External Beam Radiation of Tumors Alters Phenotype of Tumor Cells to Render Them Susceptible to Vaccine-Mediated T-Cell Killing

Chakraborty, Mala; Abrams, Scott I.; Coleman, C. Norman; Camphausen, Kevin; Schlom, Jeffrey; Hodge, James W.

doi:10.1158/0008-5472.can-04-0073

Cited by 405 publications

(293 citation statements)

References 38 publications

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“…23 In addition to confirming some of these findings in this study using TRAMP-C1 cells, we further found that IL-3-induced Fas antigen expression, as did RT. The effect of RT is similar to recent findings by Chakraborty et al [5][6][7] They have proposed that radiationinduced tumor phenotype changes could enhance tumor cell susceptibility to antigen-specific CTL-mediated killing. The mechanism that mediates this type of phenotypic switch by IL-3 is still unclear.…”

Section: Discussionsupporting

confidence: 88%

“…As radiation-induced changes in MHC class I, ICAM-1, and Fas expression by tumor cells irradiated in vitro also have been reported [5][6][7] we examined expression of these molecules on TRAMP-C1 cells with and without Doxregulated IL-3 expression 4 h following a single in vitro dose of 0 or 7 Gy. Radiation was given 24 h after Dox treatment.…”

Section: The Influence Of Il-3 Gene Transfer and Radiation On Tumor Pmentioning

confidence: 92%

“…3 The attraction of RT combined with IT is increased by findings that irradiation can modulate expression of several classes of genes in both murine and human cancers, 4 such as Fas, MHC-1, ICAM-1, and MUC-1, that might enhance their ability to serve as immune targets. 2,[5][6][7] On the other hand, while there is evidence that RT generates 'danger' signals that might mature dendritic cells (DCs) to present tumor antigen 8,9 there is no good evidence that this occurs in the clinic and such signals may be too weak to be effective. In a recent randomized phase II clinical trial study, 10 addition of recombinant vaccine administration to standard RT in patients with clinically localized prostate cancer showed that vaccination was safe and the generation of a PSAspecific cellular immune response was enhanced following RT.…”

Section: Introductionmentioning

confidence: 99%

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Tetracycline-regulated intratumoral expression of interleukin-3 enhances the efficacy of radiation therapy for murine prostate cancer

Hong

et al. 2006

Cancer Gene Ther

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The aim of this study was to investigate means of increasing the efficiency with which cancer cell death following local radiation therapy (RT) is translated into the generation of tumor immunity since, if this were to be achieved, it would be expected to enhance the rates of disease-free recurrence and survival. Our investigations centered around the use of interleukin-3 (IL-3), expressed intratumorally using an inducible adenoviral vector, to alter the immunogenicity of established murine TRAMP-C1 prostate cancer receiving a course of fractionated local RT (7 Gy per fraction per day for 5 days). Because high systemic levels of IL-3 can be associated with toxicity, a tetracycline-regulated gene delivery system was employed. The results show that while intratumoral IL-3 expression or RT alone caused a modest delay in TRAMP-C1 tumor growth, the combination was synergistic with 50% of mice being cured and developing a long-term, tumor-specific state of immunity. Immunological analyses performed on splenic lymphocytes demonstrated that, compared to RT or IL-3 alone, combined treatment significantly increased the number of tumorspecific IFN-g-secreting and cytotoxic T cells. The study demonstrates that tetracycline-regulated IL-3 gene expression within tumors can enhance the immune response to prostate cancer and this can augment the efficacy of a course of RT without additional side effects.

