scholarly journals Impaired neutralizing antibody response to COVID-19 mRNA vaccines in cancer patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Cong Zeng ◽  
John P. Evans ◽  
Sarah Reisinger ◽  
Jennifer Woyach ◽  
Christina Liscynesky ◽  
...  
Keyword(s):  
Antibody Response ◽  
B Cell ◽  
Cancer Patients ◽  
Neutralizing Antibody ◽  
Lymphocytic Leukemia ◽  
Cell Therapies ◽  
Cancer Breast ◽  
Immunization Strategies ◽  
Hematological Cancers ◽  
Hodgkin's Lymphomas

AbstractThere is currently a critical need to determine the efficacy of SARS-CoV-2 vaccination for immunocompromised patients. In this study, we determined the neutralizing antibody response in 160 cancer patients diagnosed with chronic lymphocytic leukemia (CLL), lung cancer, breast cancer, and various non-Hodgkin’s lymphomas (NHL), after they received two doses of mRNA vaccines. Serum from 46 mRNA vaccinated health care workers (HCWs) served as healthy controls. We discovered that (1) cancer patients exhibited reduced neutralizing antibody titer (NT50) compared to HCWs; (2) CLL and NHL patients exhibited the lowest NT50 levels, with 50-60% of them below the detection limit; (3) mean NT50 levels in patients with CLL and NHL was ~2.6 fold lower than those with solid tumors; and (4) cancer patients who received anti-B cell therapy exhibited significantly reduced NT50 levels. Our results demonstrate an urgent need for novel immunization strategies for cancer patients against SARS-CoV-2, particularly those with hematological cancers and those on anti-B cell therapies.

scholarly journals Impaired Neutralizing Antibody Response to COVID-19 mRNA Vaccines in Cancer Patients

2021 ◽  
Author(s):  
Cong Zeng ◽  
John P. Evans ◽  
Sarah Reisinger ◽  
Jennifer Woyach ◽  
Christina Liscynesky ◽  
...  
Keyword(s):  
Antibody Response ◽  
B Cell ◽  
Cancer Patients ◽  
Neutralizing Antibody ◽  
Lymphocytic Leukemia ◽  
Cell Therapies ◽  
Cancer Breast ◽  
Immunization Strategies ◽  
Hematological Cancers ◽  
Hodgkin's Lymphomas

There is currently a critical need to determine the efficacy of SARS-CoV-2 vaccination for immunocompromised patients. In this study, we determined the neutralizing antibody response in 160 cancer patients diagnosed with chronic lymphocytic leukemia (CLL), lung cancer, breast cancer, and various non-Hodgkin's lymphomas (NHL), after they received two doses of mRNA vaccines. Serum from 46 mRNA vaccinated health care workers (HCWs) served as healthy controls. We discovered that (1) cancer patients exhibited reduced neutralizing antibody titer (NT50) compared to HCWs; (2) CLL and NHL patients exhibited the lowest NT50 levels, with 50-60% of them below the detection limit; (3) mean NT50 levels in patients with CLL and NHL was ~2.6 fold lower than those with solid tumors; and (4) cancer patients who received anti-B cell therapy exhibited significantly reduced NT50 levels. Our results demonstrate an urgent need for novel immunization strategies for cancer patients against SARS-CoV-2, particularly those with hematological cancers and those on anti-B cell therapies.

scholarly journals Expression and release of CD27 in human B-cell malignancies

Blood ◽  
1993 ◽  
Vol 82 (11) ◽  
pp. 3430-3436 ◽  
Author(s):  
MH van Oers ◽  
ST Pals ◽  
LM Evers ◽  
CE van der Schoot ◽  
G Koopman ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Peripheral Blood ◽  
Growth Factor Receptor ◽  
Lymphocytic Leukemia ◽  
Enzyme Linked Immunosorbent Assay ◽  
Low Grade ◽  
B Cell Malignancies ◽  
Variable Intensity ◽  
Hodgkin's Lymphomas

