Bryostatin 1-activated T cells can traffic and mediate tumor regression

Tuttle, Todd M.; Bethke, Kevin P.; Inge, Thomas H.; McCrady, Carl W.; Pettit, George R.; Bear, Harry D.

doi:10.1016/0022-4804(92)90126-k

Cited by 22 publications

(8 citation statements)

References 27 publications

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“…Monoclonal antibodies, cytokines, and pharmacological methods have been used successfully in mouse models to activate lymphocytes isolated from tumors or tumor draining lymph nodes (DLN), which can then be adoptively transferred to tumor bearing hosts and cause regression of established tumors [6, 9–11, 20, 35, 36, 39, 52]. Adoptive immunotherapy (AIT), or the adoptive transfer of antigen-sensitized T cells activated and/or expanded in vitro continues to receive attention [1, 13, 22, 35, 44–46, 50]. …”

Section: Introductionmentioning

confidence: 99%

“…We have shown that in vitro treatment of tumor antigen-sensitized draining lymph node (DLN) cells with bryostatin and ionomycin (B/I) selectively activates sensitized T lymphocytes that can induce regression of several different murine tumors, either primary or metastatic, and can confer long-term resistance to re-challenge [13, 44–46]. Bryostatin 1 is a macrocyclic lactone derived from Bugula neritina , a marine invertebrate.…”

Section: Introductionmentioning

confidence: 99%

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Incubation of antigen-sensitized T lymphocytes activated with bryostatin 1 + ionomycin in IL-7 + IL-15 increases yield of cells capable of inducing regression of melanoma metastases compared to culture in IL-2

Graham

Miller

et al. 2009

Cancer Immunol Immunother

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Regression of established tumors can be induced by adoptive immunotherapy (AIT) with tumor draining lymph node (DLN) lymphocytes activated with bryostatin and ionomycin (B/I). We hypothesized that B/I-activated T cells cultured in IL-7 + IL-15 might proliferate and survive in culture better than cells cultured in IL-2, and that these cells would have equal or greater anti-tumor activity in vivo. Tumor antigen-sensitized DLN lymphocytes from either wild-type or T cell receptor transgenic mice were harvested, activated with B/I, and expanded in culture with either IL-2, IL-7 + IL-15 or a regimen of alternating cytokines. Cell yields, proliferation, apoptosis, phenotypes, and in vitro responses to tumor antigen were compared for cells grown in different cytokines. These T cells were also tested for anti-tumor activity against melanoma lung metastases established by prior i.v. injection of B16 melanoma cells. IL-7 + IL-15 or alternating cytokines resulted in much faster and prolonged proliferation and much less apopotosis of B/I-activated T cells than culturing the same cells in IL-2. This resulted in approximately tenfold greater yields of viable cells. Culture in IL-7 + IL-15 yielded higher proportions of CD8+ T cells and a higher proportion of cells with a central memory phenotype. Despite this, T cells grown in IL-7 + IL-15 had higher IFN-γ release responses to tumor antigen than cells grown in IL-2. Adoptive transfer of B/I-activated T cells grown in IL-7 + IL-15 or the alternating regimen had equal or greater efficacy on a “per-cell” basis against melanoma metastases. Activation of tumor antigen-sensitized T cells with B/I and culture in IL-7 + IL-15 is a promising modification of standard regimens for production of T cells for use in adoptive immunotherapy of cancer.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Incubation of antigen-sensitized T lymphocytes activated with bryostatin 1 + ionomycin in IL-7 + IL-15 increases yield of cells capable of inducing regression of melanoma metastases compared to culture in IL-2

Graham

Miller

et al. 2009

Cancer Immunol Immunother

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“…In addition to its direct antineoplastic activity, Bryo-1 is also a powerful activator and modulator of host immune effector cells, which may indirectly result in inhibition of a tumor's growth. Bryo-1 induces the proliferation and activation of human T and B cells (4,5), triggers the development of tumorspecific CTL that can traffic and mediate tumor regression (6), and costimulates T lymphocytes to produce a variety of cytokines, including IFN-␥ and IL-2 (7), both of which display antitumor effects.…”

mentioning

confidence: 99%

The Antineoplastic Agent Bryostatin-1 Differentially Regulates IFN-γ Receptor Subunits in Monocytic Cells: Transcriptional and Posttranscriptional Control of IFN-γR2

