donors or CLL patients conferred specific recognition of primary B-CLL and mantle cell lymphoma, including rare drug effluxing chemotherapy resistant tumor cells that have been implicated in maintaining the malignancy, but not mature normal B cells. T-cell therapies targeting ROR1 may be effective in B-CLL and other ROR1-positive tumors. However, the expression of ROR1 on some normal tissues suggests the potential for toxi-city to subsets of normal cells.

TLR-9 and B-Cell Antigen Receptor Triggering of Primary B Cells From Mantle Cell Lymphoma Induce Cell Proliferation and Telomerase Activity,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3690-3690
Author(s):  
Sonal Temburni ◽  
Ryon M. Andersen ◽  
Steven L. Allen ◽  
Jaqueline C. Barrientos ◽  
Jonathan E. Kolitz ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Telomerase Activity ◽  
B Cell Antigen Receptor ◽  
Cell Antigen ◽  
Mantle Cell ◽  
T Cell Help

Abstract Abstract 3690 Mantle cell lymphoma (MCL), a less common non-Hodgkin's lymphoma (NHL), often has a poor prognosis and a median survival time of 3–5 years. Historically, MCLs were believed to originate from mature but naive B cells; this notion has now changed based on the demonstration of somatically mutated IgHV sequences in the lymphoma cells from a subset of cases. Indirect evidence suggesting that the B-cell receptor (BCR) pathway may be at the base of the observed activation in the disease exists; however, that extent that this activation results from Toll-like receptor (TLR), B-cell antigen receptor (BCR), or a combination of signaling from both has not been adequately addressed. In this study, the responsiveness of purified primary B cells isolated from peripheral blood (PB) and/or bone marrow (BM) of MCL patients in the leukemic phase of the disease to triggering via the BCR or via TLR-9 alone or in context with selected chemokines – CCL17, CCL22, or CXCL12 - was assessed using various early and late cell signaling readouts. Phosphoflow analysis revealed that within 5 minutes of stimulation both PB and BM B cells significantly increased levels of pAkt and pNFkB in response to BCR crosslinking by an anti-IgM monoclonal antibody (mAb). When PB B cells were cultured for 3 days in the presence of various stimuli to evaluate their proliferative response (uptake of 3H-thymidine), anti-BCR triggering stimulated 2 to 5.5 fold increases in DNA synthesis, whereas the TLR-9 agonist ODN2006 elicited 55 to 235 fold increases. In addition, conditions simulating T-cell help (anti-CD40 mAb + IL-4 in the presence of CD32-transfected fibroblasts) stimulated significant (40–65 fold) proliferative responses in MCL B cells. Simultaneously, a significant increase in HLA-DR (anti-BCR: 49%; ODN2006: 61%; T-cell help: 20%) and Bcl-2 expression (anti-BCR: 21%; ODN2006: 36%; T-cell help: 25%) was induced by these stimuli. Furthermore, B cells from the BM of the same cases differed in their proliferative responses based on the agonist. Thus, in response to BCR triggering, B cells from BM proliferated to a greater extent compared with PB B cells, whereas in response to TLR-9 stimulation PB B cells proliferated to a greater extent than those from BM. In independent experiments, B cells were incubated with various stimuli including those simulating T-cell help and chemokines for 3 days. Cells were harvested and extracts prepared from viable cells to determine telomerase activity using the telomere repeat amplification protocol (TRAP). Anti-BCR stimulation and anti-TLR-9 stimulation independently increased telomerase activity 1.7 and 1.9 fold, respectively, whereas in combination with CCL17 and CCL22, anti-TLR-9 stimulation further increased telomerase activity to 2.28 and 2.36 fold, respectively. In summary, these findings suggest an important role for commonly encountered microenvironmental influences interacting with TLR9 and to a lesser extent the BCR in promoting the aggressiveness of MCL. They also suggest that responses to these stimuli differ between MCL cells residing in the BM and those circulating in the blood. Finally, the data suggest that ligands for CCR4 may play an enhancing role for signals transduced by the BCR and TLR-9 in this disease. If documented in a larger number of cases, treatment regimens that target these signaling pathways might be of therapeutic value. Disclosures: No relevant conflicts of interest to declare.