Abstract CD27, a transmembrane disulfide-linked 55-kD homodimer, belongs to the nerve growth factor-receptor family, a group of homologous molecules involved in lymphocyte differentiation and selection. It is expressed on mature thymocytes, peripheral blood T cells, and a subpopulation of B cells. We investigated the expression of CD27 on malignant B cells representative for a broad range of stages in physiologic antigen- independent and -dependent B-cell development. In normal lymphoid tissue CD27+ B cells were only found in the peripheral blood (29.8% +/- 10.8%, n = 13) and in germinal centers. With the exception of pro-B and the majority of pre-pre-B acute lymphocytic leukemias and of myelomas, CD27 expression of variable intensity was detected on almost all immature and mature malignant B cells tested. Moreover, using a sandwich enzyme-linked immunosorbent assay we could show the presence of sometimes very high (up to 6,000 U/mL; normal values < 190 U/mL) amounts of the soluble 28- to 32-kD form of CD27 (sCD27) in the sera of patients with B-cell malignancies. The highest levels of sCD27 were observed in patients with chronic lymphocytic leukemia and low-grade non-Hodgkin's lymphomas. Most importantly, both in transversal and longitudinal studies, we found a strong correlation between sCD27 levels in the serum and tumor load, indicating that sCD27 can be used as a disease-marker in patients with acute and chronic B-cell malignancies.

scholarly journals Targeting ROR1 identifies new treatment strategies in hematological cancers

2017 ◽  
Vol 45 (2) ◽  
pp. 457-464 ◽  
Author(s):  
Hanna Karvonen ◽  
Wilhelmiina Niininen ◽  
Astrid Murumägi ◽  
Daniela Ungureanu
Keyword(s):  
B Cell ◽  
Molecular Mechanism ◽  
Targeted Therapies ◽  
Lymphoblastic Leukemia ◽  
Treatment Strategies ◽  
Lymphocytic Leukemia ◽  
Orphan Receptor ◽  
Type I ◽  
Cancer Type ◽  
Hematological Cancers

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a member of the ROR receptor family consisting of two closely related type I transmembrane proteins ROR1 and ROR2. Owing to mutations in their canonical motifs required for proper kinase activity, RORs are classified as pseudokinases lacking detectable catalytic activity. ROR1 stands out for its selective and high expression in numerous blood and solid malignancies compared with a minimal expression in healthy adult tissues, suggesting high potential for this molecule as a drug target for cancer therapy. Current understanding attributes a survival role for ROR1 in cancer cells; however, its oncogenic function is cancer-type-specific and involves various signaling pathways. High interest in ROR1-targeted therapies resulted in the development of ROR1 monoclonal antibodies such as cirmtuzumab, currently in a phase I clinical trial for chronic lymphocytic leukemia. Despite these advances in translational studies, the molecular mechanism employed by ROR1 in different cancers is not yet fully understood; therefore, more insights into the oncogenic role of ROR1 signaling are crucial in order to optimize the use of targeted drugs. Recent studies provided evidence that targeting ROR1 simultaneously with inhibition of B-cell receptor (BCR) signaling is more effective in killing ROR1-positive leukemia cells, suggesting a synergistic correlation between co-targeting ROR1 and BCR pathways. Although this synergy has been previously reported for B-cell acute lymphoblastic leukemia, the molecular mechanism appears rather different. These results provide more insights into ROR1–BCR combinatorial treatment strategies in hematological malignancies, which could benefit in tailoring more effective targeted therapies in other ROR1-positive cancers.

Upregulation of Human Pim-2 in B-CLL, Involves Interactions between Oct-1, Oct-2, Bob-1 and NF-kB.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1916-1916
Author(s):  
Yosef Dicken ◽  
Amos M. Cohen ◽  
Hanna Bessler ◽  
Daphna Levi-Hirsh ◽  
Ariela Arad ◽  
...  
Keyword(s):  
Transcription Factor ◽  
B Cells ◽  
B Cell ◽  
Promoter Region ◽  
Lymphocytic Leukemia ◽  
Proximal Promoter ◽  
Luciferase Reporter ◽  
Luciferase Expression ◽  
Cell Extracts ◽  
Hodgkin's Lymphomas

