Faculty Opinions recommendation of Lymphocytes genetically modified to express tumor antigens target DCs in vivo and induce antitumor immunity.

2525 Background: Genetically-modified-lymphocytes (GML) can induce a specific immune response against the transgene product (HSV-TK), when injected into immunocompetent patients (Science 276:1719, 1997). In tumor-bearing mice the infusion of tumor-associated-antigen (TAA)-transduced lymphocytes induced protective immunity and long-term memory. In this experimental setting, the T-cell effectors were generated by a cross-presentation pathway, mediated by host dendritic cells (DCs). Indeed, DCs isolated from lymph nodes of treated mice contained fragments of labeled GML and were able to elicit antigen-specific responses ex vivo. Methods: To validate this novel vaccination strategy in humans, we treated 10 patients affected by stage IIIc/IV MAGE-A3+ melanomas with escalating doses of autologous GML expressing MAGE-A3 and the tracer antigen HSV-TK. HSV-TK allows to monitor the immune status of the patients. Immune responses were monitored by DTH and in vitro T cell assays (semi-quantitative recall assays and ELISPOT). Tumor status was monitored by conventional imaging analyses. Results: No toxicity was reported. From the 10 patients, 9 were clinically evaluable because responding to the tracer antigen HSV-TK. We observed one complete response with vitiligo surrounding the lesions and one long lasting stable disease (50 mo). Moreover, one patient with no evidence of disease remained free of disease at >48 mo. The 3 responding patients experienced both DTH reactivity to MAGE-A3 and sustained increase of circulating CD8+ and CD4+ MAGE-A3-specific effectors. The immune response was long lasting since MAGE-A3-specific effectors were still detectable both in vivo and in vitro 1 year after the last vaccination. Conclusions: We describe a new method for in vivo loading of TAA on DCs that may circumvent the limitations of ex vivo manipulation of DCs. Genetically modified lymphocytes, acting as antigen carriers, efficiently target DCs in vivo in tumor-bearing mice and in melanoma patients, resulting in the generation of TAA-specific effectors that correlate with clinical benefit. [Table: see text]

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Faculty Opinions recommendation of In vivo tracking of T cells in humans unveils decade-long survival and activity of genetically modified T memory stem cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725338082.793510500 ◽

2015 ◽

Author(s):

Nina Drize

Keyword(s):

Stem Cells ◽

T Cells ◽

Genetically Modified ◽

Long Survival

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Targeting autophagy enhances atezolizumab-induced mitochondria-related apoptosis in osteosarcoma

Cell Death and Disease ◽

10.1038/s41419-021-03449-6 ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Zhuochao Liu ◽

Hongyi Wang ◽

Chuanzhen Hu ◽

Chuanlong Wu ◽

Jun Wang ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Antitumor Immunity ◽

Reactive Oxygen ◽

Oxygen Species ◽

Specific Monoclonal Antibody ◽

Osteosarcoma Cells ◽

Jnk Pathway ◽

In Vivo Experiments

AbstractIn this study, we identified the multifaceted effects of atezolizumab, a specific monoclonal antibody against PD-L1, in tumor suppression except for restoring antitumor immunity, and investigated the promising ways to improve its efficacy. Atezolizumab could inhibit the proliferation and induce immune-independent apoptosis of osteosarcoma cells. With further exploration, we found that atezolizumab could impair mitochondria of osteosarcoma cells, resulting in increased release of reactive oxygen species and cytochrome-c, eventually leading to mitochondrial-related apoptosis via activating JNK pathway. Nevertheless, the excessive release of reactive oxygen species also activated the protective autophagy of osteosarcoma cells. Therefore, when we combined atezolizumab with autophagy inhibitors, the cytotoxic effect of atezolizumab on osteosarcoma cells was significantly enhanced in vitro. Further in vivo experiments also confirmed that atezolizumab combined with chloroquine achieved the most significant antitumor effect. Taken together, our study indicates that atezolizumab can induce mitochondrial-related apoptosis and protective autophagy independently of the immune system, and targeting autophagy is a promising combinatorial approach to amplify its cytotoxicity.