Phase II Multicenter Study of Bendamustine Plus Rituximab in Patients With Relapsed Indolent B-Cell and Mantle Cell Non-Hodgkin's Lymphoma

2008 ◽  
Vol 26 (27) ◽  
pp. 4473-4479 ◽  
Author(s):  
K. Sue Robinson ◽  
Michael E. Williams ◽  
Richard H. van der Jagt ◽  
Philip Cohen ◽  
Jordan A. Herst ◽  
...  
Keyword(s):  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Hodgkin’S Lymphoma ◽  
Cell Lymphoma ◽  
Complete Response ◽  
Hodgkin's Lymphoma ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
Mantle Cell ◽  
Grade 3

PurposeBendamustine HCl is a bifunctional mechlorethamine derivative with clinical activity in the treatment of non-Hodgkin's lymphoma. This study evaluated bendamustine plus rituximab in 67 adults with relapsed, indolent B-cell or mantle cell lymphoma without documented resistance to prior rituximab.Patients and MethodsPatients received rituximab 375 mg/m2intravenously on day 1 and bendamustine 90 mg/m2intravenously on days 2 and 3 of each 28-day cycle for four to six cycles. An additional dose of rituximab was administered 1 week before the first cycle and 4 weeks after the last cycle. Sixty-six patients (median age, 60 years) received at least one dose of both drugs.ResultsOverall response rate was 92% (41% complete response, 14% unconfirmed complete response, and 38% partial response). Median duration of response was 21 months (95% CI, 18 to 24 months). Median progression-free survival time was 23 months (95% CI, 20 to 26 months). Outcomes were similar for patients with indolent or mantle cell histologies. The combination was generally well tolerated; the primary toxicity was myelosuppression (grade 3 or 4 neutropenia, 36%; grade 3 or 4 thrombocytopenia, 9%).ConclusionBendamustine plus rituximab is an active combination in patients with relapsed indolent and mantle cell lymphoma.

Adoptive Therapy for Lymphoma with CD4 Memory T Cells Depleted of CD137-Expressing Tregs.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1693-1693
Author(s):  
Matthew J Goldstein ◽  
Roch Houot ◽  
Holbrook E Kohrt ◽  
Joshua Brody ◽  
Ronald Levy
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mantle Cell Lymphoma ◽  
Tumor Immunity ◽  
Cd4 T Cells ◽  
Memory T Cells ◽  
Cell Lymphoma ◽  
Adoptive Therapy ◽  
Mantle Cell ◽  
Ifn Γ

Abstract Abstract 1693 Poster Board I-719 A central goal of cancer immunotherapy is an adaptive immune response against tumors. The memory T cell is a critical mediator of this response as it can give rise to effector cells as well as self-renew. Regulatory T cells (Tregs) present a barrier to effective cancer immunotherapy. Indeed, cancer patients have increased numbers of CD4+CD25+ Tregs and cancer vaccination strategies in some cases expand this cell population. Here, we demonstrate that (1) CD4+CD44hi memory T cells are effective in mediating anti-tumor immunity and (2) that expression of CD137 can be used to exclude tumor-reactive Tregs from the CD4+CD44hi population. We have established a model for adoptive therapy of mantle cell lymphoma in which CD4 T cells mediate anti-tumor immunity. Specifically, we use a whole tumor-cell vaccine to induce anti-tumor immune cells in vivo. These cells are isolated and adoptively transferred into lethally irradiated, syngeneic, recipient mice. We show that CD4 but not CD8 T cells from vaccinated donor mice can prevent tumor growth when adoptively transferred into irradiated recipient mice. We observed that a majority of anti-tumor T cells display a memory phenotype. 10 days after transfer, T cells from recipient mice were co-cultured with irradiated lymphoma cells for 24 hours. Only CD4 T cells produced IFN-γ in response to co-culture and greater than 95% of IFN-γ+ CD4 T cells expressed the memory marker CD44. Finally, we observed that transferred CD4+CD44hi T cells persisted for over 100 days suggesting that this CD4 subset is important for lasting anti-tumor immunity. Contaminating Tregs may limit the effectiveness of our CD4 T cell adoptive therapy. In order to functionally deplete these Tregs from the CD4 population, we sought to identify a surface marker that could uniquely distinguish tumor-reactive Tregs from other CD4 T cells. T cells from vaccinated donor mice were co-cultured with irradiated lymphoma cells for 24 hours. We evaluated a panel of activation markers and observed that CD137 expression defined a distinct population of Tregs. Based on these results, we used flow cytometry to isolate a sub-population of CD4+CD44hiCD137- T cells from vaccinated donor mice. Adoptive transfer of less than 100,000 CD44hiCD137- but not other sub-populations of CD4 T cells provided significant protection from tumor challenge. These results suggest that CD137 defines a novel population of tumor-reactive Tregs. This marker can facilitate the enrichment of anti-tumor CD4 memory T cells within the CD44hiCD137- population. In conclusion, these findings highlight the potential use of CD4 T cells in adoptive therapy for mantle cell lymphoma. Disclosures No relevant conflicts of interest to declare.