Abstract hPim-2 is a proto-oncogene that encodes a serine/threonine kinase and inhibits apoptosis by phosphorylation of BAD. We have shown that hPim is upregulated in human non-Hodgkin’s lymphomas (NHL) and in chronic lymphocytic leukemia (B-CLL) and its cellular transcript levels in B-CLL correlates with lymphocyte doubling time. We found no mutations in the promoter region of hPim-2 in B-cells of 30 patients with CLL (~2000 bp upstream). The proximal promoter region of hPim-2 (600 bp) contains two adjacent NF-kB-binding elements, two adjacent Oct-binding elements and an SP1 element by bioinformatic analysis. Studies have recently shown that the transcription factor Oct-2 and the B-cell specific Oct cofactor Bob-1 are overexpressed in certain large B-cell lymphomas, whereas increased expression of Bob-1 has also been observed in T-cell neoplasms. Shift assays (EMSA) analysis, using nuclear extracts from B-CLL cells and various fragments of hPim-2 promoter region used as probes, revealed that complexes containing an Oct elements were consistently heavier in B-CLL extracts compared with control B-cells. Accordingly, Oct-1, Oct-2 and Bob-1 protein levels were significantly higher in B-CLL compared to healthy extracts. Moreover, chromatin immunoprecipitation (Chip) assays confirmed that in-vivo Oct-1+2 and Bob-1 are indeed physically attached to the hPim-2 promoter, and that this interaction is significantly more intensive in B-CLL cells than in control B-cells. Furthermore, we have found in addition that the p52 isoform subunit of NF-kB predominates the interaction with the kB element in the hPim-2 promoter in B-CLL cells, as compared to the p50 isoform observed in control B-cells. To determine whether these interactions are transcriptionaly significant, we fused the luciferase reporter gene to various promoter fragments, and monitored luciferase expression in-vitro after incubation with either B-CLL or normal B-cell extracts. Luciferase expression was consistently higher when Oct element-containing fragment was incubated with B-CLL cell extracts. Together, these results suggest that the upregulation of hPim-2 in B-CLL is due to enhanced expression and transcriptional activity of the Oct-1+2 and Bob-1 complex and that it might synergistically act with the p52 containing NF-kB transcription factor.

Immune Therapy for Chronic Lymphocytic Leukemia Induces the Antibody Response Against a Novel Tumor-Associated Antigen, the Orphan Tyrosine Kinase Receptor ROR1.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2976-2976
Author(s):  
Tetsuya Fukuda ◽  
Laura Z. Rassenti ◽  
Thomas J. Kipps
Keyword(s):  
Gene Therapy ◽  
Chronic Lymphocytic Leukemia ◽  
Immune Responses ◽  
Antibody Response ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Lymphocytic Leukemia ◽  
Ovary Cell ◽  
Tyrosine Kinase Receptor ◽  
Igg Antibodies

Abstract Transduction of Chronic lymphocytic leukemia (CLL) CLL cells with replication-defective adenovirus encoding CD154 (Ad-CD154) enhances the capacity of such cells to function as antigen presenting cells. In a clinical trial patients received multiple infusions of autologous CLL cells transduced ex vivo with Ad-CD154 to examine the safety and efficiency of Ad-CD154 gene therapy. Treated patients were found to mount antibody responses against the recombinant adenovirus and cellular immune responses against autologous CLL cells. We examined the antibody response generated in some of the treated patients against CLL cells. Pre and post treatment sera were incubated with CLL cells followed by detection with human anti-IgG antibody via flow cytometry. We found that 3 out of 6 patients examined developed IgG antibodies after therapy that could bind CLL cells. Microarray analyses of CLL samples identified a relatively small number of genes that were differentially expressed in CLL cells compared with normal B cell subsets or neoplastic B cells of other B cell malignancies. These CLL signature genes are candidates TAAs of CLL. One such a CLL signature gene encodes ROR1, a surface receptor tyrosine kinase. Surface expression of ROR1 was on CLL cells, but not on normal lymphocytes. We used two methods to detect the anti-ROR1 activity. One was the flow cytometric analysis using Chinese hamster ovary cell transfected with ROR1 cDNA. Another strategy used an ELISA with plates coated with recombinant ROR1protein. Both methods revealed that patients who developed anti-CLL autoantibodies following gene therapy also developed IgG antibodies reactive with ROR1. As such, ROR1 appears to be a candidate TAA that may be targeted by immune responses induced by Ad-CD154 gene therapy.

