PD-1 blockade enhances radio-immunotherapy efficacy in murine tumor models

Zhuang, Yuan; Li, Sihan; Pi, Jingbo; Xing, Yuhui; Li, Guang

doi:10.1007/s00432-018-2723-4

Cited by 11 publications

(8 citation statements)

References 36 publications

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“…The study of 46 patients with soft tissue sarcoma who received preoperative radiotherapy by Patel et al found that radiotherapy could enhance the expression of PDL-1 in tumor-associated macrophages [32]. Zhuang et al found that PD-1 inhibitor not only can enhance the curative effect of tumor in the radiation field, but also has a distant therapeutic effect on the tumor [33]. In addition to PD-I and PDL-1, commonly used immunoassays for cancer therapy include microsatellite instability (MSI) and tumor mutational burden (TMB).…”

Section: Discussionmentioning

confidence: 99%

Volumetric imaging parameters are significant for predicting the pathological complete response of preoperative concurrent chemoradiotherapy in local advanced rectal cancer

Wang

Yang

et al. 2019

Journal of Radiation Research

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Preoperative concurrent chemoradiotherapy (CCRT) as the standard treatment for locally advanced rectal cancer (LARC) has been widely used in clinic. Its efficiency influences the prognosis and the selection of subsequent treatment. The current criteria for evaluating the prognosis of patients with extremely sensitive preoperative CCRT include the clinical complete remission response (cCR) and pathological complete response (pCR), but those with cCR may not necessarily achieve pCR, and the pCR can be confirmed only after surgery. Some scholars believe that patients with pCR after CCRT can be categorized as ‘watch and wait’. Therefore, it is extremely important to find a way to predict the pCR status of patients before therapy. In this study, we examined the expression of stem cell markers and obtained direct and derivative volumetric imaging parameters before treatment. Subsequently, these factors and the general clinical data were adopted into a regression model, and the correlation between them and the pCR was analyzed. We found that the pCR of LARC was positively correlated with tumor compactness (TC), whereas it was negatively correlated with approximate tumor volume (ATV), real tumor volume (RTV), total surface area of the tumor (TSA) and tumor maximum longitudinal length (TML). In these meaningful predictors, the positive predictive values and the negative predictive values of TC were 74.73% and 94.61%, respectively. Compared with other possible predictors, TC is the most encouraging predictor of pCR. Our findings provide a way for clinicians to predict the sensitivity of preoperative CCRT and will help to select individualized treatment options for LARC patients.

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Section: Discussionmentioning

confidence: 99%

Volumetric imaging parameters are significant for predicting the pathological complete response of preoperative concurrent chemoradiotherapy in local advanced rectal cancer

Wang

Yang

et al. 2019

Journal of Radiation Research

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“…right quadriceps muscle C57Bl/6 mice +/+ Leg – 3.6 Gy/2x NHS-IL2 CR 80 to 100% 2 Upregulated expression of effector T cells (CD3, CD4, CD8, CD25) Schölch 21 2015 pancreatic adenocarcinoma cell lines: Panc-1 a+ BxPC3 Colorectal carcinoma cell lines HT29, HCT-116, and CT26 s.c. in the right flank BALB/c fg+ C57Bl/6 mice +/+ Flank – 10 Gy/5x Toll-like receptor 7/8 agonists CR: 50% 2 Upregulate antigen-presenting activity of dendritic cells + T cells Connolly 22 2016 Colon38, Glioma261, Line1 i.m. left leg C57BL/6 + BALB/cJ mice +/+ Leg – 15 Gy / 1x CCR2/CCR5 antagonist CR: 40% 2 Increase of circulating + intratumoral inflammatory monocytes, chemokines; promote migration of myeloid cells, upregulation of CCL2 and CCL5 transcripts Wu 23 2018 BNL-P2 HCC cells s.c. in the right flank Balb/c mice +/+ Flank – 10 Gy/1x adenoviral vector +,IL 12 CR: 40%; PR: 50% 2 expression of MHC class II + CD40, CD86 on tumor-infiltrating dendritic cells Zhuang 24 2018 Lewis lung carcinoma -cells s.c. in the right leg C57BL/6mice +/+ Leg – 8 Gy/1x CpG (intratumoral), Anti-PD-1 CR: 100% 2 …”