Phase I Trial Results Testing Adoptively Transferred T Cells Expressing CD20-Specific Chimeric Antigen Receptors Containing CD28 and CD137 Costimulatory Domains In Patients with Mantle Cell Lymphoma and Indolent Lymphoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 561-561
Author(s):  
Brian G. Till ◽  
Michael C. Jensen ◽  
Xiaojun Qian ◽  
Jinjuan Wang ◽  
Ajay K Gopal ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Phase I ◽  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Peripheral Blood ◽  
Cell Lymphoma ◽  
Rapid Expansion ◽  
B Cell Lymphomas ◽  
Mantle Cell

Abstract Abstract 561 Background: Mantle cell lymphoma and indolent B cell lymphomas are incurable with chemotherapy but are susceptible to the T cell-mediated graft-versus-lymphoma effect of allogeneic hematopoietic cell transplantation (HCT). However, HCT is associated with high treatment-related morbidity and mortality, and furthermore, many patients are not eligible due to age, comorbidities, and lack of a suitable donor. We have therefore pursued a novel immunotherapy for lymphoma using adoptive transfer of autologous patient-derived T lymphocytes genetically modified to express a chimeric antigen receptor (CAR) specific for the CD20 antigen, a well-established immunotherapy target expressed on B-cell lymphomas. We conducted a previous clinical trial that demonstrated this approach was safe and feasible, but revealed several areas needing improvement, including modest in vivo persistence of transferred cells and limited anti-lymphoma effect. We have attempted to address these shortcomings in the current follow-up trial. Methods: In this pilot phase I protocol, peripheral blood mononuclear cells were obtained from consenting subjects by apheresis, activated with OKT3 and IL-2, and electroporated on day 4–5 with a plasmid containing an SP163 translational enhancer and a NeoR gene and encoding a CAR consisting of a mouse anti-human CD20 scFv (Leu16), an IgG1 spacer, and CD4 transmembrane, intracellular CD28 and CD137 (4-1BB) costimulatory and CD3ζ signaling domains. Transfected cells were selected with G418 and expanded ex vivo by restimulation every 12–14 days using a rapid expansion protocol. Patients were lymphodepleted with 1000 mg/m2 cyclophosphamide (CY) two days prior to the first T cell infusion, and then received 3 infusions 2–5 days apart of 108, 109, and 3.3 × 109 cells/m2, followed by 14 days of low-dose IL-2 injections (250,000 U/m2 s.c. twice daily). Results: Four patients have been enrolled to date, and three patients received a total of 9 T cell infusions. The fourth patient, whose cells did not expand to the target level, opted to withdraw from the study rather than receive a reduced number of cells. Modified cells had an activated effector T cell phenotype (CD3+/CD45RAlow/CD45RO+/CD25+/CD27-/CD28-) and demonstrated in vitro cytotoxicity against CD20+ target cells. Toxicities related to T cell infusions occurred in 1 patient: grade 2 fever and orthostatic hypotension, and grade 3 hypoxia, which all resolved after overnight observation. Other toxicities were associated with CY and IL-2, and were mild and predictable. Modified T cells were detectable by PCR in lymph nodes and bone marrow in all treated patients, and persisted in peripheral blood for up to 5 months. Clinical responses to CY + T cell infusions + IL-2 included a complete remission in 1 patient lasting 10 months thus far, no evaluable disease in a second patient, who is progression-free after 7 months, and stable disease with a partial PET response lasting 3 months thus far in the third patient. Intermediate-dose CY resulted in significant depletion of circulating CD3+ T cells, including CD4+/FoxP3+ regulatory T cells, and CD20+ B cells in all patients, and led to increased IL-2, IL-7, and IL-15 levels in 1 patient. Conclusions: These results suggest that infusion of CD20-specific T cells expressing a CAR containing costimulatory domains is well-tolerated, and lymphodepletion with CY and inclusion of costimulatory domains in the CAR leads to improved T cell persistence and possibly enhanced anti-lymphoma activity compared with “first generation” CARs. (Supported by NIH Grants R21 CA117131 and M01-RR-00037, the Lymphoma Research Foundation, the Damon Runyon Cancer Research Foundation, the American Society of Clinical Oncology Foundation, David and Patricia Giuliani, Bezos Family Foundation, Hext Family Foundation, the Edson Foundation, and the Leukemia and Lymphoma Society). Disclosures: No relevant conflicts of interest to declare.

