Tumor Regression Induced by Intratumor Therapy with a Disabled Infectious Single Cycle (DISC) Herpes Simplex Virus (HSV) Vector, DISC/HSV/Murine Granulocyte-Macrophage Colony-Stimulating Factor, Correlates with Antigen-Specific Adaptive Immunity

Ali, Selman A.; Lynam, June; McLean, C. S.; Entwisle, Claire; Loudon, Peter T.; Rojas, José M.; McArdle, Stephanie E.B.; Geng, Li; Mian, Shahid; Rees, Robert C.

doi:10.4049/jimmunol.168.7.3512

Cited by 31 publications

(44 citation statements)

References 33 publications

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“…Similarly, using OX40R monoclonal Ab, the induced GL261 glioma regression in B6 mice was also found to be dependent on both CD4 + and CD8 + (Kaergaard et al, 2000). These results are consistent with our previous observation that both T-cell populations are involved in tumour rejection following therapy of established tumours with DISC/mGM-CSF (Ali et al, 2000(Ali et al, , 2002.…”

Section: Discussionsupporting

confidence: 93%

“…We have previously shown that direct intra-tumour injection of subcutaneous CT26 tumours with DISC/mGM-CSF induces the complete regression of tumours in a proportion of treated animals (Todryk et al, 1999;Ali et al, 2002). In the present investigation the effect of combination therapy of mOX40L fusion protein and DISC/mGM-CSF therapy on established subcutaneous 4T1 and CT26 tumours was determined.…”

Section: Combination Therapy Of Ox40l and Disc/mgm-csf Virusmentioning

confidence: 68%

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Anti-tumour therapeutic efficacy of OX40L in murine tumour model

Ali

Ahmad

Lynam

et al. 2004

Vaccine

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The OX40 ligand (OX40L), a member of TNF superfamily, is a costimulatory molecule involved in T cell activation. It is expressed on antigen presenting cells including dendritic cells (DC) and activated B cells. This molecule has been reported to provide potent costimulation in APC-T cell interactions upon binding to its cognate receptor, OX40 which is expressed by activated T cells. In this study systemic administration of OX40L fusion protein was used in the treatment of established murine subcutaneous colon and breast carcinomas.Intra-peritoneal injection of mOX40L fusion protein significantly inhibited the growth of subcutaneous 3 day established colon (CT26) and breast (4T1) carcinomas which was dose and route dependent. Effective therapy with OX40L required the the presence of tumour for 3 days prior to OX40L, concomitant therapy, given at the same time (day 0) as tumour cells was less effective. Furthermore, therapy with OX40L fusion protein was effective in significantly reducing CT26 experimental lung metastasis. In addition, inhibition of CT26 and 4T1 tumours in response to therapy with OX40L was significantly enhanced by combination treatment with intra-tumour injection of a DISC-HSV vector encoding mGM-CSF. Tumour rejection in response to OX40L therapy was correlated with splenocyte CTL activity against the gp70 CT26 tumour associated antigen. In vivo depletion studies demonstrated the requirement for both CD4+ and CD8+ T cells for effective OX40L therapy.Collectively these results demonstrate the potential role of the OX40L in cancer immunotherapy.3

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Section: Discussionsupporting

confidence: 93%

Section: Combination Therapy Of Ox40l and Disc/mgm-csf Virusmentioning

confidence: 68%

Anti-tumour therapeutic efficacy of OX40L in murine tumour model

Ali

Ahmad

Lynam

et al. 2004

Vaccine

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“…1,22 Tumor regression was correlated with the potency of CTL activity, and in the present study, we demonstrate that the adoptive transfer of antigen-specific CTLs i.v. into mice with established experimental lung metastasis significantly increased the overall survival in comparison to control animals.…”

Section: Rolling and Flying Cellssupporting

confidence: 75%

“…1 Splenocytes from regressor mice but not progressor or naive mice have demonstrated potent AH-1 peptide-specific CTL activity following in vitro stimulation (data not shown). 1 …”

Section: Inhibition Of Ct26 Tumors By Direct Intratumor Injection Witmentioning

confidence: 99%

“…12,13 We have recently shown that direct intratumor injection of a disabled infectious single-cycle herpes simplex virus (DISC-HSV)-2 virus encoding the mGM-CSF gene (DISC-mGM-CSF) into murine CT26 colon carcinomas induced a significant tumor growth delay and complete tumor regression in up to 70% of animals. 1,14 Potent tumor-specific CTLs (CD8 ϩ ) were generated from splenocytes of mice with regressing tumors following in vitro tumor-specific peptide stimulation. CD8 ϩ effector T cells were shown to be essential for tumor regression to occur, and mice that demonstrated a complete tumor rejection response remained immune to subsequent tumor challenge several months following therapy.…”

mentioning

confidence: 99%

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Trafficking of tumor peptide‐specific cytotoxic T lymphocytes into the tumor microcirculation

