Organization of clinical studies. Patients with locally advanced, unresectable or borderline rese... more Organization of clinical studies. Patients with locally advanced, unresectable or borderline resectable pancreatic adenocarcinoma with absence of distant metastatic disease were eligible for a) Conventional neoadjuvant chemoradiation scheme. b) Neoadjuvant chemoradiation with a hypofractionated scheme. In each study patients are assessed for potential resection following initial treatment and where eligible receive pancreaticoduodenectomy 4â 8 weeks after the last dose of radiation therapy. Patients ineligible for resection proceed to futher treatment, those receiving resection receive further treatment 4â 12 weeks following the operation. (PDF 233 kb)
Radiation therapy aims to kill cancer cells with a minimum of normal tissue toxicity. Dying cance... more Radiation therapy aims to kill cancer cells with a minimum of normal tissue toxicity. Dying cancer cells have been proposed to be a source of tumor antigens and may release endogenous immune adjuvants into the tumor environment. For these reasons, radiation therapy may be an effective modality to initiate new anti-tumor adaptive immune responses that can target residual disease and distant metastases. However, tumors engender an environment dominated by M2 differentiated tumor macrophages that support tumor invasion, metastases and escape from immune control. In this study, we demonstrate that following radiation therapy of tumors in mice, there is an influx of tumor macrophages that ultimately polarize towards immune suppression. We demonstrate using in vitro models that this polarization is mediated by transcriptional regulation by NFkB p50, and that in mice lacking NFkB p50, radiation therapy is more effective. We propose that despite the opportunity for increased antigen-specifi...
The immune infiltrate in colorectal cancer has been correlated with outcome, such that individual... more The immune infiltrate in colorectal cancer has been correlated with outcome, such that individuals with higher infiltrations of T cells have increased survival independent of the disease stage. For patients with lower immune infiltrates, overall survival is limited. Because the patients with colorectal cancer studied have received conventional cancer therapies, these data may indicate that the pretreatment tumor environment increases the efficacy of treatments such as chemotherapy, surgery, and radiotherapy. This study was designed to test the hypothesis that an improved immune environment in the tumor at the time of treatment will increase the efficacy of radiotherapy.Wedemonstrate that inhibition of TGFbusing the orally available small-molecule inhibitor SM16 improved the immune environment of tumors in mice and significantly improved the efficacy of subsequent radiotherapy. This effect was not due to changes in radiosensitivity, epithelial–mesenchymal transition, or changes in va...
e23117Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a fibrotic stroma a... more e23117Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a fibrotic stroma and poor immune infiltrate, in part driven by cancer-associated fibroblasts (CAFs). CAFs contribute t...
Radiation therapy provides a means to kill large numbers of cancer cells in a controlled location... more Radiation therapy provides a means to kill large numbers of cancer cells in a controlled location resulting in the release of tumor-specific antigens and endogenous adjuvants. However, by activating pathways involved in apoptotic cell recognition and phagocytosis, irradiated cancer cells engender suppressive phenotypes in macrophages. We demonstrate that the macrophage-specific phagocytic receptor, Mertk is upregulated in macrophages in the tumor following radiation therapy. Ligation of Mertk on macrophages results in anti-inflammatory cytokine responses via NF-kB p50 upregulation, which in turn limits tumor control following radiation therapy. We demonstrate that in immunogenic tumors, loss of Mertk is sufficient to permit tumor cure following radiation therapy. However, in poorly immunogenic tumors, TGFβ inhibition is also required to result in tumor cure following radiation therapy. These data demonstrate that Mertk is a highly specific target whose absence permits tumor control in combination with radiation therapy.
