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            ‐L1 blockade enhances response of pancreatic ductal adenocarcinoma to radiotherapy

Azad, Abul Kalam; Lim, Su Yin; D’Costa, Zenobia; Jones, Keaton; Diana, Angela; Sansom, Owen J.; Krüger, Philipp; Liu, Stanley K.; McKenna, W. Gillies; Dushek, Omer; Muschel, Ruth J.; Fokas, Emmanouil

doi:10.15252/emmm.201606674

Cited by 192 publications

(181 citation statements)

References 58 publications

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“…tumour regressions ( Fig 6G). KPC tumours are highly resistant to immune checkpoint blockade, and we observed no tumour regression in mice treated with IR and anti-PD-L1 ( Fig 6H; Winograd Azad et al, 2016). However, the addition of aCSF led to tumour regression in three of eight tumours ( Fig 6H).…”

Section: Macrophage Depletion Renders Tumours Sensitive To Immune Chementioning

confidence: 82%

“…In the absence of tumour regression, we questioned whether a T‐cell response was additionally limited by the engagement of immune checkpoint, potentially exacerbated by the upregulation of checkpoint molecules following radiation (Deng et al , ; Azad et al , ; Derer et al , ). In our models, both PD‐L1 and PD‐L2 were already expressed at high levels on macrophages regardless of radiation.…”

Section: Discussionmentioning

confidence: 99%

“…MC38 is microsatellite unstable, hypermutated, immunogenic and has shown sensitivity to immune checkpoint blockade (Deng et al, 2014a;Juneja et al, 2017;Lau et al, 2017). Conversely, KPC tumours fail to generate robust adaptive immunity and are highly resistant to checkpoint blockade (Azad et al, 2016;Evans et al, 2016). In addition, the relative contribution of host vs. tumour cell expression of PD-L1 to the sensitivity of tumours is different across different tumour types (Juneja et al, 2017;Lau et al, 2017).…”

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confidence: 99%

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Radiation combined with macrophage depletion promotes adaptive immunity and potentiates checkpoint blockade

et al. 2018

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Emerging evidence suggests a role for radiation in eliciting anti‐tumour immunity. We aimed to investigate the role of macrophages in modulating the immune response to radiation. Irradiation to murine tumours generated from colorectal (MC38) and pancreatic (KPC) cell lines induced colony‐stimulating factor 1 (CSF‐1). Coincident with the elevation in CSF‐1, macrophages increased in tumours, peaking 5 days following irradiation. These tumour‐associated macrophages (TAMs) were skewed towards an immunosuppressive phenotype. Macrophage depletion via anti‐CSF (aCSF) reduced macrophage numbers, yet only achieved tumour growth delay when combined with radiation. The tumour growth delay from aCSF after radiation was abrogated by depletion of CD8 T cells. There was enhanced recognition of tumour cell antigens by T cells isolated from irradiated tumours, consistent with increased antigen priming. The addition of anti‐PD‐L1 (aPD‐L1) resulted in improved tumour suppression and even regression in some tumours. In summary, we show that adaptive immunity induced by radiation is limited by the recruitment of highly immunosuppressive macrophages. Macrophage depletion partly reduced immunosuppression, but additional treatment with anti‐PD‐L1 was required to achieve tumour regression.

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Section: Macrophage Depletion Renders Tumours Sensitive To Immune Chementioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Radiation combined with macrophage depletion promotes adaptive immunity and potentiates checkpoint blockade

et al. 2018

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“…Unfortunately, immune checkpoint inhibitors have shown little effects in pancreatic cancer patients (Brahmer et al 2012, Delitto et al 2016. However, combination of high-dose radiotherapy with anti-PD-L1 significantly improved tumour responses in pancreatic ductal adenocarcinoma (PDAC) cell allografts (Azad et al 2017). Radiotherapy induced a large population of tumour cells susceptible to cytotoxic killing, and the early administration of anti-PD-L1 prevented the growth of immunosuppressive cells and increased recruitment and activation of T cells (Azad et al 2017).…”

Section: Pancreatic Cancer Microenvironmentmentioning

confidence: 99%

“…However, combination of high-dose radiotherapy with anti-PD-L1 significantly improved tumour responses in pancreatic ductal adenocarcinoma (PDAC) cell allografts (Azad et al 2017). Radiotherapy induced a large population of tumour cells susceptible to cytotoxic killing, and the early administration of anti-PD-L1 prevented the growth of immunosuppressive cells and increased recruitment and activation of T cells (Azad et al 2017). Activation of stimulator of IFN genes (STING) can induce anti-tumour effects via type I interferons in various cancers including PCs in animal models (Gasser et al 2016).…”

