scholarly journals Idiotype Vaccines for Non-Hodgkin's Lymphoma Induce Polyclonal Immune Responses That Cover Mutated Tumor Idiotypes: Comparison of Different Vaccine Formulations

Blood ◽  
1997 ◽  
Vol 90 (9) ◽  
pp. 3699-3706 ◽  
Author(s):  
Clemens B. Caspar ◽  
Shoshana Levy ◽  
Ronald Levy
Keyword(s):  
Immune Response ◽  
Hodgkin’S Lymphoma ◽  
Test System ◽  
Active Immunization ◽  
Hodgkin's Lymphoma ◽  
Dna Encoding ◽  
Single Chain ◽  
Original Tumor ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma

Abstract The idiotype (Id) of the Ig expressed on the surface of non-Hodgkin's lymphoma cells is a suitable target for immunotherapy. Indeed, treatment with monoclonal anti-Id antibodies (Abs) can induce long-lasting clinical remissions. However, some of the treated patients relapse with a tumor expressing Ig with point mutations in the idiotope recognized by the particular monoclonal antibody (MoAb). The alternative approach of active immunization with tumor Id can cure the disease in mice with established tumors and is now being studied in clinical trials. Here, we tested the hypothesis that active immunization with the idiotype would evoke a polyclonal immune response that would cover mutated tumor variants. As a test system, we chose the tumor from a patient who had achieved a complete remission after therapy with anti-Id Ab but subsequently relapsed with a mutated tumor variant no longer binding the treatment Ab. Mice were immunized with proteins and genetic vaccines derived from the original tumor, including (1) Id-keyhole limpet hemocyanin protein, (2) Id single-chain variable fragment (scFv) granulocyte-macrophage colony-stimulating factor (GM-CSF) protein, (3) DNA encoding the Id, and (4) an adenovirus encoding the Id. All immunized mice developed a specific immune response detecting tumor-derived Id proteins from the original tumor and from all tumor variants. We conclude that active immunization with tumor Id can induce a polyclonal immune response and therefore may prevent the escape of mutated tumor variants.

Development of Effective Immunotherapy for B-Cell Non-Hodgkin’s Lymphoma with CD19-Specific Cytotoxic T Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3277-3277
Author(s):  
Keichiro Mihara ◽  
Kazuyoshi Yanagihara ◽  
Chihaya Imai ◽  
Akiro Kimura ◽  
Dario Campana
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Lymphocytes ◽  
B Cell ◽  
Hodgkin’S Lymphoma ◽  
Cell Killing ◽  
Hodgkin's Lymphoma ◽  
Single Chain ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma

Abstract Less than 60% of patients with B-cell non-Hodgkin’s lymphoma (B-NHL) can be cured with contemporary therapy. Using artificial receptors it is possible to redirect the specificity of immune cells to tumor-associated antigens, a strategy that holds great potential as a novel cancer therapy. Since B-NHL cells invariably express CD19, we transduced human peripheral blood T lymphocytes with a recently developed receptor (anti-CD19-BB-ζ), which consists of the single-chain variable domain (scFv) of an anti-CD19 monoclonal antibody, the hinge and transmembrane domains of CD8α, and the signaling domains of CD3ζ and 4-1BB. CD3ζ delivers the primary stimulus upon receptor engagement, while 4-1BB delivers co-stimulatory signals that are crucial for T-cell cytotoxicity. It has been shown that elicitation of 4-1BB signaling enhances the immune response to tumors in vivo, even when an immune response cannot be induced by CD28 stimulation. Retroviral transduction led to anti-CD19-BB-ζ expression in T cells with high efficiency: median percent of transduced cells was 60.3% (range, 25.7%–83.4%; n = 9). T lymphocytes expressing anti-CD19-BB-ζ expanded more vigorously that T cells transduced with receptors lacking 4-1BB and exerted powerful cytotoxicity against the CD19+ B-NHL cell lines Raji, Daudi, RL, and HT in vitro: at a 0.5: 1 effector: target ratio, mean (± SD) cell specific lymphoma cell killing was 96.6% ± 4.6% after 5–7 days of culture (4 experiments in each cell line). Transduced T cells were also effective against freshly isolated cells from patients with diffuse large, follicular large, Burkitt, and mantle cell lymphoma cultured on bone marrow-derived mesenchymal cells: in 10 samples, cell killing was 93.6% ± 5.7% at a 0.5: 1 ratio after 5–7 days of culture. Sensitivity to anti-CD19-BB-ζ-mediated killing was observed regardless of high Bcl-2 expression. T cells expressing anti-CD19-BB-ζ were also effective in a xenograft model of NHL, in which NOD/SCID mice were inoculated subcutaneously with lymphoma cells (1 x 107). Subsequent inoculation of T cells (2 x 106) transduced with anti-CD19-BB-ζ receptors significantly suppressed tumor growth, whereas inoculation of T cells transduced with empty control vector had no effect (3 mice for each treatment). These results provide a rationale for clinical testing of autologous T cells modified with anti-CD19-BB-ζ receptors in patients with aggressive or relapsed B-NHLs refractory to conventional therapy.

