Immunogenic cancer cell death selectively induced by near infrared photoimmunotherapy initiates host tumor immunity.
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ABSTRACT:
SUBMITTER: Ogawa M
PROVIDER: S-EPMC5354669 | biostudies-literature | 2017 Feb
REPOSITORIES: biostudies-literature
Publications
Immunogenic cancer cell death selectively induced by near infrared photoimmunotherapy initiates host tumor immunity.
Ogawa Mikako M Tomita Yusuke Y Nakamura Yuko Y Lee Min-Jung MJ Lee Sunmin S Tomita Saori S Nagaya Tadanobu T Sato Kazuhide K Yamauchi Toyohiko T Iwai Hidenao H Kumar Abhishek A Haystead Timothy T Shroff Hari H Choyke Peter L PL Trepel Jane B JB Kobayashi Hisataka H
Oncotarget 20170201 6
Immunogenic cell death (ICD) is a form of cell death that activates an adaptive immune response against dead-cell-associated antigens. Cancer cells killed via ICD can elicit antitumor immunity. ICD is efficiently induced by near-infrared photo-immunotherapy (NIR-PIT) that selectively kills target-cells on which antibody-photoabsorber conjugates bind and are activated by NIR light exposure. Advanced live cell microscopies showed that NIR-PIT caused rapid and irreversible damage to the cell membra ...[more]
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Project description:Near-infrared photoimmunotherapy (NIR-PIT) is a highly selective cancer treatment that employs an antibody photoabsorber conjugate (APC) composed of a targeting monoclonal antibody (mAb) conjugated with a photoactivatable phthalocyanine-derivative dye. Once injected and allowed to bind to a tumor, the APC is activated by local near-infrared light which kills cancer cells and induces a strong immune response in the tumor microenvironment by unmasking of new tumor antigens emerging from damaged tumor cells. Due to its ability to incite an immune reaction, even in poorly immunogenic tumors, NIR-PIT has the potential to enhance immunogenicity in tumors especially after immune checkpoint inhibition. In this study, we employ a poorly immunogenic MOC2-luc syngeneic tumor model and evaluate the efficacy of cancer-targeting CD44-targeted NIR-PIT. Increased infiltration of CD8+ T cells observed after NIR-PIT suggested an enhanced immune environment. Next, we evaluated tumor progression and survival after the combination of CD44-targeted NIR-PIT and short-term administration of an anti-PD1 immune checkpoint inhibitor (ICI) to further activate CD8+ T cells. Additionally, in mice in which the tumors were eradicated by this combination therapy, a re-challenge with fresh MOC2-luc cells demonstrated failure of tumor implantation implying acquired long-term immunity against the cancer cells. Combination therapy decreased tumor progression and prolonged survival significantly. Therefore, we concluded that NIR-PIT was able to convert a minimally immunogenic tumor unresponsive to anti-PD-1 ICI into a highly immunogenic tumor responsive to anti-PD-1 ICI, and this therapy was capable of inducing long-term immunity against the treated cancer.
| S-EPMC7763141 | biostudies-literature
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| S-EPMC8559243 | biostudies-literature
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| S-EPMC6704485 | biostudies-literature
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Project description:Near-infrared photoimmunotherapy (NIR-PIT) is a recently developed hybrid cancer therapy that directly kills cancer cells as well as producing a therapeutic host immune response. Conventional immunotherapies, such as immune-activating cytokine therapy, checkpoint inhibition, engineered T cells and suppressor cell depletion, do not directly destroy cancer cells, but rely exclusively on activating the immune system. NIR-PIT selectively destroys cancer cells, leading to immunogenic cell death that initiates local immune reactions to released cancer antigens from dying cancer cells. These are characterized by rapid maturation of dendritic cells and priming of multi-clonal cancer-specific cytotoxic T cells that kill cells that escaped the initial direct effects of NIR-PIT. The NIR-PIT can be applied to a wide variety of cancers either as monotherapy or in combination with conventional immune therapies to further activate anti-cancer immunity. A global Phase 3 clinical trial (https://clinicaltrials.gov/ct2/show/NCT03769506) of NIR-PIT targeting the epidermal growth factor receptor (EGFR) in patients with recurrent head and neck cancer is underway, employing RM1929/ASP1929, a conjugate of anti-EGFR antibody (cetuximab) plus the photo-absorber IRDye700DX (IR700). NIR-PIT has been given fast-track recognition by regulators in the USA and Japan. A variety of imaging methods, including direct IR700 fluorescence imaging, can be used to monitor NIR-PIT. As experience with NIR-PIT grows, additional antibodies will be employed to target additional antigens on other cancers or to target immune-suppressor cells to enhance host immunity. NIR-PIT will be particularly important in patients with localized and locally advanced cancers and may help such patients avoid side-effects associated with surgery, radiation and chemotherapy.