Section: Resultsmentioning

confidence: 99%

Immunotherapy as sensitizer for local radiotherapy

et al. 2020

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The purpose of this report was to systematically review the radiation enhancement factor (REF) effects of immunotherapy on radiotherapy (RT) to the local tumor in comparison with other traditional radiation sensitizers such as cisplatin. PubMed and Medline databases were searched until February 2019. Reports with abscopal effect in the results were excluded. Graphs of the selected papers were digitized using Plot Digitizer (Sourceforge.net) in order to calculate the tumor growth delay (TGD) caused by immunotherapy. To enable comparison between different studies,the TGD were used to define the REF between RT versus the RT/immunotherapy combination. Thirty-two preclinical papers, and nine clinical series were selected. Different mouse models were exposed to RT doses ranging from 1 to 10 fractions of 1.8 to 20 Gray (Gy) per fraction. Endpoints were heterogeneous, ranging from regression to complete local response. No randomized clinical studies were identified. The median preclinical REF effect of different immunotherapy was varying from 1.7 to 9.1. There was no relationship observed either with subclasses of immunotherapy orRT doses. In the clinical studies, RT doses ranged from 1 to 37 fractions of 1.8 to 24 Gy per fraction. Most clinical trials used ipilimumab and interleukin-2. Local control rate in the clinical series ranged from 66% to 100%. A strong REF of immunotherapy (1.7 to 9.1) was observed, this being higher than traditionally sensitizers such as cisplatin (1.1). This result implies that for the same RT dose, a higher local control was achieved with a combination of immunotherapy and RT in preclinical settings. This study therefore supports the use of combined RT and immunotherapy to improve local tumor control in clinical settings without exacerbation of toxicities.

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“…The activation of PD1/PD-L1 pathway leads to T cell tolerance, exhaustion and apoptosis, and enhancement of immunosuppressive Treg cell function, by which tumors evade immune surveillance [7]. Since tumor-cell surface PD-L1 is upregulated by local high-dose radiotherapy, concomitant PD-1 inhibition was recommended in radio-immunotherapy [16, 17]. This therapy was found to be effective in murine models and some tumor case reports [17–20].…”

Section: Discussionmentioning

confidence: 99%

“…Since tumor-cell surface PD-L1 is upregulated by local high-dose radiotherapy, concomitant PD-1 inhibition was recommended in radio-immunotherapy [16, 17]. This therapy was found to be effective in murine models and some tumor case reports [17–20].…”

Section: Discussionmentioning

confidence: 99%

Analysis of Plasma EBV-DNA and Soluble Checkpoint Proteins in Nasopharyngeal Carcinoma Patients after Definitive Intensity-Modulated Radiotherapy

Ruan

et al. 2019

BioMed Research International

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Background. Tumor immunotherapy and immunological checkpoint-related proteins are research hotspots. Intensity-modulated radiotherapy (IMRT) is the main treatment for nasopharyngeal carcinoma (NPC). Hence, the evaluation of its effect is very important. The aim of this study was to assess the relationship between the concentrations of soluble checkpoint proteins, plasma EBV-DNA, and cytokines in NPC patients treated with IMRT. Methods. In this study, the plasma samples of 37 NPC patients and 40 healthy controls were collected. Luminex MAGPIX was used to detect the concentrations of 32 plasma targets, including soluble programmed cell death 1 (sPD-1). RT-qPCR was used to measure EBV-DNA. Results. The concentrations of 33 plasma targets were detected in NPC patients before and after IMRT to explore the changes after IMRT. The results showed that IMRT could increase the expression of sPD-1 and significantly reduce the level of EBV-DNA in the plasma of NPC patients. The expression level of sPD-1 in TNM I/II patients was significantly higher than that in III/IV patients. Besides, the concentrations of 12 other targets were significantly different after IMRT, including LAG-3, PD-L1, TIM-3, IFN-γ, IL-12p70, IL-1β, IL-5, IL-6, TNF-α, IL-10, IL-17A, and IL-22. High sPD-1 patients had longer survival than those with low sPD-1. Also, patients with lower EBV-DNA and TNM grades I and II/III had longer survival than those with higher EBV-DNA or TNM IV. Conclusions. This study demonstrated that the concentration of sPD-1 was significantly increased and EBV-DNA was significantly reduced in the NPC patients after IMRT. Plasma EBV-DNA level was a highly specific and sensitive biomarker for NPC diagnosis. Both sPD-1 expression and EBV-DNA concentration in plasma were related to the survival of patients.

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PD-1 blockade enhances radio-immunotherapy efficacy in murine tumor models

Abstract: These results suggest that this triple therapy promotes a local antitumor immune response with systemic consequences. The efficacy and limited toxicity of this strategy are attractive for clinical translation.

Cited by 11 publications

References 36 publications

Volumetric imaging parameters are significant for predicting the pathological complete response of preoperative concurrent chemoradiotherapy in local advanced rectal cancer

Volumetric imaging parameters are significant for predicting the pathological complete response of preoperative concurrent chemoradiotherapy in local advanced rectal cancer

Immunotherapy as sensitizer for local radiotherapy

Analysis of Plasma EBV-DNA and Soluble Checkpoint Proteins in Nasopharyngeal Carcinoma Patients after Definitive Intensity-Modulated Radiotherapy

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