Preclinical Safety and Efficacy of Two Novel Immunotoxins Consisting of Ranpirnase (Rap) Fused to an Internalizing Anti-CD74 Humanized IgG4 Antibody in Human Non-Hodgkin’s Lymphoma Xenografts.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 346-346 ◽  
Author(s):  
Puja Sapra ◽  
Chien-Hsing Chang ◽  
Sailaja Vanama ◽  
Sharon Singh ◽  
Hans J. Hansen ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin’S Lymphoma ◽  
Specific Binding ◽  
B Cell Lymphoma ◽  
Hodgkin's Lymphoma ◽  
Therapeutic Effects ◽  
Single Chain ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
Recombinant Immunotoxins

Abstract Rap, an amphibian ribonuclease, is a single-chain protein of 104 amino acids that kills cells by degrading t-RNA upon internalization. CD74 is a rapidly internalizing type-II transmembrane chaperone molecule associated with HLA-DR, and has high expression on hematological malignancies including B-cell non-Hodgkin’s lymphoma (NHL) and multiple myeloma (MM). We have constructed and evaluated two novel immunotoxins, 2L-Rap-hLL1-γ 4P and 2L-Rap(N69Q)-hLL1-γ 4P, each composed of two Rap molecules fused to hLL1, an internalizing anti-CD74 humanized monoclonal antibody. The Rap gene was inserted at the N-terminus of the light chain in the expression vector of hLL1 and expressed in NS0 mouse myeloma cells. To reduce unwanted cytotoxicity, the CH1, CH2, CH3 and the hinge regions of the γ 1 chain of hLL1 were replaced with those of γ 4. Additionally, the serine residue in the hinge region was converted to proline to prevent the formation of IgG4 half-molecules. Noting that Rap contains a potential N-glycosylation site at the 69th residue of asparagine(N69), a variant of Rap, referred to as Rap(N69Q), was constructed by changing N to Q (glutamine) and this variant was used to make 2L-Rap(N69Q)-hLL1-γ 4P. Purified recombinant immunotoxins were shown to be a single peak by SE-HPLC and their MW determined by MALDI-TOF to be 177,150, which is in agreement with the MW of one IgG (150,000) plus two Rap molecules (24,000). In vitro, both immunotoxins retained RNase activity, specific binding to CD74, and were significantly more potent against CD74-positive NHL and MM cell lines (Daudi, Raji and MC/CAR) than naked hLL1 or non-specific control immunotoxin, 2L-Rap(N69Q)-hRS7(immunotoxin against EGP-1). In Raji and Daudi Burkitt’s lymphoma xenograft models, treatment with a single 5- to 50-μg dose of 2L-Rap-hLL1-γ 4P, given as early or delayed treatment, resulted in cures of most animals. Additionally, treatment with a single 15-μg dose of 2L-Rap(N69Q)-hLL1-γ 4P 1-day post injection of cells resulted in 100% cures. Treatment with 2L-Rap-hLL1-γ 4P or 2L-Rap(N69Q)-hLL1-γ 4P was significantly better than all controls, including saline, naked hLL1 and non-specific immunotoxin. The maximum tolerated dose of 2L-Rap-hLL1-γ 4P or 2L-Rap(N69Q)-hLL1-γ 4P in SCID or BALB/c mice was 50 μg/mouse and the dose-limiting toxicity was hepatic. In our preliminary studies, we have observed that treating animals with NSAID’s, such as indomethacin, can ameliorate the hepatoxicity of 2L-Rap-hLL1-γ 4P. All animals that were injected with 100 μg/mouse 2L-Rap-hLL1-γ 4P alone died with a median survival time of 7 days; however, animals treated with 1.25mg/kg indomethacin prior and post-treatment of 2L-Rap-hLL1-γ 4P survived the duration of study (day 40). Experiments to determine the possible causes of liver toxicity produced by 2L-Rap-hLL1-γ 4P and to determine the MTD of Rap-immunotoxins in mice after treatment with indomethacin are ongoing. In conclusion, we have constructed two CD74-targeted novel recombinant immunotoxins containing Rap molecules that have demonstrated curative therapeutic effects in animal models of human B-cell lymphoma, and thus could be potential therapeutics for CD74-postive lymphomas and myelomas.

