scholarly journals Suboptimal response to COVID-19 mRNA vaccines in hematologic malignancies patients

2021 ◽  
Author(s):  
Mounzer Agha ◽  
Maggie Blake ◽  
Charles Chilleo ◽  
Alan Wells ◽  
Ghady Haidar
Keyword(s):  
High Risk ◽  
Cancer Therapy ◽  
Immune Responses ◽  
B Cell ◽  
Hematologic Malignancies ◽  
Routine Measurement

Studies describing SARS-CoV-2 immune responses following mRNA vaccination in hematology malignancy (HM) patients are virtually non-existent. We measured SARS-CoV-2 IgG production in 67 HM patients who received 2 mRNA vaccine doses. We found that 46% of HM patients did not produce antibodies and were therefore vaccine non-responders. Patients with B-cell CLL were at a particularly high risk, as only 23% had detectable antibodies despite the fact that nearly 70% of these patients were not undergoing cancer therapy. HM patients should be counseled about the ongoing risk of COVID-19 despite vaccination. Routine measurement of post-vaccine antibodies in HM patients should be considered. Novel strategies are needed to prevent COVID-19 in these individuals.

Spontaneous Mutations of Bcor and Jak1/2 genes Lead to an Aggressive Leukemia of B-1 Progenitor B Cells

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3573-3573
Author(s):  
Sheryl M Gough ◽  
Liat Goldberg ◽  
Marbin Pineda ◽  
Robert L Walker ◽  
Yuelin J Zhu ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Progenitor Cell ◽  
Conflicts Of Interest ◽  
Fusion Gene ◽  
Hot Spot ◽  
Lymphoblastic Leukemia ◽  
Hematologic Malignancies ◽  
Janus Kinase ◽  
Hematopoietic Stem

Abstract NUP98 gene fusions, generated by non-random chromosomal translocations, are associated with a wide spectrum of high risk hematologic malignancies and have been shown to alter normal hematopoietic stem and progenitor cell (HSPC) gene expression programs. A recurrent t(11;17)(p15;p13) translocation in patients with AML leads to the production of a NUP98–PHF23 (NP23) fusion gene. The consequent NP23 fusion protein retains the PHD domain, known to bind H3K4me3, and is thought to have aberrant chromatin regulation properties. We have generated a transgenic mouse model of the NUP98-PHF23 gene fusion which develops a range of hematologic malignancies, most commonly pre-T LBL and AML. However, approximately 10% of NP23 mice develop an aggressive B-1 progenitor acute lymphoblastic leukemia (pro B-1 ALL). B-1 and B-2 lymphocytes have distinct developmental pathways and are thought to represent arms of the innate and adaptive immune systems, respectively. Mature B-2 lymphocytes predominate in the peripheral circulation, and are characterized by expression of B220; whereas B-1 lymphocytes are more prevalent in the pleural and peritoneal cavities, and do not express B220. Murine B cell malignancies typically stain positive for B220, and represent transformed B-2 cells. In the present study, NP23 progenitor ALLs displayed an immunophenotype (Lin-B220- CD19+ AA4.1+) that was identical to that of the recently described B-1 progenitor cell. All B-1 progenitor ALLs exhibited clonal rearrangements of the IgH gene locus. Specifically, these rearrangements involve favored usage of 3’ VH regions, similar to observations with fetal B-1 progenitor cells, further supporting the notion that these are leukemias of B-1 progenitors. Using whole exome sequencing, we found acquired mutations in the BCL6 interacting corepressor (Bcor) gene in 5 out of 7 B-1 progenitor leukemias. The mutations were all frame shift or nonsense mutations, and were located within a 9 bp “hot spot” in Bcor exon 8. In addition, 4 of 7 cases had somatic mutations of Janus kinase 1 (Jak1) or 2 (Jak2), and 7/7 cases showed hyperphosphorylation of Stat3 or Stat5, consistent with the contention that the Jak1/2 mutations are activating mutations, and leading to a hypothesis that the NP23 pro B-1 ALLs which do not harbor Jak1/2 mutations may have acquired an unidentified mutation in the Jak-Stat pathway. Of note, Jak1/2 mutations have previously been identified in a subset of high-risk pediatric B-cell precursor ALL patients. The striking correlation between Bcor and Jak1/2 mutations, occurring specifically in a subset of NP23 leukemias, implies that these three mutations (NP23, Bcor, and Jak1/2) collaborate and provide the oncogenic setting for B-1 progenitor transformation. Disclosures No relevant conflicts of interest to declare.