Expression of programmed death ligand 1 (PD-L1) by non-Hodgkin's lymphomas (NHL) and effect on tumor-associated T cells

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8526-8526
Author(s):  
D. J. Andorsky ◽  
R. Yamada ◽  
K. Steward ◽  
S. De Vos ◽  
J. Said ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Cell Lines ◽  
Inflammatory Cytokines ◽  
Cell Lymphoma ◽  
Blocking Antibody ◽  
Mantle Cell

8526 Background: PD-L1 is expressed on antigen presenting cells and inhibits activation of T cells through its receptor, PD-1. PD-L1 is aberrantly expressed on epithelial malignancies and may prevent an effective host anti-tumor immune response. The role of PD-L1 in NHL is unknown. Methods: PD-L1 expression was analyzed in 16 NHL cell lines by flow cytometry (FC) and in 111 lymphoma specimens by immunohistochemistry (IHC) (n=92) or FC (n=19). In functional studies, irradiated anaplastic large cell lymphoma (ALCL) cells were co-cultured with allogeneic T cells in the presence of anti-PD-L1 blocking antibody, and IFNγ secretion and thymidine incorporation was used to assess T cell function and proliferation. To further test tumor-T cell interactions, malignant ascites from a patient with ALK+ ALCL and peripheral blood mononuclear cells from a patient with leukemic mantle cell lymphoma, both containing PD-L1-expressing tumor cells and tumor-associated T cells, were stimulated with phytohemagglutinin (a polyclonal T cell activator) and incubated with anti-PD-L1 antibody. Levels of 16 inflammatory cytokines were measured as an assessment of T cell activity. Results: All 9 B cell lymphoma lines were negative for PD-L1, while all 5 ALCL cell lines were strongly positive. One T-cell ALL line was positive, and one peripheral T cell lymphoma was negative. Strong PD-L1 staining was detected by IHC in all 14 ALCL specimens and in 83% of diffuse large B cell lymphomas (DLBCL) analyzed (n=35). Activity of allogeneic T cells co-cultured with irradiated ALCL cells, as measured by IFNγ secretion and proliferation, was markedly enhanced in the presence of anti-PD-L1 blocking antibody. In the autologous setting using cultures of ALCL and mantle cell lymphoma specimens containing host T cells, secretion of inflammatory cytokines by tumor-associated T cells, including GMCSF, IFNγ, IL-1, IL-6, IL-8, TNFα, and MIP1α, were increased by incubation with anti-PD-L1 antibody. Conclusions: PD-L1 is highly expressed in ALCL and in a majority of DLBCL. Blockade of tumor-associated PD-L1 promoted activation of adjacent T cells. PD-L1 may play a role in thwarting an effective anti-tumor immune response and represents an attractive target for lymphoma immunotherapy. No significant financial relationships to disclose.

