HER2 Support Group Forums - View Single Post - BPH-715 (revised Zoledronate) A New Weapon Against Tumor Cells

Rich66 · 06-22-2009, 03:32 PM

1: Eur J Clin Invest. 2009 Jun 12. [Epub ahead of print] Links: Mesenchymal cells inhibit expansion but not cytotoxicity exerted by gamma-delta T cells.

Petrini I, Pacini S, Petrini M, Fazzi R, Trombi L, Galimberti S.
Department of Oncology, Transplant and New Advances in Medicine, University of Pisa and RRMR-CUCCS Regione Toscana, Pisa, Italy.
Eur J Clin Invest 2009Abstract Background; Multipotent mesenchymal stromal cells (MSCs) exert a relevant immunosuppressive activity by inhibiting T- and B-lymphocytes, natural killer (NK) cells and dendritic cell expansion. Nevertheless, a possible activity on gamma/delta T cells has still not been evaluated. Gamma-delta T lymphocytes play an important role in the control of cancer and they have been shown to be implicated in graft-vs.-host disease. Thus, modulation of activation and proliferation of these cells could be relevant for therapeutic purposes. Materials and methods Peripheral blood mononuclear cells from 21 healthy donors were used as source for gamma-delta T cells, expanded in presence of 10 IU mL(-1) interleukin-2 (IL-2) and 1 muM zoledronate. MSCs were recovered from patients undergoing routine total hip replacement surgery, and characterised by flow cytometry. Cytotoxicity on multiple myeloma and melanoma cell lines was assessed by measuring dilution of the carboxyfluorescein diacetate succinimydylester dye (CFSE). Gamma-delta T cells were then incubated with MSCs in contact cultures, and with addition of MSC-conditioned medium. Results In this article we confirmed that (1) in vitro expanded gamma-delta T cells play a significant anti-proliferative effect on multiple myeloma and melanoma cells and (2) multipotent mesenchymal stromal cells effectively suppress the ex vivo expansion of T cells carrying a specific T-cell receptor gene (TCR) rearrangement, Vgamma9/Vdelta2, induced by the combination of IL-2 and zoledronate, without interfering with their cytotoxic activity. Discussion These findings contribute to explain the activity of ex vivo expanded mesenchymal cells, suggesting that MSCs would interact with gamma-delta T lymphocytes. Conclusion This effect could be relevant in separating graft-vs.-host from the graft-vs.-tumour effect, especially considering the possibility of modulating T-lymphocytes activity by the immunomodulating drugs now available.
PMID: 19522834 [PubMed - as supplied by publish

Cancer Res. 2007 Aug 1;67(15):7450-7.
Targeting human {gamma}delta} T cells with zoledronate and interleukin-2 for immunotherapy of hormone-refractory prostate cancer.

Dieli F, Vermijlen D, Fulfaro F, Caccamo N, Meraviglia S, Cicero G, Roberts A, Buccheri S, D'Asaro M, Gebbia N, Salerno A, Eberl M, Hayday AC.
Dipartimento di Biopatologia e Metodologie Biomediche, UniversitÃ* di Palermo, Palermo, Italy. dieli@unipa.it
The increasing evidence that gammadelta T cells have potent antitumor activity suggests their value in immunotherapy, particularly in areas of unmet need such as metastatic carcinoma. To this end, we initiated a phase I clinical trial in metastatic hormone-refractory prostate cancer to examine the feasibility and consequences of using the gammadelta T-cell agonist zoledronate, either alone or in combination with low-dose interleukin 2 (IL-2), to activate peripheral blood gammadelta cells. Nine patients were enlisted to each arm. Neither treatment showed appreciable toxicity. Most patients were treated with zoledronate + IL-2, but conversely only two treated with zoledronate displayed a significant long-term shift of peripheral gammadelta cells toward an activated effector-memory-like state (T(EM)), producing IFN-gamma and perforin. These patients also maintained serum levels of tumor necrosis factor-related apoptosis inducing ligand (TRAIL), consistent with a parallel microarray analysis showing that TRAIL is produced by gammadelta cells activated via the T-cell receptor and IL-2. Moreover, the numbers of T(EM) gammadelta cells showed a statistically significant correlation with declining prostate-specific antigen levels and objective clinical outcomes that comprised three instances of partial remission and five of stable disease. By contrast, most patients treated only with zoledronate failed to sustain either gammadelta cell numbers or serum TRAIL, and showed progressive clinical deterioration. Thus, zoledronate + IL-2 represents a novel, safe, and feasible approach to induce immunologic and clinical responses in patients with metastatic carcinomas, potentially providing a substantially increased window for specific approaches to be administered. Moreover, gammadelta cell phenotypes and possibly serum TRAIL may constitute novel biomarkers of prognosis upon therapy with zoledronate + IL-2 in metastatic carcinoma.