Hepatology research : the official journal of the Japan Society of Hepatology, Jan 8, 2016
Small, solitary hepatocellular carcinoma (HCC) is curable with stereotactic radiation or other me... more Small, solitary hepatocellular carcinoma (HCC) is curable with stereotactic radiation or other methods of tumor ablation, however regional and systemic tumor recurrence occurs in over 70% of patients. Here we describe the ability of immuno-radiotherapy to induce an anti-tumor immune response and delay the growth of tumors in immune-competent mice. A syngeneic HCC cell line (Hep-55.1c) was injected directly into the livers of C57BL/6 mice using ultrasound guidance, then tumors were treated with stereotactic radiation using a Small Animal Radiation Research Platform with computed tomography (CT) guidance. Delivery of three doses of 250 ug anti-programmed cell death protein-1 (αPD-1) antibody concurrently with 30 Gy SBRT in 3 fractions reduced the growth rate of tumors and improved survival (p < 0.05). Combined treatment was associated with increased CD8+ cytotoxic T cells in the tumor; depletion of CD8 T cells eliminated the efficacy of combined treatment. Combined treatment also i...
Preclinical studies have shown synergy between radiation therapy and immunotherapy. However, in a... more Preclinical studies have shown synergy between radiation therapy and immunotherapy. However, in almost all preclinical models, radiation is delivered in single doses or short courses of high doses (hypofractionated radiation). By contrast in most clinical settings, radiation is delivered as standard small daily fractions of 1.8-2 Gy to achieve total doses of 50-54 Gy (fractionated radiation). We do not yet know the optimal dose and scheduling of radiation for combination with chemotherapy and immunotherapy. To address this, we analyzed the effect of neoadjuvant standard fractionated and hypofractionated chemoradiation on immune cells in patients with locally advanced and borderline resectable pancreatic adenocarcinoma. We found that standard fractionated chemoradiation resulted in a significant and extended loss of lymphocytes that was not explained by a lack of homeostatic cytokines or response to cytokines. By contrast, treatment with hypofractionated radiation therapy avoided the loss of lymphocytes associated with conventional fractionation. Hypofractionated neoadjuvant chemoradiation is associated with reduced systemic loss of T cells. ClinicalTrials.gov NCT01342224, April 21, 2011; NCT01903083, July 2, 2013.
The anecdotal reports of promising results seen with immunotherapy and radiation in advanced mali... more The anecdotal reports of promising results seen with immunotherapy and radiation in advanced malignancies have prompted several trials combining immunotherapy and radiation. However, the ideal timing of immunotherapy with radiation has not been clarified. Tumor bearing mice were treated with 20Gy radiation delivered only to the tumor combined with either anti-CTLA4 antibody or anti-OX40 agonist antibody. Immunotherapy was delivered at a single timepoint around radiation. Surprisingly, the optimal timing of these therapies varied. Anti-CTLA4 was most effective when given prior to radiation therapy, in part due to regulatory T cell depletion. Administration of anti-OX40 agonist antibody was optimal when delivered one day following radiation during the post-radiation window of increased antigen presentation. Combination treatment of anti-CTLA4, radiation, and anti-OX40 using the ideal timing in a transplanted spontaneous mammary tumor model demonstrated tumor cures. These data demonstr...
Cytotoxic therapies prime adaptive immune responses to cancer by stimulating the release of tumor... more Cytotoxic therapies prime adaptive immune responses to cancer by stimulating the release of tumor-associated antigens. However, the tumor microenvironment into which these antigens are released is typically immunosuppressed, blunting the ability to initiate immune responses. Recently, activation of the DNA sensor molecule STING by cyclic dinucleotides was shown to stimulate infection-related inflammatory pathways in tumors. In this study, we report that the inflammatory pathways activated by STING ligands generate a powerful adjuvant activity for enhancing adaptive immune responses to tumor antigens released by radiation therapy. In a murine model of pancreatic cancer, we showed that combining CT-guided radiation therapy with a novel ligand of murine and human STING could synergize to control local and distant tumors. Mechanistic investigations revealed T cell-independent and TNFAlpha-dependent hemorrhagic necrosis at early times followed by later CD8 T cell-dependent control of res...