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Administration of interleukin-12 and -18 enhancing the antitumor immunity of genetically modified dendritic cells that had been pulsed with Semliki Forest virus—mediated tumor complementary DNA

Journal of Neurosurgery ◽

10.3171/jns.2002.97.5.1184 ◽

2002 ◽

Vol 97 (5) ◽

pp. 1184-1190 ◽

Cited By ~ 17

Author(s):

Ryuya Yamanaka ◽

Naoki Yajima ◽

Naoto Tsuchiya ◽

Junpei Honma ◽

Ryuichi Tanaka ◽

...

Keyword(s):

Dendritic Cells ◽

Antitumor Immunity ◽

Semliki Forest Virus ◽

Malignant Gliomas ◽

Glioma Cells ◽

Antitumor Effects ◽

Content Type ◽

Immunogene Therapy ◽

Fine Print

Object. Immunogene therapy for malignant gliomas was further investigated in this study to improve its therapeutic efficacy. Methods. Dendritic cells (DCs) were isolated from bone marrow and pulsed with phosphate-buffered saline or Semliki Forest virus (SFV)—mediated 203 glioma complementary (c)DNA with or without systemic administration of interleukin (IL)-12 and IL-18 to treat mice bearing the 203 glioma. To study the immune mechanisms involved in tumor regression, the authors investigated tumor growth of an implanted 203 glioma model in T cell subset—depleted mice and in interferon (IFN) γ—neutralized mice. To examine the protective immunity produced by tumor inoculation, a repeated challenge of 203 glioma cells was given by injecting the cells into the left thighs of surviving mice and the growth of these cells was monitored. The authors demonstrated that the combined administration of SFV-cDNA, IL-12, and IL-18 produced significant antitumor effects against the growth of murine glioma cells in vivo and also can induce specific antitumor immunity. The synergic effects of the combination of SFV-cDNA, IL-12, and IL-18 in vivo were also observed to coincide with markedly augmented IFNγ production. The antitumor effects of this combined therapy are mediated by CD4+ and CD8+ T cells and by NK cells. These results indicate that the use of IL-18 and IL-12 in DC-based immunotherapy for malignant glioma is beneficial. Conclusions. Immunogene therapy combined with DC therapy, IL-12, and IL-18 may be an excellent candidate in the development of a new treatment protocol. The self-replicating SFV system may therefore provide a novel approach for the treatment of malignant gliomas.

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Visualizing Angiogenesis by Multiphoton Microscopy In Vivo in Genetically Modified 3D-PLGA/nHAp Scaffold for Calvarial Critical Bone Defect Repair

Journal of Visualized Experiments ◽

10.3791/55381 ◽

2017 ◽

Cited By ~ 2

Author(s):

Jian Li ◽

Holger Jahr ◽

Wei Zheng ◽

Pei-Gen Ren

Keyword(s):

Bone Defect ◽

Genetically Modified ◽

Multiphoton Microscopy ◽

Bone Defect Repair ◽

Defect Repair

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WDFY4 is required for cross-presentation in response to viral and tumor antigens

Science ◽

10.1126/science.aat5030 ◽

2018 ◽

Vol 362 (6415) ◽

pp. 694-699 ◽

Cited By ~ 69

Author(s):

Derek J. Theisen ◽

Jesse T. Davidson ◽

Carlos G. Briseño ◽

Marco Gargaro ◽

Elvin J. Lauron ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Tumor Antigens ◽

Critical Role ◽

Tumor Rejection ◽

Interleukin 12 ◽

Cross Presentation ◽

Histocompatibility Complex ◽

Crispr Screen

During the process of cross-presentation, viral or tumor-derived antigens are presented to CD8+ T cells by Batf3-dependent CD8α+/XCR1+ classical dendritic cells (cDC1s). We designed a functional CRISPR screen for previously unknown regulators of cross-presentation, and identified the BEACH domain–containing protein WDFY4 as essential for cross-presentation of cell-associated antigens by cDC1s in mice. However, WDFY4 was not required for major histocompatibility complex class II presentation, nor for cross-presentation by monocyte-derived dendritic cells. In contrast to Batf3–/– mice, Wdfy4–/– mice displayed normal lymphoid and nonlymphoid cDC1 populations that produce interleukin-12 and protect against Toxoplasma gondii infection. However, similar to Batf3–/– mice, Wdfy4–/– mice failed to prime virus-specific CD8+ T cells in vivo or induce tumor rejection, revealing a critical role for cross-presentation in antiviral and antitumor immunity.

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