Photothermal therapy with immune-adjuvant nanoparticles together with checkpoint blockade for effective cancer immunotherapy methods

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    "name": "Photothermal therapy with immune-adjuvant nanoparticles together with checkpoint blockade for effective cancer immunotherapy methods",
    "description": "Evidence-backed execution summary for Photothermal therapy with immune-adjuvant nanoparticles together with checkpoint blockade for effective cancer immunotherapy methods from Photothermal therapy with immune-adjuvant nanoparticles together with checkpoint blockade for effective cancer immunotherapy.",
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        "position": 1,
        "name": "Photothermal tumour ablation for immune system activation",
        "text": "In our further in vivo experiment, BALB/c mice-bearing subcutaneous 4T1 tumours were intratumourally (i.t.) injected with PLGA-ICG or PLGA-ICG-R837 and then irradiated by an 808 nm laser at the power density of 0.5 W cm -2 for 10 min. As monitored by an infrared thermal camera (Fotric 225), the tumour temperature of mice injected with PLGA-ICG or PLGA-ICG-R837 under laser irradiation quickly rose to ∼60 °C, which was high enough to effectively ablate tumours ( ). To analyse the status of DCs in treated tumours after PTT, tumour cells were collected and co-stained with CD11c/propidium iodide for assessment by flow cytometry 4 h post-PTT treatment with PLGA-ICG-R837. After photothermal ablation of the tumour with PLGA-ICG-R837 nanoparticles, more DCs would be recruited into the initial tumour site, although DCs pre-existing in the tum..."
      },
      {
        "@type": "HowToStep",
        "position": 2,
        "name": "Photothermal tumour ablation for immune system activation",
        "text": "Cytokines secretion is also important in the process of immune responses. In a parallel experiment, sera of mice bearing either 4T1 tumours or CT26 tumours after different treatments were collected at 24, 72 and 168 h to analyse the changes of various cytokines including IL-6, TNF-α and IL-12p70. Similarly, although PLGA-ICG-R837 injection alone or PTT with PLGA-ICG was able to increase the secretion of pro-inflammatory cytokines, their secretions induced by PLGA-ICG-R837-based PTT were obviously higher and lasted longer, favourable for triggering anti-tumour immune response ( and ). The non significant increase of IL-4 secretion, an important indicator for humoral immunity, in those treated mice ( ), indicates that humoral immunity may play a less important role in this system. Considering the risk of high cytokine levels to induce possible harmful effects to normal organs..."
      },
      {
        "@type": "HowToStep",
        "position": 3,
        "name": "PTT plus CTLA4 blockade to inhibit growth of distant tumours",
        "text": "The majority of cancer deaths are caused by metastases, which if occurred can hardly be effectively treated by conventional therapies such as surgery, chemotherapy and radiotherapy. Therefore, we wondered if photothermal immunotherapy with our PLGA-ICG-R837 could provide any opportunity in treating metastatic cancer. Cytotoxic T lymphocyte-associate antigen-4 (CTLA-4) is a critical negative regulator of immune responses, and its blockade by antibodies (for example, anti-CTLA-4) to inhibit the activities of immune-suppressive Tregs has been approved by FDA as a cancer immunotherapy approach currently used in the clinic. Therefore, in our animal experiments, CTLA-4 blockade therapy was introduced, aiming at enhancing the anti-cancer therapeutic efficacy of 'tumour vaccines' that are in situ generated after PLGA-ICG-R837-based photothermal ablation of primary tumours."
      },
      {
        "@type": "HowToStep",
        "position": 4,
        "name": "PTT plus CTLA4 blockade to inhibit growth of distant tumours",
        "text": "The design of our animal experiment is shown in. Tumour cells including breast cancer (4T1) and colorectal cancer (CT26) were inoculated on the left flank of each mouse. A week later, a second tumour was inoculated on the right flank of the same mouse as an artificial mimic of metastasis. In the following day, the first tumours were eliminated by PLGA-ICG-R837-based photothermal therapy or surgery. Afterwards, mice were intravenously (i.v.) injected with anti-CTLA4 (clone 9H10) at doses of 10 µg per mouse three times on day 1, 4 and 7 (ref. ). The growth of secondary tumours in different groups was measured by a caliper every other day ( ). For mice with their primary tumours removed by surgery, the secondary tumours in both tumour model showed rather rapid growth, whose speed could only be slightly delayed if the mice were either s.c. injected with PLGA-ICG-R837, or i.v...."
      },
      {
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        "position": 5,
        "name": "PTT plus CTLA4 blockade to inhibit growth of distant tumours",
        "text": "In addition to the above subcutaneous tumour models, we further tested the efficacy of our method in the treatment of a more aggressive whole-body spreading tumour model. In this experiment, while the treatment plan was not changed, the second wave of tumour cells was induced by i.v. injection of 4T1 cells expressing firefly luciferase(fLuc-4T1) into mice before their primary tumours are eliminated either by surgery or PLGA-ICG-R837-based PTT ( ). In the following days, mice were i.v. injected with anti-CTLA-4 antibody as aforementioned (dose=20 µg per mouse for each time). Considering the much higher aggressiveness of the lung metastasis tumour model, the dose of anti-CTLA-4 antibody used here was doubled. In vivo bioluminescence imaging was conducted to track the spreading and growth of fLuc-4T1 cancer cells in different groups of mice. From bioluminescence imaging, it wa..."