Organization of clinical studies. Patients with locally advanced, unresectable or borderline rese... more Organization of clinical studies. Patients with locally advanced, unresectable or borderline resectable pancreatic adenocarcinoma with absence of distant metastatic disease were eligible for a) Conventional neoadjuvant chemoradiation scheme. b) Neoadjuvant chemoradiation with a hypofractionated scheme. In each study patients are assessed for potential resection following initial treatment and where eligible receive pancreaticoduodenectomy 4â 8 weeks after the last dose of radiation therapy. Patients ineligible for resection proceed to futher treatment, those receiving resection receive further treatment 4â 12 weeks following the operation. (PDF 233 kb)
Radiation therapy aims to kill cancer cells with a minimum of normal tissue toxicity. Dying cance... more Radiation therapy aims to kill cancer cells with a minimum of normal tissue toxicity. Dying cancer cells have been proposed to be a source of tumor antigens and may release endogenous immune adjuvants into the tumor environment. For these reasons, radiation therapy may be an effective modality to initiate new anti-tumor adaptive immune responses that can target residual disease and distant metastases. However, tumors engender an environment dominated by M2 differentiated tumor macrophages that support tumor invasion, metastases and escape from immune control. In this study, we demonstrate that following radiation therapy of tumors in mice, there is an influx of tumor macrophages that ultimately polarize towards immune suppression. We demonstrate using in vitro models that this polarization is mediated by transcriptional regulation by NFkB p50, and that in mice lacking NFkB p50, radiation therapy is more effective. We propose that despite the opportunity for increased antigen-specifi...
The immune infiltrate in colorectal cancer has been correlated with outcome, such that individual... more The immune infiltrate in colorectal cancer has been correlated with outcome, such that individuals with higher infiltrations of T cells have increased survival independent of the disease stage. For patients with lower immune infiltrates, overall survival is limited. Because the patients with colorectal cancer studied have received conventional cancer therapies, these data may indicate that the pretreatment tumor environment increases the efficacy of treatments such as chemotherapy, surgery, and radiotherapy. This study was designed to test the hypothesis that an improved immune environment in the tumor at the time of treatment will increase the efficacy of radiotherapy.Wedemonstrate that inhibition of TGFbusing the orally available small-molecule inhibitor SM16 improved the immune environment of tumors in mice and significantly improved the efficacy of subsequent radiotherapy. This effect was not due to changes in radiosensitivity, epithelial–mesenchymal transition, or changes in va...
e23117Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a fibrotic stroma a... more e23117Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a fibrotic stroma and poor immune infiltrate, in part driven by cancer-associated fibroblasts (CAFs). CAFs contribute t...
Radiation therapy provides a means to kill large numbers of cancer cells in a controlled location... more Radiation therapy provides a means to kill large numbers of cancer cells in a controlled location resulting in the release of tumor-specific antigens and endogenous adjuvants. However, by activating pathways involved in apoptotic cell recognition and phagocytosis, irradiated cancer cells engender suppressive phenotypes in macrophages. We demonstrate that the macrophage-specific phagocytic receptor, Mertk is upregulated in macrophages in the tumor following radiation therapy. Ligation of Mertk on macrophages results in anti-inflammatory cytokine responses via NF-kB p50 upregulation, which in turn limits tumor control following radiation therapy. We demonstrate that in immunogenic tumors, loss of Mertk is sufficient to permit tumor cure following radiation therapy. However, in poorly immunogenic tumors, TGFβ inhibition is also required to result in tumor cure following radiation therapy. These data demonstrate that Mertk is a highly specific target whose absence permits tumor control in combination with radiation therapy.