An Index of SNPs in Immune Genes May Enhance the Prognostic Value of IPI in Patients with Aggressive Non-Hodgkin's Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2653-2653
Author(s):  
Nancy M Pennell ◽  
Neil L Berinstein
Keyword(s):  
Immune Response ◽  
Overall Survival ◽  
Hodgkin’S Lymphoma ◽  
Prognostic Index ◽  
Hodgkin's Lymphoma ◽  
Aggressive Lymphoma ◽  
Low Grade ◽  
Immune Genes ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma

Abstract Abstract 2653 INTRODUCTION: Non-Hodgkin's lymphoma (NHL) is a heterogeneous disease. The current International Prognostic Index (IPI) is useful, but not perfectly predictive and there is a need for a more precise prognostic index. The host immune response to cancer has been shown to predict outcome in multi-variate analyses in many types of cancer. We hypothesized that its genetics may contribute to prognostication. We focused on an evaluation of inherited functional polymorphisms in key immune genes that have previously been shown by others to influence outcome in various cancers. The objective was to determine whether an index of SNPs that alter function of critical immune system genes would enhance the predictive value of the IPI in patients with aggressive NHL. PATIENTS AND METHODS: Our study cohort consisted of 192 patients with NHL enrolled at diagnosis between 1990 and 1996. Patients provided informed consent and demographic, clinical and outcome data as well as tumor and blood samples were collected and stored on all patients. Patients were treated as per the standard of care at the time. 124 were of the aggressive type while 68 were low grade. We focused on the aggressive cohort in this analysis. DNA was extracted from blood, bone marrow and biopsy tissue. We evaluated the following genes; IL1A rs1800587, CXCR2 rs1126580, IL4R rs2107356, TNF rs1800629, IL4R175V rs454078, IL8 rs4073, FCGR3A rs396991, P2RX7 rs3751143, IL12B rs3212227. Genotyping was performed using allele-specific PCR primers tagged with GC tails to enhance melting point discrimination. PCR reactions were set up with the aid of a robot and run on a real-time PCR instrument. Kaplan-Meyer curves were generated for the overall survival of each genotype. Univariate analysis was performed to compare genotypes with IPI score, IPI factors and disease bulk. RESULTS: We evaluated relationships to existing standard prognostic factors. We found a significant relationship between IL12B CC carriers and IPI score 0–1 (p=0.0012). Patients with IL12B CC had less extranodal disease, lower stage and bulk. We modeled the data to identify combinations of SNPs with the most predictive power. The most predictive genotype combination included the genes for IL8, IL12B, IL4R, CXCR2 and TNF. A SNP score, determined by the number of favourable genotypes, showed significance in survival, p=0.004 [fig.1]. The group of 68 patients with an IPI score of 2–3 was analyzed to determine whether the SNP score could distinguish outcome within this IPI group [fig 2]. Patients with 3 of these favourable alleles had significantly improved survival [HR= 2.791]. Scoring with an index made up of three genes-IL8, CXCR2 and TNF alone -was also significant, p=0.02 [not shown]. CONCLUSIONS: We evaluated 10 SNPs with functional consequences on the immune response in a population of previously untreated aggressive lymphoma patients undergoing standard management. We found that a combination of SNPs statistically predicted outcome of these 124 patients with aggressive lymphoma. Although Habermann et al [Blood 2008 112(7); 2694–2702] had created a SNP score based on IL1A, IL8RB (CXCR2), IL4R and TNF, we have found that outcome is best predicted in our cohort with IL8, IL12, CXCR2, IL4R and TNF. A useful model could also be obtained using 3 SNPS (IL8, CXCR2 and TNF). Our results are important in that we have shown that this combination of SNPs can further enhance prognostification beyond IPI. Specifically statistically significant overall survival differences in IPI 2,3 patients was found based upon the SNP score using IL8, IL12, CXCR2, IL4R and TNF and the three-SNP combination. Incorporating SNP scores into IPI may be a useful strategy to further identify patients with increased likelihood of improved or adverse outcomes. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Generation of a highly stable, internalizing anti-CD22 single-chain Fv fragment for targeting non-Hodgkin's lymphoma