scholarly journals 149. Immunogenicity, Safety, and Post-hoc Efficacy Assessment of the Adjuvanted Recombinant Zoster Vaccine in Adults with Hematologic Malignancies: A Phase 3, Randomized Clinical Trial

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S9-S10 ◽  
Author(s):  
Alemnew F Dagnew ◽  
Osman Ilhan ◽  
Won-Sik Lee ◽  
Dariusz Woszczyk ◽  
Jae-Yong Kwak ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Immune Responses ◽  
B Cell Lymphoma ◽  
Hematologic Malignancies ◽  
Zoster Vaccine ◽  
Research Support ◽  
Phase 3 ◽  
Study Results ◽  
Recombinant Zoster Vaccine ◽  
Post Hoc

Abstract Background Patients with hematologic malignancies treated with anticancer immunosuppressive therapies (ITs) are at increased risk of herpes zoster (HZ). In a previous report of this phase 3, observer-blind, multicenter trial (NCT01767467), the adjuvanted recombinant zoster vaccine (RZV) was shown to be immunogenic and well-tolerated in ≥18 years of age patients with hematologic malignancies who completed or were undergoing anticancer IT.1 Here we report end-of-study results from the same trial. Methods Participants were randomized 1:1 to receive 2 doses of RZV or placebo (PL) 1–2 months apart, either ≥10 days before or after a cancer therapy cycle, or 10 days to 6 months after cancer therapy ended. Humoral and cell-mediated immune (CMI) responses were evaluated at 1 month and 12 months post-dose 2 (month 2 and month 13, respectively). Confirmatory objectives were to evaluate humoral response rate to RZV and to compare humoral immune responses to RZV and PL at month 2 excluding either subjects with chronic lymphocytic leukemia and non-Hodgkin B-cell lymphoma (NHBCL), or only those with NHBCL. Efficacy against HZ was explored in a post-hoc analysis of confirmed HZ cases. Solicited and unsolicited adverse events (AEs) were recorded for 7 and 30 days after each dose, respectively. Serious AEs (SAEs) and potential immune-mediated diseases (pIMDs) were recorded throughout the study. Results Of the 562 (RZV: 283, PL: 279) treated participants, 415 (RZV: 217, PL: 198)/310 (RZV: 168, PL: 142) were included in the according-to-protocol (ATP) cohort for humoral immunogenicity/immune persistence. The ATP sub-cohort for CMI included 132 (RZV: 69, PL: 63) participants at month 2 and 100 (RZV: 54, PL: 46) at month 13. All confirmatory immunogenicity objectives were met (Table 1). RZV efficacy against HZ, assessed post-hoc, was 87.2% (Table 2). RZV was more reactogenic than PL. The occurrence of unsolicited AEs, SAEs, and pIMDs was similar between the study groups (Table 3). Conclusion RZV induced robust humoral and cellular immune responses and showed an effect in the reduction of HZ incidence in patients with hematologic malignancies who completed or were undergoing anticancer IT. No safety concerns were identified. Reference 1. Oostvogels et al. IDWeek2017, abs 1344. Funding. GlaxoSmithKline Biologicals SA. Disclosures A. F. Dagnew, GSK: Employee and Shareholder, Salary. J. Murphy, GSK: Investigator, Research support. S. A. McNeil, GSK group of companies: Grant Investigator, Research grant and Research support. B. Salaun, GSK group of companies: Employee and Shareholder, Salary. E. Di Paolo, GSK group of companies: Employee, Salary. L. Campora, GSK group of companies: Employee and Shareholder, Salary. M. López-Fauqued, GSK group of companies: Employee, Salary. M. El Idrissi, GSK group of companies: Employee, Salary. A. Schuind, GSK: Employee, Salary. T. C. Heineman, GSK group of companies: Consultant, Employee and Shareholder, Consulting fee and Salary. P. Van Den Steen, GSK: Employee and Shareholder, Restricted shares and Salary. L. Oostvogels, GSK: Employee, Salary and Stock and stock options.