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Section: Discussionsupporting

confidence: 88%

Section: The Influence Of Il-3 Gene Transfer and Radiation On Tumor Pmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Tetracycline-regulated intratumoral expression of interleukin-3 enhances the efficacy of radiation therapy for murine prostate cancer

Hong

et al. 2006

Cancer Gene Ther

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“…Sublethal doses of radiation up-regulated surface expression of Fas, ICAM-1, and MHC class I on tumor cells in a dose-dependent manner. In addition, destruction of the MC38-CEA tumors by this combination regimen was shown to be associated with a massive infiltration of tumor-specific CD8 + T cells [8].…”

Section: Vaccine and Radiationmentioning

confidence: 93%

“…To study this, the authors showed that radiation was able to improve the lytic sensitivity of tumor cells by TAA-specific CTL. A subsequent study [8] showed that irradiation-induced up-regulation of Fas on tumor cells could be combined with an active immunotherapy regimen. CEA-transgenic mice bearing MC38-CEA murine colon tumors were given priming vaccinations of recombinant vaccinia (rV) containing the transgenes for CEA and a triad of costimulatory molecules (B7.1, ICAM-1, LFA-3, designated TRICOM), followed by recombinant fowlpox (rF)-CEA-TRICOM booster vaccines.…”

Section: Vaccine and Radiationmentioning

confidence: 99%

Enhancing efficacy of therapeutic vaccinations by combination with other modalities

Gulley

Madan

Arlen

2007

Vaccine

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Novel strategies are emerging from preclinical and clinical investigations for combining vaccines with conventional and experimental anticancer therapies. Several lines of research show that combining either radiation or certain chemotherapeutic agents with vaccine can alter the phenotype of tumor cells, rendering them more susceptible to T-cell-mediated killing. Furthermore, there is emerging data suggesting that an immune response elicited by vaccine may augment the antitumor effectiveness of subsequent therapies. This article reviews and discusses therapeutic cancer strategies that employ vaccines sequentially or in combination with conventional cytotoxic therapies such as local radiation, chemotherapy, and hormone therapy, or immunopotentiating therapies such as anti-CTLA-4 monoclonal antibodies. Preliminary results of clinical studies using these combination strategies have demonstrated a postvaccination antigen cascade, prolonged time to disease progression, and evidence of improved overall survival. Large randomized studies are currently underway to further investigate these findings.

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Carcinoembryonic Antigen Transgenic Mouse Models for Immunotherapy and Development of Cancer Vaccines

Bhattacharya‐Chatterjee

Saha

Foon

et al. 2008

CP in Immunology

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The goal of cancer therapy remains as the long-term eradication of tumor cells without adverse effects on normal tissue. Conventional approaches utilizing chemotherapy and radiotherapy are limited by both their toxicity and lack of specificity. In recent years, investigators have carried out several studies designed to evaluate whether human tumor-associated antigens (TAAs) can be exploited as targets for immunotherapy, specifically for human cancer vaccine development. A major limitation in immunotherapy studies of human cancer is the general lack of appropriate preclinical models. Clinical studies can be difficult to implement, particularly when a clear understanding of the potential efficacy, limitation, and safety of an immunotherapeutic strategy is not available from relevant animal investigations. However, mice carrying a transgene for a human tumor self-antigen may provide a more acceptable experimental model in which knowledge about immunotherapeutic strategies aiming at the TAA of interest can be enhanced prior to initiating clinical trials. Since the different strategies in experimental immunotherapy of cancer have been directed to activate different immune system components, a variety of transgenic mouse models have been generated expressing either TAA, human leukocyte antigen (HLA), oncogene, or immune effector cell molecules. These models may serve as an excellent platform for the identification of novel targets for immunotherapy as well as to evaluate the efficacy of targeted therapies and will lead to the development of clinical trials for cancer patients. In this unit, a brief overview of the generation and study of different vaccine approaches in carcinoembryonic antigen (CEA) transgenic mouse models and the experimental findings in mouse models that spontaneously develop gastrointestinal tumors and express the CEA transgene is provided.

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External Beam Radiation of Tumors Alters Phenotype of Tumor Cells to Render Them Susceptible to Vaccine-Mediated T-Cell Killing

Abstract: ABSTRACT

Cited by 405 publications

References 38 publications

Tetracycline-regulated intratumoral expression of interleukin-3 enhances the efficacy of radiation therapy for murine prostate cancer

Tetracycline-regulated intratumoral expression of interleukin-3 enhances the efficacy of radiation therapy for murine prostate cancer

Enhancing efficacy of therapeutic vaccinations by combination with other modalities

Carcinoembryonic Antigen Transgenic Mouse Models for Immunotherapy and Development of Cancer Vaccines

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