Section: Pancreatic Cancer Microenvironmentmentioning

confidence: 99%

The role of the tumour microenvironment in immunotherapy

Gasser

Lim

Cheung

2017

Endocrine-Related Cancer

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Recent success in immunomodulating strategies in lung cancer and melanoma has prompted much enthusiasm in their potential to treat other advanced solid malignancies. However, their applications have shown variable success and are even ineffective against some tumours. The efficiency of immunotherapies relies on an immunogenic tumour microenvironment. The current field of cancer immunology has focused on understanding the interaction of cancer and host immune cells to break the state of immune tolerance and explain how molecular patterns of cytokines and chemokines affect tumour progression. Here, we review our current knowledge of how inherent properties of tumours and their different tumour microenvironments affect therapeutic outcome. We also discuss insights into recent multimodal therapeutic approaches that target tumour immune evasion and suppression to restore anti-tumour immunity.

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Durvalumab With or Without Tremelimumab for Patients With Metastatic Pancreatic Ductal Adenocarcinoma

et al. 2019

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IMPORTANCE New therapeutic options for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) are needed. This study evaluated dual checkpoint combination therapy in patients with mPDAC. OBJECTIVE To evaluate the safety and efficacy of the anti-PD-L1 (programmed death-ligand 1) antibody using either durvalumab monotherapy or in combination with the anticytotoxic T-lymphocyte antigen 4 antibody using durvalumab plus tremelimumab therapy in patients with mPDAC. DESIGN, SETTING, AND PARTICIPANTS Part A of this multicenter, 2-part, phase 2 randomized clinical trial was a lead-in safety, open-label study with planned expansion to part B pending an efficacy signal from part A. Between November 26, 2015, and March 23, 2017, 65 patients with mPDAC who had previously received only 1 first-line fluorouracil-based or gemcitabine-based treatment were enrolled at 21 sites in 6 countries. Efficacy analysis included the intent-to-treat population; safety analysis included patients who received at least 1 dose of study treatment and for whom any postdose data were available. INTERVENTIONS Patients received durvalumab (1500 mg every 4 weeks) plus tremelimumab (75 mg every 4 weeks) combination therapy for 4 cycles followed by durvalumab therapy (1500 mg every 4 weeks) or durvalumab monotherapy (1500 mg every 4 weeks) for up to 12 months or until the onset of progressive disease or unacceptable toxic effects. MAIN OUTCOMES AND MEASURES Safety and efficacy were measured by objective response rate, which was used to determine study expansion to part B. The threshold for expansion was an objective response rate of 10% for either treatment arm. RESULTS Among 65 randomized patients, 34 (52%) were men and median age was 61 (95% CI, 37-81) years. Grade 3 or higher treatment-related adverse events occurred in 7 of 32 patients (22%) receiving combination therapy and in 2 of 32 patients (6%) receiving monotherapy; 1 patient randomized to the monotherapy arm did not receive treatment owing to worsened disease. Fatigue, diarrhea, and pruritus were the most common adverse events in both arms. Overall, 4 of 64 patients (6%) discontinued treatment owing to treatment-related adverse events. Objective response rate was 3.1% (95% CI, 0.08-16.22) for patients receiving combination therapy and 0% (95% CI, 0.00-10.58) for patients receiving monotherapy. Low patient numbers limited observation of the associations between treatment response and PD-L1 expression or microsatellite instability status. CONCLUSION AND RELEVANCE Treatment was well tolerated, and the efficacy of durvalumab plus tremelimumab therapy and durvalumab monotherapy reflected a population of patients with mPDAC who had poor prognoses and rapidly progressing disease. Patients were not enrolled in part B because the threshold for efficacy was not met in part A.

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PD ‐L1 blockade enhances response of pancreatic ductal adenocarcinoma to radiotherapy

Cited by 192 publications

References 58 publications

Radiation combined with macrophage depletion promotes adaptive immunity and potentiates checkpoint blockade

Radiation combined with macrophage depletion promotes adaptive immunity and potentiates checkpoint blockade

The role of the tumour microenvironment in immunotherapy

Durvalumab With or Without Tremelimumab for Patients With Metastatic Pancreatic Ductal Adenocarcinoma

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