Hepatology research : the official journal of the Japan Society of Hepatology, Jan 8, 2016
Small, solitary hepatocellular carcinoma (HCC) is curable with stereotactic radiation or other me... more Small, solitary hepatocellular carcinoma (HCC) is curable with stereotactic radiation or other methods of tumor ablation, however regional and systemic tumor recurrence occurs in over 70% of patients. Here we describe the ability of immuno-radiotherapy to induce an anti-tumor immune response and delay the growth of tumors in immune-competent mice. A syngeneic HCC cell line (Hep-55.1c) was injected directly into the livers of C57BL/6 mice using ultrasound guidance, then tumors were treated with stereotactic radiation using a Small Animal Radiation Research Platform with computed tomography (CT) guidance. Delivery of three doses of 250 ug anti-programmed cell death protein-1 (αPD-1) antibody concurrently with 30 Gy SBRT in 3 fractions reduced the growth rate of tumors and improved survival (p < 0.05). Combined treatment was associated with increased CD8+ cytotoxic T cells in the tumor; depletion of CD8 T cells eliminated the efficacy of combined treatment. Combined treatment also i...
Preclinical studies have shown synergy between radiation therapy and immunotherapy. However, in a... more Preclinical studies have shown synergy between radiation therapy and immunotherapy. However, in almost all preclinical models, radiation is delivered in single doses or short courses of high doses (hypofractionated radiation). By contrast in most clinical settings, radiation is delivered as standard small daily fractions of 1.8-2 Gy to achieve total doses of 50-54 Gy (fractionated radiation). We do not yet know the optimal dose and scheduling of radiation for combination with chemotherapy and immunotherapy. To address this, we analyzed the effect of neoadjuvant standard fractionated and hypofractionated chemoradiation on immune cells in patients with locally advanced and borderline resectable pancreatic adenocarcinoma. We found that standard fractionated chemoradiation resulted in a significant and extended loss of lymphocytes that was not explained by a lack of homeostatic cytokines or response to cytokines. By contrast, treatment with hypofractionated radiation therapy avoided the loss of lymphocytes associated with conventional fractionation. Hypofractionated neoadjuvant chemoradiation is associated with reduced systemic loss of T cells. ClinicalTrials.gov NCT01342224, April 21, 2011; NCT01903083, July 2, 2013.
The anecdotal reports of promising results seen with immunotherapy and radiation in advanced mali... more The anecdotal reports of promising results seen with immunotherapy and radiation in advanced malignancies have prompted several trials combining immunotherapy and radiation. However, the ideal timing of immunotherapy with radiation has not been clarified. Tumor bearing mice were treated with 20Gy radiation delivered only to the tumor combined with either anti-CTLA4 antibody or anti-OX40 agonist antibody. Immunotherapy was delivered at a single timepoint around radiation. Surprisingly, the optimal timing of these therapies varied. Anti-CTLA4 was most effective when given prior to radiation therapy, in part due to regulatory T cell depletion. Administration of anti-OX40 agonist antibody was optimal when delivered one day following radiation during the post-radiation window of increased antigen presentation. Combination treatment of anti-CTLA4, radiation, and anti-OX40 using the ideal timing in a transplanted spontaneous mammary tumor model demonstrated tumor cures. These data demonstr...
Cytotoxic therapies prime adaptive immune responses to cancer by stimulating the release of tumor... more Cytotoxic therapies prime adaptive immune responses to cancer by stimulating the release of tumor-associated antigens. However, the tumor microenvironment into which these antigens are released is typically immunosuppressed, blunting the ability to initiate immune responses. Recently, activation of the DNA sensor molecule STING by cyclic dinucleotides was shown to stimulate infection-related inflammatory pathways in tumors. In this study, we report that the inflammatory pathways activated by STING ligands generate a powerful adjuvant activity for enhancing adaptive immune responses to tumor antigens released by radiation therapy. In a murine model of pancreatic cancer, we showed that combining CT-guided radiation therapy with a novel ligand of murine and human STING could synergize to control local and distant tumors. Mechanistic investigations revealed T cell-independent and TNFAlpha-dependent hemorrhagic necrosis at early times followed by later CD8 T cell-dependent control of res...
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Papers by Benjamin Cottam