PMID: 17671215 [PubMed - indexed for MEDLINE]

06-22-2009, 03:32 PM	#11
Rich66 Senior Member Join Date: Feb 2008 Location: South East Wisconsin Posts: 3,431	1: Eur J Clin Invest. 2009 Jun 12. [Epub ahead of print] Links Mesenchymal cells inhibit expansion but not cytotoxicity exerted by gamma-delta T cells. Petrini I, Pacini S, Petrini M, Fazzi R, Trombi L, Galimberti S. Department of Oncology, Transplant and New Advances in Medicine, University of Pisa and RRMR-CUCCS Regione Toscana, Pisa, Italy. Eur J Clin Invest 2009Abstract Background Multipotent mesenchymal stromal cells (MSCs) exert a relevant immunosuppressive activity by inhibiting T- and B-lymphocytes, natural killer (NK) cells and dendritic cell expansion. Nevertheless, a possible activity on gamma/delta T cells has still not been evaluated. Gamma-delta T lymphocytes play an important role in the control of cancer and they have been shown to be implicated in graft-vs.-host disease. Thus, modulation of activation and proliferation of these cells could be relevant for therapeutic purposes. Materials and methods Peripheral blood mononuclear cells from 21 healthy donors were used as source for gamma-delta T cells, expanded in presence of 10 IU mL(-1) interleukin-2 (IL-2) and 1 muM zoledronate. MSCs were recovered from patients undergoing routine total hip replacement surgery, and characterised by flow cytometry. Cytotoxicity on multiple myeloma and melanoma cell lines was assessed by measuring dilution of the carboxyfluorescein diacetate succinimydylester dye (CFSE). Gamma-delta T cells were then incubated with MSCs in contact cultures, and with addition of MSC-conditioned medium. Results In this article we confirmed that (1) in vitro expanded gamma-delta T cells play a significant anti-proliferative effect on multiple myeloma and melanoma cells and (2) multipotent mesenchymal stromal cells effectively suppress the ex vivo expansion of T cells carrying a specific T-cell receptor gene (TCR) rearrangement, Vgamma9/Vdelta2, induced by the combination of IL-2 and zoledronate, without interfering with their cytotoxic activity. Discussion These findings contribute to explain the activity of ex vivo expanded mesenchymal cells, suggesting that MSCs would interact with gamma-delta T lymphocytes. Conclusion This effect could be relevant in separating graft-vs.-host from the graft-vs.-tumour effect, especially considering the possibility of modulating T-lymphocytes activity by the immunomodulating drugs now available. PMID: 19522834 [PubMed - as supplied by publish Cancer Res. 2007 Aug 1;67(15):7450-7. Targeting human {gamma}delta} T cells with zoledronate and interleukin-2 for immunotherapy of hormone-refractory prostate cancer. Dieli F, Vermijlen D, Fulfaro F, Caccamo N, Meraviglia S, Cicero G, Roberts A, Buccheri S, D'Asaro M, Gebbia N, Salerno A, Eberl M, Hayday AC. Dipartimento di Biopatologia e Metodologie Biomediche, UniversitÃ* di Palermo, Palermo, Italy. dieli@unipa.it The increasing evidence that gammadelta T cells have potent antitumor activity suggests their value in immunotherapy, particularly in areas of unmet need such as metastatic carcinoma. To this end, we initiated a phase I clinical trial in metastatic hormone-refractory prostate cancer to examine the feasibility and consequences of using the gammadelta T-cell agonist zoledronate, either alone or in combination with low-dose interleukin 2 (IL-2), to activate peripheral blood gammadelta cells. Nine patients were enlisted to each arm. Neither treatment showed appreciable toxicity. Most patients were treated with zoledronate + IL-2, but conversely only two treated with zoledronate displayed a significant long-term shift of peripheral gammadelta cells toward an activated effector-memory-like state (T(EM)), producing IFN-gamma and perforin. These patients also maintained serum levels of tumor necrosis factor-related apoptosis inducing ligand (TRAIL), consistent with a parallel microarray analysis showing that TRAIL is produced by gammadelta cells activated via the T-cell receptor and IL-2. Moreover, the numbers of T(EM) gammadelta cells showed a statistically significant correlation with declining prostate-specific antigen levels and objective clinical outcomes that comprised three instances of partial remission and five of stable disease. By contrast, most patients treated only with zoledronate failed to sustain either gammadelta cell numbers or serum TRAIL, and showed progressive clinical deterioration. Thus, zoledronate + IL-2 represents a novel, safe, and feasible approach to induce immunologic and clinical responses in patients with metastatic carcinomas, potentially providing a substantially increased window for specific approaches to be administered. Moreover, gammadelta cell phenotypes and possibly serum TRAIL may constitute novel biomarkers of prognosis upon therapy with zoledronate + IL-2 in metastatic carcinoma. PMID: 17671215 [PubMed - indexed for MEDLINE]