Phase II Study of Proteasome Inhibitor Bortezomib in Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma

2005 ◽  
Vol 23 (4) ◽  
pp. 667-675 ◽  
Author(s):  
Andre Goy ◽  
Anas Younes ◽  
Peter McLaughlin ◽  
Barbara Pro ◽  
Jorge E. Romaguera ◽  
...  
Keyword(s):  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Hodgkin’S Lymphoma ◽  
Cell Lymphoma ◽  
Hodgkin's Lymphoma ◽  
B Cell Lymphomas ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
Mantle Cell ◽  
Large B Cell

Purpose Evaluate efficacy and toxicity of bortezomib in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma. Patients and Methods Patients were stratified, based on preclinical data, into arm A (mantle-cell lymphoma) or arm B (other B-cell lymphomas) without limitation in number of prior therapies. Bortezomib was administered as an intravenous push (1.5 mg/m2) on days 1, 4, 8, and 11 every 21 days for a maximum of six cycles. Results Sixty patients with a median number of prior therapies of 3.5 (range, one to 12 therapies) were enrolled; 33 patients were in arm A and 27 were in arm B, including 12 diffuse large B-cell lymphomas, five follicular lymphomas (FL), three transformed FLs, four small lymphocytic lymphomas (SLL), two Waldenström's macroglobulinemias (WM), and one marginal zone lymphoma. In arm A, 12 of 29 assessable patients responded (six complete responses [CR] and six partial responses [PR]) for an overall response rate (ORR) of 41% (95% CI, 24% to 61%), and a median time to progression not reached yet, with a median follow-up of 9.3 months (range, 1.7 to 24 months). In arm B, four of 21 assessable patients responded (one SLL patient had a CR, one FL patient had a CR unconfirmed, one diffuse large B-cell lymphoma patient had a PR, and one WM patient had a PR) for an ORR of 19% (95% CI, 5% to 42%). Grade 3 toxicity included thrombocytopenia (47%), gastrointestinal (20%), fatigue (13%), neutropenia (10%), and peripheral neuropathy (5%). Grade 4 toxicity occurred in nine patients (15%), and three deaths from progression of disease occurred within 30 days of withdrawal from study. Conclusion Bortezomib showed promising activity in relapsed mantle-cell lymphoma and encouraging results in other B-cell lymphomas. Future studies will explore bortezomib in combination with other cytotoxic or biologic agents.

scholarly journals Spectrum of lymphomas across different drug treatment groups in rheumatoid arthritis: a European registries collaborative project

2017 ◽  
Vol 76 (12) ◽  
pp. 2025-2030 ◽  
Author(s):  
Louise K Mercer ◽  
Anne C Regierer ◽  
Xavier Mariette ◽  
William G Dixon ◽  
Eva Baecklund ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cell ◽  
General Population ◽  
B Cell ◽  
Hodgkin’S Lymphoma ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Hodgkin's Lymphoma ◽  
Treatment Groups ◽  
Increased Risk