Characteristics and Outcome of B-Cell Chronic Lymphocytic Leukemia in HCV-Positive Patients.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4986-4986
Author(s):  
Stefano Molica ◽  
Rosanna Mirabelli ◽  
Demetrio Misuraca ◽  
Caterina Battaglia
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Monoclonal Gammopathy ◽  
Absolute Lymphocyte Count ◽  
Serum Levels ◽  
Autoimmune Disorders ◽  
Lymphocytic Leukemia ◽  
Severe Infections ◽  
Hodgkin's Lymphomas ◽  
Cell Chronic Lymphocytic Leukemia

Abstract HCV-associated B-cell non-Hodgkin’s lymphomas (NHL) show distinctive clinico-pathological features such as older age, liver damage, presence of monoclonal gammopathy, increased incidence of autoimmune disorders, extranodal localizations and restricted histological subtypes. As far as B-cell chronic lymphocytic leukemia (CLL) is concerned, information dealing with either characteristics or outcome of HCV-associated CLL are limited. With this background we compared clinico-hematological features and outcome of 34 HCV-positive patients diagnosed at our institution as having immunologically typical B-cell CLL (i.e., CD5+/CD23+/CD79b-/SmIg dim) with 161 unselected CLL HCV-negative patients followed-up in the last 10 years. The two groups were alike with respect to main clinico-hematological features such as age (P=0.780), sex (P=0.650), absolute lymphocyte count (P=0.788), platelet count (P=0.362), haemoglobin level (P=0.704), β2-microglobulin (P=0.192), Binet stage distribution (P=0.224) and lymphocyte doubling time (LDT)(P= 0.620). As expected either ALT or AST serum levels at the time of CLL diagnosis were significantly higher in HCV-positive patients in comparison to HCV-negative ones (P&lt;0.0001 for both). In contrast, no difference was found in the incidence of monoclonal gammopathy between HCV-positive and HCV-negative patients (10.3% versus 7.7%; P=0.708). The same applied for autoimmune disorders which were homogeneously distributed in the two subgroups (P=0.711) and accounted, more frequently, for autoimmune emolytic anemia (AEA)(HCV-negative subgroup, 5.5%; HCV-positive subgroup, 9.0%). The proportion of severe infections registered did not reflect the HCV-status (HCV-negative subgroup, 9.6%; HCV-positive subgroup 6.4%; P= 0.510). Also second tumours were equally distributed among HCV-positive and HCV-negative subgroups (10% versus 6.8%; P=0.655). Survival curves projected at 10 years did not show any statistical in terms overall survival (Hazard Risk, 0.690; 95% CI: 0.216–1.304; P=0.167). Finally, the short term hepatic toxicity of chemotherapy did not increase among HCV-positive patients (P=0.671). In conclusion, HCV-positive patients with B-cell CLL do not differ from other patients both for presentation and clinical outcome. The need to activate specific protocols of antiviral therapy appears less urgent in comparison to NHL, however, younger CLL patients HCV-positive who are eligible for therapies at higher immunosuppressive potential (i.e., chemo-immunotherapy) should be taken in special consideration.

scholarly journals Autoantibody-associated cross-reactive idiotypes expressed at high frequency in chronic lymphocytic leukemia relative to B-cell lymphomas of follicular center cell origin

Blood ◽  
1988 ◽  
Vol 72 (2) ◽  
pp. 422-428 ◽  
Author(s):  
TJ Kipps ◽  
BA Robbins ◽  
P Kuster ◽  
DA Carson
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Light Chain ◽  
Variable Region ◽  
Lymphocytic Leukemia ◽  
Kappa Light Chain ◽  
Region Gene ◽  
Variable Regions ◽  
Hodgkin's Lymphomas ◽  
Center Cell

Using murine monoclonal antibodies (MoAbs) specific for immunoglobulin (Ig) cross-reactive idiotypes (CRI), we performed immunohistochemical analyses on frozen tissue sections and cytocentrifuge preparations of Ig-expressing malignant cells from patients with chronic lymphocytic leukemia (CLL) and B-cell non-Hodgkin's lymphomas (NHL) of follicular center cell origin. Twenty percent (4/20) of the Ig kappa light chain- expressing CLL cells reacted with 17.109, a MoAb against a major CRI on human IgM autoantibodies that is encoded by a conserved Ig variable- region gene (V gene) of the V kappa IIIb sub-subgroup. Another MoAb specific for V kappa IIIb framework determinant(s) reacted exclusively with all the 17.109-reactive CLL cells. Only one of 20 kappa light- chain-expressing CLL cells reacted with 6B6.6, a monoclonal antibody specific for a CRI commonly found on rheumatoid factor (RF) paraproteins with light-chain variable regions of the V kappa IIIa sub- subgroup. Finally, greater than 20% (8/34) of all CLL reacted with G6, a MoAb specific for an Ig heavy chain-associated CRI present on several RF paraproteins. In contrast, these CRIs were expressed at significantly lower frequencies in NHL of follicular center cell origin. Only one of 30 NHL expressing kappa light chains reacted with the 17.109 MoAb. Also, in contrast to the concordance between the 17.109-CRI and V kappa IIIb framework determinant(s) in CLL, two lymphomas in addition to the 17.109-reactive lymphoma were recognized by the anti-V kappa IIIb framework MoAb. None of the NHL reacted with either the 6B6.6 or the G6 MoAbs. These results are the first to demonstrate that CLL and NHL differ with respect to the expression of autoantibody-associated CRIs. The data support the notion that NHL of follicular center cell origin differs from CLL in its utilization and/or somatic mutation of Ig variable-region genes. The physiological and immunotherapeutic implications of these findings are discussed.