| S-EPMC7771006 | biostudies-literature
Project description:Near-infrared photoimmunotherapy (NIR-PIT) induces immunogenic cell death but has mostly failed to induce durable antitumor responses in syngenic tumor mouse models. We hypothesized that adaptive immune resistance could be limiting durable responses after treatmemt with NIR-PIT. We investigated the effects of combining NIR-PIT targeting cell-surface CD44 and PD-1 blockade in multiple syngeneic tumor models. In two of three models, NIR-PIT monotherapy halted tumor growth, enhanced dendritic cell tumor infiltration, and induced de novo tumor antigen-specific T-cell responses absent at baseline. The addition of PD-1 blockade reversed adaptive immune resistance, resulting in both enhanced preexisting tumor antigen-specific T-cell responses and enhanced de novo T-cell responses induced by NIR-PIT. Enhanced immune responses correlated with shared tumor antigen expression, suggesting that antigenicity is a major determinant of response to combination NIR-PIT and PD-1 blockade. Combination treatment induced complete rejection of MC38 tumors treated with NIR-PIT, as well as untreated, distant tumors. Accordingly, tumor antigen-specific T-cell responses were measured in both treated and untreated tumors, validating the development of systemic antitumor immunity. Mice that cleared tumors resisted subsequent tumor challenge, indicating the presence of systemic immune memory. Cumulatively, these results demonstrate reversal of adaptive immune resistance following induction of innate and adaptive immunity by NIR-PIT, resulting in high rates of tumor rejection and/or significant tumor growth control in antigenic syngeneic models of cancer.
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Project description:BackgroundNear infrared (NIR) photoimmunotherapy (PIT) is a new type of cancer treatment based on a monoclonal antibody (mAb)-NIR phthalocyanine dye, (IR700) conjugate. In vitro cancer-specific cell death occurs during NIR light exposure in cells previously incubated with mAb-IR700 conjugates. However, documenting rapid cell death in vivo is more difficult.MethodsA luciferase-transfected breast cancer cell (epidermal growth factor receptor+, MDA-MB-468luc cells) was produced and used for both in vitro and in vivo experiments for monitoring the cell killing effect of PIT. After validation of cytotoxicity with NIR exposure up to 8 J/cm2in vitro, we employed an orthotopic breast cancer model of bilateral MDA-MB-468luc tumors in female athymic mice, which subsequently received a panitumumab-IR700 conjugate in vivo. One side was used as a control, while the other was treated with NIR light of dose ranging from 50 to 150 J/cm2. Bioluminescence imaging (BLI) was performed before and after PIT.ResultsDose-dependent cell killing and regrowth was successfully monitored by the BLI signal in vitro. Although tumor sizes were unchanged, BLI signals decreased by >95% immediately after PIT in vivo when light intensity was high (>100 J/cm2), however, in mice receiving lower intensity NIR (50 J/cm2), tumors recurred with gradually increasing BLI signal.ConclusionPIT induced massive cell death of targeted tumor cells immediately after exposure of NIR light that was demonstrated with BLI in vivo.