BackgroundLymphomas comprise a heterogeneous group of malignant diseases with highly variable prognosis. Rheumatoid arthritis (RA) is associated with a twofold increased risk of both Hodgkin’s lymphoma (HL) and non-Hodgkin’s lymphoma (NHL). It is unknown whether treatment with biologic disease-modifying antirheumatic drugs (bDMARDs) affect the risk of specific lymphoma subtypes.MethodsPatients never exposed to (bionaïve) or ever treated with bDMARDs from 12 European biologic registers were followed prospectively for the occurrence of first ever histologically confirmed lymphoma. Patients were considered exposed to a bDMARD after having received the first dose. Lymphomas were attributed to the most recently received bDMARD.ResultsAmong 124 997 patients (mean age 59 years; 73.7% female), 533 lymphomas were reported. Of these, 9.5% were HL, 83.8% B-cell NHL and 6.8% T-cell NHL. No cases of hepatosplenic T-cell lymphoma were observed. Diffuse large B-cell lymphoma (DLBCL) was the most frequent B-cell NHL subtype (55.8% of all B-cell NHLs). The subtype distributions were similar between bionaïve patients and those treated with tumour necrosis factor inhibitors (TNFi). For other bDMARDs, the numbers of cases were too small to draw any conclusions. Patients with RA developed more DLBCLs and less chronic lymphocytic leukaemia compared with the general population.ConclusionThis large collaborative analysis of European registries has successfully collated subtype information on 533 lymphomas. While the subtype distribution differs between RA and the general population, there was no evidence of any modification of the distribution of lymphoma subtypes in patients with RA treated with TNFi compared with bionaïve patients.

Efficient Transfer of CD40L mRNA into Mantle Cell Lymphoma for the Production of a Whole Tumor Cell Vaccine.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2591-2591
Author(s):  
Joshua D. Brody ◽  
Linhong Li ◽  
Stephanie Feller ◽  
Joseph Fratantoni ◽  
Ronald Levy
Keyword(s):  
T Cell ◽  
B Cells ◽  
Mantle Cell Lymphoma ◽  
Tumor Cells ◽  
Residual Disease ◽  
Cell Lymphoma ◽  
Cell Vaccine ◽  
Tumor Cell Vaccine ◽  
Mantle Cell

Abstract Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin’s lymphoma with the worst long-term prognosis of any NHL subtype. Current therapeutic options are unsatisfactory. MCL patients’ malignant B cells are ineffective antigen-presenting cells (APCs), perhaps resulting from low level expression of the immune co-stimulatory molecules that are essential to activate T cells upon interaction with the T-cell receptor. The MCL cells can be engineered to be effective APCs and thereby function as a therapeutic cellular vaccine in combination with chemotherapy and/or stem cell transplantation to eradicate residual disease. However, primary MCL cells are difficult targets for gene transfer by both viral and non-viral methodologies. Ligation of CD40 resulting from co-culturing with hCD40L expressing murine fibroblasts was shown to be superior to a panel of other immune stimulants and cytokines in upregulating co-stimulatory markers and inducing anti-tumor T cell responses (Hoogendoorn et al. 2005). We now report on a technology platform, based on electroporation of mRNA for CD40L, for the introduction of CD40L protein expression and subsequent induction of immune co-stimulatory molecules by MCL tumor cells. Primary MCL malignant B cells were obtained from patients’ lymph node biopsies by mechanical dissociation, placed in single cell suspension and cryopreserved prior to modification. Full-length 5′-end capped hCD40L mRNA transcript was generated by in vitro transcription with a commercially available T7 polymerase kit. The transfected MCL cells were immunostained with fluorophore-conjugated monoclonal antibodies against hCD40L, hCD80 and 86 then analyzed by FACS. Data showed hCD40L could be detected in ≥ 80% of the transfected MCL cells as early as 2 hrs post transfection. At 3 days post manipulation, hDC40L expression could be detected on approximately 30% of the transfected MCL cells. Cell viability remained at approximately 80% during the 3 day in vitro culturing. FACS analysis of the immune co-stimulatory molecules revealed that forced expression of hCD40L caused an up-regulation of CD80/86, which was increased approximately 10 fold compared to the expression levels in naïve, non modified cells. The increased expression level of CD80/86 was maintained for 3 days. Furthermore, when the hCD40L modified MCL cells were mixed with allogeneic PBMC, they stimulated IFN-γ production at a level 4 fold higher than was observed with naïve, non modified MCL cells mixed with allogeneic PBMC. This provides proof-of-concept that MCL cells modified by mRNA-hCD40L transfection have the potential to be used as a cellular vaccine. Such transduced cells function to protect animals from tumor challenge. The process can be scaled up to produce >2×1010 modified tumor cells. This simple, non-viral cell manipulation system is practical and will be a useful tool for immunotherapy of human hematopoietic malignancies such as MCL.

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