      },
      {
        "@type": "HowToStep",
        "position": 6,
        "name": "PTT plus CTLA4 blockade to inhibit growth of distant tumours",
        "text": "To further evaluate the therapeutic outcomes of combined PLGA-ICG-R837-based PTT and anti-CTLA-4 therapy, mice after various treatments were closely monitored. We found 7 seven out of 10 mice receiving i.v. injection of 4T1 cells could survive for 70 days after PLGA-ICG-R837-based PTT plus anti-CTLA4 therapy ( ), in marked contrast to mice in the other five control groups which all died within 25-40 days. The survived seven mice in this last group behaved normally and were killed at day 70 for careful necropsy, which uncovered no noticeable metastatic tumours in these seven mice."
      },
      {
        "@type": "HowToStep",
        "position": 7,
        "name": "PTT plus CTLA4 blockade to inhibit growth of distant tumours",
        "text": "In addition to the metastatic tumour model induced artificially, an orthotopic murine breast cancer model with spontaneous metastasis was created and used to evaluate the therapeutic efficacy of our treatment strategy. As shown in, fLuc-4T1 tumour cells were inoculated into the breast pad of each mouse. Two weeks later, when spontaneous metastases of tumour cells should have occurred, the primary tumour on each mouse was eliminated by PLGA-ICG-R837-based photothermal therapy or surgery. Afterwards, anti-CTLA4 with the same dose was i.v. injected (dose=20 µg per mouse for each time). Then, the in vivo bioluminescence imaging was conducted to track the metastases of fLuc-4T1 tumour cells after different treatments. It was also found that mice after PTT based on PLGA-ICG-R837 together with CTLA-4 blockade therapy showed effective inhibition of cancer metastasis, in marked con..."
      },
      {
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        "position": 8,
        "name": "PTT plus CTLA4 blockade to inhibit growth of distant tumours",
        "text": "Besides CTLA-4, programmed death 1 (PD-1), as another important T-cell inhibitory receptor, and PD-L1, one of its ligands, play important roles in helping cancer cells to evade the immune attack. Blockade of PD-L1, sometimes in combination with CTLA-4 blockade, to enhance anti-tumour activity has been approved for cancer immunotherapy in the clinic. In our experiments, mice post spreading of 4T1 tumour cells (i.v. injection) with surgical removal of their primary tumours and treated with the combination of CTLA-4 and PD-L1 co-blockade, or even together with the treatment of PLGA-ICG-R837 but no laser irradiation, showed obvious cancer metastases as indicated by bioluminescence imaging ( ). Therefore, our current strategy by combining nano-adjuvant-based PTT with anti-CTLA-4 appears to be more effective than the clinically adopted PD-L1+CTLA-4 co-blockade therapy. However, when we com..."
      }
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        "@type": "HowToTool",
        "name": "Photothermal tumour ablation for immune system activation"
      },
      {
        "@type": "HowToTool",
        "name": "Photothermal tumour ablation for immune system activation"
      },
      {
        "@type": "HowToTool",
        "name": "Photothermal tumour ablation for immune system activation"
      },
      {
        "@type": "HowToTool",
        "name": "PTT plus CTLA4 blockade to inhibit growth of distant tumours"
      },
      {
        "@type": "HowToTool",
        "name": "Reformulated nanoparticles for systemic administration"
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      {
        "@type": "HowToTool",
        "name": "Reformulated nanoparticles for systemic administration"
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        "name": "Nanoparticle characterization"
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    "supply": [
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        "name": "Cytokine detection"
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        "@type": "HowToSupply",
        "name": "Photothermal tumour ablation for immune system activation"
      },
      {
        "@type": "HowToSupply",
        "name": "PTT plus CTLA4 blockade to inhibit growth of distant tumours"
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      {
        "@type": "HowToSupply",
        "name": "Long-term immune-memory effects"
      },
      {
        "@type": "HowToSupply",
        "name": "Long-term immune-memory effects"
      },
      {
        "@type": "HowToSupply",
        "name": "Reformulated nanoparticles for systemic administration"
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      {
        "@type": "HowToSupply",
        "name": "Methods"
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      {
        "@type": "HowToSupply",
        "name": "Synthesis of PLGA-ICG-R837 nanoparticles"
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    ],
    "isBasedOn": {
      "@type": "ScholarlyArticle",
      "headline": "Photothermal therapy with immune-adjuvant nanoparticles together with checkpoint blockade for effective cancer immunotherapy",
      "datePublished": "2016",
      "author": [
        {
          "@type": "Person",
          "name": "Qian Chen"
        },
        {
          "@type": "Person",
          "name": "Ligeng Xu"
        },
        {
          "@type": "Person",
          "name": "Chao Liang"
        },
        {
          "@type": "Person",
          "name": "Chao Wang"
        },
        {
          "@type": "Person",
          "name": "Rui Peng"
        },
        {
          "@type": "Person",
          "name": "Zhuang Liu"
        }
      ],
      "identifier": "10.1038/ncomms13193"
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