2003 ◽  
Vol 107 (5) ◽  
pp. 822-829 ◽  
Author(s):  
Michaela A.E. Arndt ◽  
J�rgen Krauss ◽  
Robert Schwarzenbacher ◽  
Bang K. Vu ◽  
Shailen Greene ◽  
...  
Keyword(s):  
Hodgkin’S Lymphoma ◽  
Hodgkin's Lymphoma ◽  
Single Chain ◽  
Non Hodgkin’S Lymphoma ◽  
Single Chain Fv ◽  
Non Hodgkin's Lymphoma ◽  
Single Chain Fv Fragment

Antiphospholipid Antibodies: Prevalence, Clinical Significance and Correlation to Cytokine Levels in Acute Myeloid Leukemia and Non-Hodgkin’s Lymphoma

1993 ◽  
Vol 70 (04) ◽  
pp. 568-572 ◽  
Author(s):  
Roberto Stasi ◽  
Elisa Stipa ◽  
Mario Masi ◽  
Felicia Oliva ◽  
Alessandro Sciarra ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Clinical Significance ◽  
Antiphospholipid Antibodies ◽  
Myeloid Leukemia ◽  
Hodgkin’S Lymphoma ◽  
Hodgkin's Lymphoma ◽  
Tnf Alpha ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
Acute Myeloid

SummaryThis study was designed to explore the prevalence and clinical significance of elevated antiphospholipid antibodies (APA) titres in patients affected by acute myeloid leukemia (AML) and highgrade non-Hodgkin’s lymphoma (NHL). We also analyzed possible correlations with circulating levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and the soluble form of the receptor for interleukin-2 (sIL-2r). Nineteen patients with de novo AML and 14 patients with newly-diagnosed NHL were investigated. Tests for APA included the measurement of anticardiolipin antibodies (ACA) with a solid-phase immunoassay, and the detection of the lupus-like anticoagulant (LA) activity. Five patients with AML (26.3%) and 5 patients with NHL (35.7%) presented elevated APA at diagnosis, as compared to 3 of 174 persons of the control group (p <0.0001). APA titres became normal in all patients responding to treatment, whereas nonresponders retained elevated levels. In addition, 6 patients (4 with AML and 2 with NHL), who had normal APA at diagnosis and were either refractory to treatment or in relapse, subsequently developed LA and/or ACA positivity. At presentation, the mean levels of IgG- and IgM-ACA in patients were not significantly different from Controls, and concordance between ACA and LA results reached just 30%. With regard to the clinical course, we were not able to detect any statistically significant difference between patients with normal and elevated APA. Pretreatment concentrations of IL-6 and TNF-alpha in AML, and sIL-2r in NHL were found significantly elevated compared to Controls (p = 0.003, p = 0.009 and p = 0.024 respectively). In addition, the levels of these cytokines correlated with IgG-ACA at the different times of laboratory investigations. These results demonstrate that APA may have a role as markers of disease activity and progression in some haematological malignancies.

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