Sublethal Irradiation of Human Tumor Cells Modulates Phenotype Resulting in Enhanced Killing by Cytotoxic T Lymphocytes

Garnett, Charlie T.; Palena, Claudia; Chakarborty, Mala; Tsang, Kwong-Yok; Schlom, Jeffrey; Hodge, James W.

doi:10.1158/0008-5472.can-04-1525

Cited by 484 publications

(432 citation statements)

References 36 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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“…Further preclinical studies showed similar findings with human cell lines [9]. Twenty-three human carcinoma cell lines (12 colon, 7 lung, 4 prostate) were subjected to 10 Gy of radiation.…”

Section: Vaccine and Radiationmentioning

confidence: 54%

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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“…Radiotherapy may also contribute to enhance killing activity of immune cells since irradiation mediates many effects on cells and tissues that may stimulate an immune response [30]. For example, low doses of ionising irradiation upregulate expression of MHC class I molecules [31] and tumourassociated antigens [32], as well as adhesion molecules by endothelial cells [33], thereby boosting cytotoxic T-cell activity [34].…”

Section: Discussionmentioning

confidence: 99%

Trifunctional antibodies induce efficient antitumour activity with immune cells from head and neck squamous cell carcinoma patients after radio-chemotherapy treatment

et al. 2011

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Background Trifunctional antibodies, such as catumaxomab (anti-EpCAManti-CD3) and ertumaxomab (anti-HER-2/neuanti-CD3), transiently link immune effector cells to tumour cells, which results in cellular cytotoxicity towards the tumour cells. A functional immune system is therefore essential for effective anti-tumour activity. However, the commonly observed haematotoxicity of chemotherapeutics and radiation therapy may be associated with some degree of immunosuppression. Combining chemotherapy and trifunctional antibodies in cancer treatment requires understanding of the impact of chemotherapeutics on immune cell function and, thus, on the activity of trifunctional antibodies. Methods The effect of chemotherapeutic treatment on trifunctional antibody-mediated anti-tumour activity was assessed in vitro. Blood samples were collected from 12 head and neck squamous cell carcinoma patients after chemotherapy (5-fl uorouracil, cisplatin) and radiotherapy, and from one healthy control donor. The immune cell status was analysed and mononuclear cells (MNC) were isolated. The potency of catumaxomab and ertumaxomab was assessed in a cytotoxicity assay using MNC isolated from each patient sample in co-culture with a tumour target cell line. The release of infl ammatory cytokines was also monitored in the cell culture supernatant. Results Most patients included in this study had decreased immune cell counts during the course of chemotherapy. Nonetheless, an effective and concentration-dependent anti-tumour activity mediated by trifunctional antibodies was demonstrated using these patient immune effector cells. The immune response activity of the patient immune cells was not impaired one week after cisplatin administration or even three days after the last 5-fl uorouracil treatment. Conclusion This study shows for the fi rst time that immune effector cells from cancer patients undergoing standard chemotherapy and radiotherapy can be activated by trifunctional antibodies for effi cient killing of tumour cells.

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Sublethal Irradiation of Human Tumor Cells Modulates Phenotype Resulting in Enhanced Killing by Cytotoxic T Lymphocytes

Cited by 484 publications

References 36 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

Trifunctional antibodies induce efficient antitumour activity with immune cells from head and neck squamous cell carcinoma patients after radio-chemotherapy treatment

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