scholarly journals Broad anti-SARS-CoV-2 antibody immunity induced by heterologous ChAdOx1/mRNA-1273 prime-boost vaccination

2021 ◽  
Author(s):  
Chengzi I Kaku ◽  
Elizabeth Champney ◽  
Johan Normark ◽  
Carl E Johnson ◽  
Clas Ahlm ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
B Cell ◽  
Molecular Basis ◽  
Booster Vaccination ◽  
Neutralizing Antibody ◽  
Binding Affinities ◽  
Booster Immunization ◽  
Boost Vaccination ◽  
Immunization Strategies ◽  
Boost Immunization

Heterologous prime-boost immunization strategies have the potential to augment COVID-19 vaccine efficacy and address ongoing vaccine supply challenges. Here, we longitudinally profiled SARS-CoV-2 spike (S)-specific serological and memory B cell (MBC) responses in individuals receiving either homologous (ChAdOx1:ChAdOx1) or heterologous (ChAdOx1:mRNA-1273) prime-boost vaccination. Heterologous mRNA booster immunization induced significantly higher serum neutralizing antibody and MBC responses compared to homologous ChAdOx1 boosting. Specificity mapping of circulating S-specific B cells revealed that mRNA-1273 booster immunization dramatically immunofocused ChAdOx1-primed responses onto epitopes expressed on prefusion-stabilized S. Monoclonal antibodies isolated from mRNA-1273-boosted participants displayed higher binding affinities and increased breadth of reactivity against variants of concern (VOCs) relative to those isolated from ChAdOx1-boosted participants. Overall, the results provide fundamental insights into the B cell response induced by ChAdOx1 and a molecular basis for the enhanced immunogenicity observed following heterologous mRNA booster vaccination.

scholarly journals Distribution of complement receptor subtypes in non-Hodgkin's lymphomas of B-cell origin

Blood ◽  
1981 ◽  
Vol 58 (1) ◽  
pp. 20-26 ◽  
Author(s):  
J Cossman ◽  
ES Jaffe
Keyword(s):  
B Cell ◽  
Lymphocytic Leukemia ◽  
Lymphoid Tissues ◽  
Receptor Subtypes ◽  
Complement Receptor ◽  
B Cell Differentiation ◽  
Lymphoid Follicles ◽  
Surface Receptors ◽  
Cr2 Cells ◽  
Hodgkin's Lymphomas

Abstract Surface receptors specific for either the C4b (CR1) or C3d (CR2) component of complement were examined on the neoplastic cells from 30 cases of non-Hodgkin's lymphoma of B-cell origin and on cells derived from 9 normal lymphoid tissues. Lymphocyte suspensions from non- neoplastic peripheral blood, tonsils, and lymph node contained three categories of complement receptor lymphocytes (CRL): cells with receptors for both C4b and C3d (CR1+, CR2+); cells with receptors for C4b but not C3d (CR1+, CR2-), and cells with receptors for C3d but not C4b (CR1-, CR2+). The mean of the proportion of total CRL expressing receptors only of C3d (CR1-, CR2+) was 0.35 for non-neoplastic tissues and 0.28 for malignant lymphomas of follicular center cell (FCC) origin. However, the proportion of cells with this phenotype was significantly higher in well differentiated lymphocytic lymphomas (WDL) and chronic lymphocytic leukemia (CLL) (0.65) and in intermediately differentiated lymphocytic lymphomas (IDL) (0.59). Histologic compartmentalization of the CRL subtypes was observed in frozen sections of normal lymphoid tissue. CR1+ cells were present in lymphoid follicles interfollicular areas, and in splenic red pulp. CR2+ cells were confined to lymphoid follicles. These findings strongly suggest that complement receptor phenotypes may be useful markers of B-cell differentiation.

Sign in / Sign up

Export Citation Format

Share Document