Recent studies performed in the laboratory have established that interleukin-4 (IL-4) used in combination with anti-CD40 monoclonal antibody (MoAb) 89 presented on Ltk- mouse fibroblasts stably expressing human Fc gamma RII/CDw32 (referred to as the CD40 system) sustains long-term proliferation of normal human B cells. In the present study, B-cell chronic lymphocytic leukemias (B-CLLs) activated through slgs or CD40 were examined for their capacity to proliferate and differentiate in response to various cytokines. Our results indicate that the outcome of IL-4 stimulation on the in vitro growth of B-CLL depends on the signalling pathway used for their activation. Whereas IL-4 did not display any growth-stimulatory effect on B-CLL activated by Ig cross-linking agents, it could stimulate DNA synthesis and enhance the viable cell recovery when leukemic B cells were cultured in the CD40 system. Most B-CLL samples were induced for IgM synthesis upon Staphylococcus aureus strain Cowan I stimulation. This Ig response was potentiated by IL-2 and antagonized by IL-4. Anti-CD40 MoAb used alone or in combination with cytokines (IL-1 alpha to IL-6, interferon gamma, tumor necrosis factor gamma, and transforming growth factor beta) failed to induce Ig secretion from B-CLL cells. No evidence for Ig isotype switching was obtained with the cytokines listed above, regardless of the mode of activation. Taken together, our results suggest that B-CLL cells can be partially released from their apparent maturation block by IL-2 and Ig cross-linking agents. In contrast, combinations of IL-4 and cross-linked anti-CD40 antibodies induced entry of B-CLL cell into cycle, but poorly stimulated their differentiation into Ig secreting cells.
Recent studies performed in the laboratory have established that interleukin-4 (IL-4) used in combination with anti-CD40 monoclonal antibody (MoAb) 89 presented on Ltk- mouse fibroblasts stably expressing human Fc gamma RII/CDw32 (referred to as the CD40 system) sustains long-term proliferation of normal human B cells. In the present study, B-cell chronic lymphocytic leukemias (B-CLLs) activated through slgs or CD40 were examined for their capacity to proliferate and differentiate in response to various cytokines. Our results indicate that the outcome of IL-4 stimulation on the in vitro growth of B-CLL depends on the signalling pathway used for their activation. Whereas IL-4 did not display any growth-stimulatory effect on B-CLL activated by Ig cross-linking agents, it could stimulate DNA synthesis and enhance the viable cell recovery when leukemic B cells were cultured in the CD40 system. Most B-CLL samples were induced for IgM synthesis upon Staphylococcus aureus strain Cowan I stimulation. This Ig response was potentiated by IL-2 and antagonized by IL-4. Anti-CD40 MoAb used alone or in combination with cytokines (IL-1 alpha to IL-6, interferon gamma, tumor necrosis factor gamma, and transforming growth factor beta) failed to induce Ig secretion from B-CLL cells. No evidence for Ig isotype switching was obtained with the cytokines listed above, regardless of the mode of activation. Taken together, our results suggest that B-CLL cells can be partially released from their apparent maturation block by IL-2 and Ig cross-linking agents. In contrast, combinations of IL-4 and cross-linked anti-CD40 antibodies induced entry of B-CLL cell into cycle, but poorly stimulated their differentiation into Ig secreting cells.
The pattern of in vitro growth response of freshly isolated non-Hodgkin malignant lymphoma B cells (NHML) to cytokines was investigated. Ten tumor specimens of low- or intermediate-grade malignancy were selected for study. To assess their proliferative capacity in vitro, B-lymphoma cells were activated through ligation of their surface Ig receptor with insolubilized anti-IgM antibodies or Staphylococcus aureus strain Cowan I (SAC). In the great majority of cases, interleukin-2 (IL-2) was the sole factor that significantly and reproducibly stimulated DNA synthesis in NHML activated through their surface Igs. Other B-cell tropic factors, including IL-4, IL-5, IL-6, and tumor necrosis factor- alpha (TNF-alpha), failed to elicit a growth response in most of the IL- 2-responsive neoplastic samples. However, one specimen among 10 exhibited the opposite pattern of response and proliferated following culture with IL-4 and anti-Ig reagents, but not after IL-2 stimulation. Three specimens could also be induced for DNA synthesis on cross- linking of their surface Igs in the absence of exogenous growth factors. Although IL-4 could not support the in vitro growth of the majority of NHML cases, it strongly suppressed the proliferative signals delivered to these cells by anti-Ig reagents used alone or in combination with IL-2. Our data suggest that, in most cases, IL-4 essentially provides growth-inhibitory signals to NHML when they are activated through their surface Ig receptors and as such may be considered to be a valid candidate for future therapy of this type of mature B-cell malignancy.
Background: Cytomegalovirus (CMV) antigens have been reported in over 90% of GBM tumors. We have completed the first portion of an on-going phase I/IIa clinical trial for recurrent GBM patients using CMV gB/pp65 enveloped virus-like particles (eVLPs) formulated with GM-CSF and administered intradermally. We have reported that tumor responses were observed only among Vaccine Responders, based on increases in CMV-specific IFN-g ELISPOT responses, which translated to a 6-month improvement in median overall survival. We evaluated the HLA restriction and TCR repertoires of patients to determine if either correlated with those patients likely to observe tumor response and clinical benefit.Methods: PBMC samples prior to treatment were available for 17 patients, with a variable number of additional samples obtained from each patient obtained, two weeks after each monthly treatment with VBI-1901. TCR repertoire analysis was performed on a total of 29 PBMC samples from 6 Vaccine Responders (range 3-9 samples/patient, median 4.5) and on 29 PBMC samples from 11 Non-responders (range 1-4 samples/patient, median 3).Results: Quantitative analysis of the TCR repertoire suggests a trend towards a reduced number of unique CDR3 sequences in the TCR b chain over time in Vaccine Responders vs. Non-Responders, associated with a modest reduction in TCR b chain diversity over time. HLA class I alleles known to present CMV pp65 antigens were present in the majority of patients, regardless of whether they were Vaccine Responders or Non-Responders. Among the 4 patients with tumor responses, the HLA-B*0702 allele, known to present both CMV pp65 and IE-1 peptides, was present in 3/ 4 patients whereas it was present in only 2/13 patients with progressive disease.Conclusions: TCR repertoire analysis suggests a narrowing of the T cell repertoire with repeat vaccination, and HLA analysis suggests that epitope spreading to a CMV antigen (IE-1) not contained in VBI-1901 may be associated with tumor responses in patients that respond to the vaccine. Clinical trial identification: NCT03382977.Legal entity responsible for the study: VBI Vaccines.
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