Ali¹,

Ahmad²,

Lynam³

et al. 2004

Intl Journal of Cancer

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The major histocompatibility complex class I-restricted CD8 ؉ cytotoxic T-lymphocyte (CTL) effector arm of the adaptive immune response can specifically recognize and destroy tumor cells expressing peptide antigens. Although adoptive T-cell therapy has been successfully used for the treatment of viral and malignant diseases, little is known of the trafficking and fate of adoptively transferred antigenspecific T cells. In the present study, splenocytes derived from mice that rejected their tumors (CT26 or CT26-clone 25 tumors) in response to direct intratumor injection of disabled infectious single-cycle herpes simplex virus (DISC-HSV) encoding murine GM-CSF were restimulated with peptide in vitro. CTLs specific for the AH-1 and ␤-gal peptides expressed by CT26 and CT26-clone 25 tumor cells, respectively, were generated and used for adoptive cellular therapy and trafficking studies. Intravenous administration of AH-1-specific CTLs 3 days following i.v. injection of CT26 cells resulted in significant tumor growth inhibition, whereas administration of control CTLs generated against a bacterial ␤-gal peptide did not inhibit the growth of tumors. Trafficking of AH-1-specific lymphocytes and their interaction with the CT26 tumor microcirculation was analyzed using realtime in vivo microscopy (IVM). AH-1-specific but not ␤-galspecific CTLs adhered and localized in the CT26 tumor microvasculature, but neither population adhered to the endothelium of the normal microcirculation. This study provides direct visual evidence suggesting that AH-1-specific CTLs that mediate a therapeutic response traffic to and localize within the tumor microenvironment. © 2004 Wiley-Liss, Inc. Key words: cytotoxic T lymphocytes; adoptive transfer; traffickingThe immune system consists of a complex network of cells that mediate innate and antigen-specific responses to invading microbes and tumors. Processing and presentation of antigen by antigen-presenting cells (dendritic cells) via peptide antigens bound to cell surface major histocompatibility complex (MHC) antigens is a prerequisite for the stimulation of T-cell responses (cytotoxic and helper T cells). 1,2 Tumor-specific cytotoxic T lymphocytes (CTLs) play an important role against cancer; this has been demonstrated using a number of experimental approaches, including the adoptive transfer of tumor-specific CTLs in animal models and clinical trials. 3,4 Beneficial antitumor effects have been reported using adoptive cellular therapy with lymphokine-activated killer (LAK) cells, autolymphocyte therapy (ALT) and in vitro expanded tumor-infiltrating lymphocytes. [5][6][7] The efficacy of adoptive cellular immunotherapy with cultured lymphocytes activated toward tumor antigens requires effector cells to migrate into tumor tissue and, once resident at the tumor site, to mediate an antitumor rejection response either by direct killing of tumor cells and/or indirectly through cytokine release and recruitment of other cells. Using the A2/K b transgenic mouse model, Sutmuller et al. 3 have shown t...

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Regulation of CTL responses to MHC‐restricted class I peptide of the gp70 tumour antigen by splenic parenchymal CD4⁺ T cells in mice failing immunotherapy with DISC–mGM‐CSF

Ahmad

Rees

McArdle

et al. 2005

Intl Journal of Cancer

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Direct intratumour injection of the disabled infectious singlecycle-herpes simplex virus-encoding murine granulocyte/macrophage colony-stimulating factor (DISC-HSV-mGM-CSF) into established colon carcinoma CT26 tumours induced complete tumour rejection in up to 70% of treated animals (regressors), while the remaining mice developed progressive tumours (progressors). This murine Balb/c model was used to dissect the cellular mechanisms involved in tumour regression or progression following immunotherapy. CTLs were generated by coculturing lymphocytes and parenchymal cells from the same spleens of individual regressor or progressor animals in the presence of the relevant AH-1 peptide derived from the gp70 tumour-associated antigens expressed by CT26 tumours. Tumour regression was correlated with potent CTL responses, spleen weight and cytokine (IFN-g) production. Conversely, progressor splenocytes exhibited weak to no CTL activity and poor IFN-g production, concomitant with the presence of a suppressor cell population in the progressor splenic parenchymal cell fraction. Further fractionation of this parenchymal subpopulation demonstrated that cells inhibitory to the activation of AH-1-specific CTLs, restimulated in vitro with peptide, were present in the nonadherent parenchymal fraction. In vitro depletion of progressor parenchymal CD3 + /CD4 + T cells restored the CTL response of the cocultured splenocytes (regressor lymphocytes and progressor parenchymal cells) and decreased the production of IL-10, suggesting that CD3 + CD4+ T lymphocytes present in the parenchymal fraction regulated the CTL response to AH-1. We examined the cellular responses associated with tumour rejection and progression, identifying regulatory pathways associated with failure to respond to immunotherapy. ' 2005 Wiley-Liss, Inc.

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Tumor Regression Induced by Intratumor Therapy with a Disabled Infectious Single Cycle (DISC) Herpes Simplex Virus (HSV) Vector, DISC/HSV/Murine Granulocyte-Macrophage Colony-Stimulating Factor, Correlates with Antigen-Specific Adaptive Immunity

Cited by 31 publications

References 33 publications

Anti-tumour therapeutic efficacy of OX40L in murine tumour model

Anti-tumour therapeutic efficacy of OX40L in murine tumour model

Trafficking of tumor peptide‐specific cytotoxic T lymphocytes into the tumor microcirculation

Regulation of CTL responses to MHC‐restricted class I peptide of the gp70 tumour antigen by splenic parenchymal CD4⁺ T cells in mice failing immunotherapy with DISC–mGM‐CSF

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Tumor Regression Induced by Intratumor Therapy with a Disabled Infectious Single Cycle (DISC) Herpes Simplex Virus (HSV) Vector, DISC/HSV/Murine Granulocyte-Macrophage Colony-Stimulating Factor, Correlates with Antigen-Specific Adaptive Immunity

Cited by 31 publications

References 33 publications

Anti-tumour therapeutic efficacy of OX40L in murine tumour model

Anti-tumour therapeutic efficacy of OX40L in murine tumour model

Trafficking of tumor peptide‐specific cytotoxic T lymphocytes into the tumor microcirculation

Regulation of CTL responses to MHC‐restricted class I peptide of the gp70 tumour antigen by splenic parenchymal CD4+ T cells in mice failing immunotherapy with DISC–mGM‐CSF

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Product

Resources

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Regulation of CTL responses to MHC‐restricted class I peptide of the gp70 tumour antigen by splenic parenchymal CD4⁺ T cells in mice failing immunotherapy with DISC–mGM‐CSF