Gene expression and immunologic consequence of SPAN-Xb in myeloma and other hematologic malignancies

Blood ◽  
2003 ◽  
Vol 101 (3) ◽  
pp. 955-960 ◽  
Author(s):  
Zhiqing Wang ◽  
Yana Zhang ◽  
Haichao Liu ◽  
Emanuela Salati ◽  
Maurizio Chiriva-Internati ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Immune Responses ◽  
B Cell ◽  
Myeloid Leukemia ◽  
Normal Tissue ◽  
High Titer ◽  
Hematologic Malignancies ◽  
Rt Pcr ◽  
Cancer Testis

Abstract Recent studies in tumor immunology indicate that malignant cells frequently express normal testicular-specific proteins. Because these proteins show restricted normal tissue distribution, they are usually highly immunogenic and may be potential targets for immunotherapy. In the present study, we have used a pair of sequence-specific primers in reverse transcription–polymerase chain reaction (RT-PCR) and sequence analysis to demonstrate that the X-linked gene encoding SPAN-Xb is expressed in multiple myeloma and other hematologic malignancies such as chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and acute myeloid leukemia (AML). RT-PCR analysis demonstrates that SPAN-Xb is a cancer/testis antigen and shows a restricted normal tissue expression. It is not expressed in any normal tissue except testis. SPAN-Xb recombinant protein was produced and used in enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. High-titer immunoglobulin G (IgG) antibodies, of IgG3 or IgG2 subclass, against SPAN-Xb were detectable in the sera of these patients. In contrast, SPAN-Xb mRNA or antibodies could not be detected in any of the healthy donors. There was a good correlation betweenSPAN-Xb gene expression and B-cell immune responses. These results suggest the in vivo immunogenicity of the SPAN-Xb protein. The presence of high-titer IgG responses suggests that the B-cell responses are likely to have been generated with CD4 T-cell cognitive help. Based on these data, we conclude that SPAN-Xb is a novel member of the family of cancer/testis antigens aberrantly expressed by, and capable of inducing, immune responses in patients with multiple myeloma and other hematologic malignancies.

scholarly journals Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK

2015 ◽  
Vol 112 (9) ◽  
pp. E966-E972 ◽  
Author(s):  
Idit Sagiv-Barfi ◽  
Holbrook E. K. Kohrt ◽  
Debra K. Czerwinski ◽  
Patrick P. Ng ◽  
Betty Y. Chang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
B Cell ◽  
Solid Tumors ◽  
Cell Receptor ◽  
Hematologic Malignancies ◽  
Cellular Interactions ◽  
T Cell Immune Responses ◽  
Essential Enzyme

Monoclonal antibodies can block cellular interactions that negatively regulate T-cell immune responses, such as CD80/CTLA-4 and PD-1/PD1-L, amplifying preexisting immunity and thereby evoking antitumor immune responses. Ibrutinib, an approved therapy for B-cell malignancies, is a covalent inhibitor of BTK, a member of the B-cell receptor (BCR) signaling pathway, which is critical to the survival of malignant B cells. Interestingly this drug also inhibits ITK, an essential enzyme in Th2 T cells and by doing so it can shift the balance between Th1 and Th2 T cells and potentially enhance antitumor immune responses. Here we report that the combination of anti–PD-L1 antibody and ibrutinib suppresses tumor growth in mouse models of lymphoma that are intrinsically insensitive to ibrutinib. The combined effect of these two agents was also documented for models of solid tumors, such as triple negative breast cancer and colon cancer. The enhanced therapeutic activity of PD-L1 blockade by ibrutinib was accompanied by enhanced antitumor T-cell immune responses. These preclinical results suggest that the combination of PD1/PD1-L blockade and ibrutinib should be tested in the clinic for the therapy not only of lymphoma but also in other hematologic malignancies and solid tumors that do not even express BTK.

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