García

Curiel

Mwatibo

et al. 2006

The Journal of Immunology

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Bryostatin-1 (Bryo-1) is a potent ligand and modulator of protein kinase C that exerts antineoplastic and immunomodulatory activities both in vitro and in vivo. We have previously reported that Bryo-1 synergized with IFN-γ to induce NO synthase and NO by macrophages. To determine whether this effect was associated with changes in levels of IFN-γR, we investigated the effects of Bryo-1 on the expression and regulation of IFN-γR chains in monocytic cells. Northern blot analysis revealed that Bryo-1 treatment of the human monocytic cell lines MonoMac6 and THP-1 and human monocytes enhanced the expression of IFN-γR2 mRNA but did not affect IFN-γR1 mRNA expression. Bryo-1 increased IFN-γR2 mRNA in a dose-dependent manner as early as 3 h posttreatment. Bryo-1-induced up-regulation of IFN-γR2 mRNA levels is not dependent on de novo protein synthesis as shown by cell treatment with the protein-synthesis inhibitor cycloheximide. Bryo-1 treatment increased the IFN-γR2 mRNA half-life by 2 h. EMSA analysis from Bryo-1-treated MonoMac6 cells showed an increased nuclear protein binding to the NF-κB motif present in the 5′ flanking region of the human IFN-γR2 promoter that was markedly decreased by pretreatment with the NF-κB inhibitor SN50. These results show for the first time that Bryo-1 up-regulates IFN-γR2 expression in monocytic cells. Given the pivotal role that IFN-γ exerts on monocyte activation and in the initiation and outcome of the immune response, the induction of IFN-γR2 by Bryo-1 has significant implications in immunomodulation and could overcome some of the immune defects observed in cancer patients.

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“…In that report we demonstrated that subnanomolar concentrations of Bryo-1 induce the production and secretion of IL-l, IL-6, IL-8, and TNF-␣, which are proinflammatory cytokines endowed with antitumor and immunomodulatory properties (17). Bryo-1 also induces the proliferation and activation of B and T cells (18 -20) and triggers tumor-specific T cells that can traffic and mediate tumor regression (21,22). Furthermore, Bryo-1 induces IL-2R␣ and IL-2R␥ chains expression on human PBMC leading to an enhanced response to IL-2 (17,19).…”

mentioning

confidence: 99%

Bryostatin-1 and IL-2 Synergize to Induce IFN-γ Expression in Human Peripheral Blood T Cells: Implications for Cancer Immunotherapy

Curiel

García

Farooq

et al. 2001

The Journal of Immunology

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Bryostatin-1 (Bryo-1), a protein kinase C modulator with antineoplastic activity, may exert some of its antitumor activity through activation of the immune response. Studies in tumor-bearing hosts have indicated that the T cell response, particularly IFN-γ production, is impaired. To evaluate whether Bryo-1 plus IL-2 may affect the activation pattern of T cells, we investigated the expression of IFN-γ mRNA and protein in human primary T cells. Northern blot analysis and ELISAs demonstrated that Bryo-1 and IL-2 synergized to induce both IFN-γ mRNA and protein expression. This synergistic induction was seen within 3 h of treatment and with as little as 10 U/ml IL-2 and 1.0 ng/ml Bryo-1. In vitro transcription assays revealed that Bryo-1 plus IL-2 induced transcriptional activation of the IFN-γ gene. Furthermore, mRNA stability studies indicated that this treatment also enhanced the IFN-γ mRNA half-life. Both CD4+ and CD8+ T cells responded to the treatment with IFN-γ expression. The induction of the IFN-γ expression was decreased by a specific p38 mitogen-activated protein kinase inhibitor, but not by a protein kinase C inhibitor. Our results demonstrate for the first time that Bryo-1 in combination with IL-2 control IFN-γ gene expression at both the transcriptional and post-transcriptional levels through a p38 mitogen-activated protein kinase-dependent process. Given the pivotal role that IFN-γ plays in the orchestration of an effective Th1 type of response, our results suggest that Bryo-1 plus IL-2 may be a valuable combined therapy for cancer treatment.

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Bryostatin 1-activated T cells can traffic and mediate tumor regression

Cited by 22 publications

References 27 publications

Incubation of antigen-sensitized T lymphocytes activated with bryostatin 1 + ionomycin in IL-7 + IL-15 increases yield of cells capable of inducing regression of melanoma metastases compared to culture in IL-2

Incubation of antigen-sensitized T lymphocytes activated with bryostatin 1 + ionomycin in IL-7 + IL-15 increases yield of cells capable of inducing regression of melanoma metastases compared to culture in IL-2

The Antineoplastic Agent Bryostatin-1 Differentially Regulates IFN-γ Receptor Subunits in Monocytic Cells: Transcriptional and Posttranscriptional Control of IFN-γR2

Bryostatin-1 and IL-2 Synergize to Induce IFN-γ Expression in Human Peripheral Blood T Cells: Implications for Cancer Immunotherapy

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