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Project description:Lung metastases are a leading cause of cancer related deaths; nonetheless current treatments are limited. Near infrared photoimmunotherapy (NIR-PIT) is a new cancer treatment that combines the specificity of intravenously injected antibodies that target tumors with the toxicity induced by photosensitizers activated by NIR-light. Herein, we demonstrate the efficacy of NIR-PIT in a mouse model of lung metastases. Experiments were conducted with a HER2, luciferase and GFP expressing cell line (3T3/HER2-luc-GFP). An antibody-photosensitizer conjugate (APC) consisting of trastuzumab and a phthalocyanine dye, IRDye700DX, was synthesized. In vitro NIR-PIT-induced cytotoxicity was light dose dependent. With 3D culture, repeated NIR-PIT could eradicate entire spheroids. In vivo anti-tumor effects of NIR-PIT included significant reductions in both tumor volume (p?=?0.0141 vs. APC) and bioluminescence image (BLI) (p?=?0.0086 vs. APC) in the flank model, and prolonged survival (p?<?0.0001). BLI demonstrated a significant reduction in lung metastases volume (p?=?0.0117 vs. APC). Multiple NIR-PIT doses significantly prolonged survival in the lung metastasis model (p?<?0.0001). These results suggested that NIR-PIT is a potential new therapy for the local control of lung metastases.
| S-EPMC4508660 | biostudies-literature
Project description:Near infrared photoimmunotherapy (NIR-PIT) is a new, highly-selective cancer theranostics that employs an antibody-photo absorber conjugate (APC). NIR-PIT has successfully treated preclinical tumor models with APCs and is now in the first-in-human phase 1 clinical trial for head and neck cancer patients against EGFR. CD20 is highly expressed in many B-cell lymphomas and is emerging as a molecular target for this disease. Here, we describe the use of the anti-CD20 monoclonal antibody (mAb), rituximab-IR700 APC for NIR-PIT of B-cell lymphoma in two CD20-expressing lymphoma mouse models. CD20 expressing B-cell lymphoma cell lines (Daudi and Ramos) were used in this study. Rituximab-IR700, rituximab conjugated with IRDye700DX, showed specific binding, and cell-specific killing only after exposure of NIR light to both cells in vitro. To evaluate effects of NIR-PIT in vivo, tumor-bearing mice were separated into 4 groups: (1) control; (2) APC i.v. only; (3) NIR light exposure only; (4) APC and NIR light (NIR-PIT). These were performed every week for up to 3 weeks. Rituximab-IR700 showed high tumor accumulation and high target-to-background ratio in vivo. Tumor growth was significantly inhibited by NIR-PIT in comparison with the other groups (p < 0.001 for both tumors), and survival was significantly prolonged in both tumors (p < 0.001 for Daudi tumors and p < 0.0001 for Ramos tumors vs other groups). More than half of tumors were cured with this single regimen of NIR-PIT. In conclusion, anti-CD20 rituximab-IR700 works as a highly effective APC for NIR-PIT against B-cell lymphoma.
| S-EPMC5067212 | biostudies-literature
Project description:Near-infrared photoimmunotherapy (NIR-PIT) is a new cancer phototherapy modality using an antibody conjugated to a photosensitizer, IRDye700DX. When the conjugate binds to the plasma membrane and is exposed to NIR light, NIR-PIT-treated cells undergo swelling, and target-selective necrotic/immunogenic cell death is induced. However, the cytotoxic mechanism of NIR-PIT has not been elucidated. In order to understand the mechanism, it is important to elucidate how the damage to the plasma membrane induced by NIR light irradiation changes over time. Thus, in the present study, we investigated the changes in plasma membrane permeability using ions and molecules of various sizes. Na+ flowed into cells immediately after NIR light irradiation, even when the function of transporters or channels was blocked. Subsequently, fluorescent molecules larger than Na+ entered the cells, but the damage was not large enough for dextran to pass through at early time points. To assess these phenomena quantitatively, membrane permeability was estimated using radiolabeled ions and molecules: 111 InCl3 , 111 In-DTPA, and 3 H-H2 O, and comparable results were obtained. Although minute plasma membrane perforations usually do not induce cell death, our results suggest that the minute damage induced by NIR-PIT was irreversibly extended with time. In conclusion, minute plasma membrane damage is a trigger for the increase in plasma membrane permeability, cell swelling, and necrotic/immunogenic cell death in NIR-PIT. Our findings provide new insight into the cytotoxic mechanism of NIR-PIT.
| S-EPMC6125438 | biostudies-literature