Phase I Trial of TGF-β2 Antisense GM-CSF Gene-Modified Autologous Tumor Cell (TAG) Vaccine

Olivares, Jairo; Kumar, Padmasini; Yu, Yang; Maples, Phillip B.; Senzer, Neil; Bedell, Cynthia; Barve, Minal; Tong, Alex W.; Pappen, Beena O.; Kuhn, Joseph A.; Magee, Mitchell J.; Wallraven, Gladice; Nemunaitis, John

doi:10.1158/1078-0432.ccr-10-2195

Cited by 50 publications

(35 citation statements)

References 56 publications

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“…42-46 The efficacy of vaccination may be further improved by engineering the tumor cells to engage immunostimulatory molecules such as GM-CSF, CD40, CD80, CD83, CD137 etc. 4-6, 47-49 However, to achieve therapeutic efficacy against tumors which are larger than a few mm in diameter, the powerful immunosuppressive mechanisms at tumor sites need to be overcome.…”

Section: Discussionmentioning

confidence: 99%

Silencing of the TGF-β1 Gene Increases the Immunogenicity of Cells From Human Ovarian Carcinoma

Wei

Liu

Swisher

et al. 2012

Journal of Immunotherapy

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Cells from many tumors produce transforming growth factor (TGF)-βwhich facilitates their escape from control by the immune system. We previously reported that non-immunogenic cells from either of two transplantable mouse tumors became effective as therapeutic tumor vaccines after lentivirus-mediated shRNA interference to ‘silence’the TGF-β1 gene. We now show that cells from in vitro cultured human ovarian carcinomas (OvC) make large amounts of TGF-β1 and that this can be prevented by ‘silencing’ the TGF-β1 gene. We further show that in vitro sensitization of peripheral blood mononuclear cells (PBMC) in the presence of either mitomycin-treated OvC cells whose TGF-β1 gene was silenced or in vitro matured dendritic cells (DC) which had been pulsed with homogenates from OvC cells with silenced TGF-β1 generated a stronger Th1/Tc1 immune response to the respective WT OvC and also to the OvC antigens mesothelin and HE4 as measured by ELIspot assays. The percentage of interferon (IFN)-γ and tumor necrosis factor (TNF)-α-producing CD4+ and CD8+ T cells increased while there were fewer cells expressing markers characteristic for regulatory T cells or myeloid derived suppressor cells. Similar results were obtained when PBMC from a patient with OvC were sensitized to DC pulsed with homogenate from autologous TGF-β1-silenced tumor cells, and a cytolytic lymphocyte response was generated to autologous OvC cells. Our results support clinical evaluation of TGF-β1-silenced tumor vaccines for immunotherapy of OvC.

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Section: Discussionmentioning

confidence: 99%

Silencing of the TGF-β1 Gene Increases the Immunogenicity of Cells From Human Ovarian Carcinoma

Wei

Liu

Swisher

et al. 2012

Journal of Immunotherapy

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“…The ELISPOT (enzyme-linked immunospot) assay was performed using the enzyme-linked immunospot assay for interferon gamma (BD Biosciences, San Jose, Calif., USA), as previously described [27,31]. The reading of the ELISPOT plates was performed by ZellNet Consulting, Inc. (Fort Lee, N.J., USA).…”

Section: Methodsmentioning

confidence: 99%

Summary of bi-shRNA<sup>furin</sup>/GM-CSF Augmented Autologous Tumor Cell Immunotherapy (FANG™) in Advanced Cancer of the Liver

et al. 2014

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Therapies for advanced hepatocellular carcinoma (HCC) are limited. We carried out a phase I trial of a novel autologous whole-cell tumor cell immunotherapy (FANG™), which incorporates a dual granulocyte macrophage colony-stimulating factor (GM-CSF) expressive/bifunctional small hairpin RNA interference (bi-shRNAi) vector. The bi-shRNAi DNA targets furin, which is a proconvertase of transforming growth factors beta (TGFβ) 1 and 2. Safety, mechanism, immunoeffectiveness, and suggested benefit were previously shown [Senzer et al.: Mol Ther 2012;20:679-689; Senzer et al.: J Vaccines Vaccin 2013;4:209]. We now provide further follow-up of a subset of 8 HCC patients. FANG manufacturing was successful in 7 of 8 attempts (one failure due to insufficient cell yield). Median GM-CSF expression was 144 pg/10⁶ cells, TGFβ₁ knockdown was 100%, and TGFβ₂ knockdown was 93% of the vector-transported cells. Five patients were vaccinated (1 or 2.5 × 10⁷ cells/intradermal injection, 6-11 vaccinations). No FANG toxicity was observed. Three of these patients demonstrated evidence of an immune response to the autologous tumor cell sample. Long-term follow-up demonstrated survival of 319, 729, 784, 931+, and 1,043+ days of the FANG-treated patients. In conclusion, evidence supports further assessment of the FANG immunotherapy in HCC.

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“…3,4 During phase 1 trial, 22 advanced cancer patients were treated. 3 Patients were infused with either 1 × 10 7 (n = 7) or 2.5 x 10 7 (n = 15) cells. There was little evidence of adverse events, apart from injection site pain.…”

Section: Tgfβ2 Antisense + Rhgmcsf Tumor-associated Glycoprotein (Tag)mentioning

confidence: 99%

Cancer targeting vaccines: Surrogate measures of activity

Nemunaitis

2013

Human Vaccines & Immunotherapeutics

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R ecent FDA approval of sipuleucel-Tand Ipilimumab as indicated immunologic therapy in patients with advanced prostate cancer and melanoma, respectively, has established a foothold for broader utilization of vaccine based technology in managing cancer. Despite difficulty of cell harvest and processing with sipuleucel-T and modest toxicity to Ipilimumab, when matched up with the appropriate cancer patient these immunologic approaches have provided significant benefit and have stimulated exciting forward progress in the development of new potent and less toxic (more targeted) vaccines. However, surrogate measures of activity to optimally define more sensitive subset populations and to determine length of treatment time in order to optimize management with other treatment options remain elusive. Key clinically tested vaccines under development which demonstrate correlation of patient benefit to induced immune responsiveness will be discussed. Results suggest with some vaccines correlation of patient benefit and surrogate measures of activity actually do exist. Examples will be discussed.

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Phase I Trial of TGF-β2 Antisense GM-CSF Gene-Modified Autologous Tumor Cell (TAG) Vaccine

Cited by 50 publications

References 56 publications

Silencing of the TGF-β1 Gene Increases the Immunogenicity of Cells From Human Ovarian Carcinoma

Silencing of the TGF-β1 Gene Increases the Immunogenicity of Cells From Human Ovarian Carcinoma

Summary of bi-shRNA<sup>furin</sup>/GM-CSF Augmented Autologous Tumor Cell Immunotherapy (FANG™) in Advanced Cancer of the Liver

Cancer targeting vaccines: Surrogate measures of activity

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