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  1. Article ; Online: Blood-based biomarkers in patients with non-small cell lung cancer treated with immune checkpoint blockade.

    Tsai, Yo-Ting / Schlom, Jeffrey / Donahue, Renee N

    Journal of experimental & clinical cancer research : CR

    2024  Volume 43, Issue 1, Page(s) 82

    Abstract: The paradigm of non-small cell lung cancer (NSCLC) treatment has been profoundly influenced by the development of immune checkpoint inhibitors (ICI), but the range of clinical responses observed among patients poses significant challenges. To date, ... ...

    Abstract The paradigm of non-small cell lung cancer (NSCLC) treatment has been profoundly influenced by the development of immune checkpoint inhibitors (ICI), but the range of clinical responses observed among patients poses significant challenges. To date, analyses of tumor biopsies are the only parameter used to guide prognosis to ICI therapy. Tumor biopsies, however, are often difficult to obtain and tissue-based biomarkers are limited by intratumoral heterogeneity and temporal variability. In response, there has been a growing emphasis on the development of "liquid biopsy"‒ derived biomarkers, which offer a minimally invasive means to dynamically monitor the immune status of NSCLC patients either before and/or during the course of treatment. Here we review studies in which multiple blood-based biomarkers encompassing circulating soluble analytes, immune cell subsets, circulating tumor DNA, blood-based tumor mutational burden, and circulating tumor cells have shown promising associations with the clinical response of NSCLC patients to ICI therapy. These investigations have unveiled compelling correlations between the peripheral immune status of patients both before and during ICI therapy and patient outcomes, which include response rates, progression-free survival, and overall survival. There is need for rigorous validation and standardization of these blood-based assays for broader clinical application. Integration of multiple blood-based biomarkers into comprehensive panels or algorithms also has the potential to enhance predictive accuracy. Further research aimed at longitudinal monitoring of circulating biomarkers is also crucial to comprehend immune dynamics and resistance mechanisms and should be used alongside tissue-based methods that interrogate the tumor microenvironment to guide treatment decisions and may inform on the development of novel therapeutic strategies. The data reviewed here reinforce the opportunity to refine patient stratification, optimize treatments, and improve outcomes not only in NSCLC but also in the wider spectrum of solid tumors undergoing immunotherapy.
    MeSH term(s) Humans ; Carcinoma, Non-Small-Cell Lung/pathology ; Immune Checkpoint Inhibitors/pharmacology ; Immune Checkpoint Inhibitors/therapeutic use ; Lung Neoplasms/genetics ; Biomarkers, Tumor/genetics ; Prognosis ; Tumor Microenvironment
    Chemical Substances Immune Checkpoint Inhibitors ; Biomarkers, Tumor
    Language English
    Publishing date 2024-03-16
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 803138-1
    ISSN 1756-9966 ; 0392-9078
    ISSN (online) 1756-9966
    ISSN 0392-9078
    DOI 10.1186/s13046-024-02969-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Phosphoflow cytometry to assess cytokine signaling pathways in peripheral immune cells: potential for inferring immune cell function and treatment response in patients with solid tumors.

    Toney, Nicole J / Schlom, Jeffrey / Donahue, Renee N

    Journal of experimental & clinical cancer research : CR

    2023  Volume 42, Issue 1, Page(s) 247

    Abstract: Tumor biopsy is often not available or difficult to obtain in patients with solid tumors. Investigation of the peripheral immune system allows for in-depth and dynamic profiling of patient immune response prior to and over the course of treatment and ... ...

    Abstract Tumor biopsy is often not available or difficult to obtain in patients with solid tumors. Investigation of the peripheral immune system allows for in-depth and dynamic profiling of patient immune response prior to and over the course of treatment and disease. Phosphoflow cytometry is a flow cytometry‒based method to detect levels of phosphorylated proteins in single cells. This method can be applied to peripheral immune cells to determine responsiveness of signaling pathways in specific immune subsets to cytokine stimulation, improving on simply defining numbers of populations of cells based on cell surface markers. Here, we review studies using phosphoflow cytometry to (a) investigate signaling pathways in cancer patients' peripheral immune cells compared with healthy donors, (b) compare immune cell function in peripheral immune cells with the tumor microenvironment, (c) determine the effects of agents on the immune system, and (d) predict cancer patient response to treatment and outcome. In addition, we explore the use and potential of phosphoflow cytometry in preclinical cancer models. We believe this review is the first to provide a comprehensive summary of how phosphoflow cytometry can be applied in the field of cancer immunology, and demonstrates that this approach holds promise in exploring the mechanisms of response or resistance to immunotherapy both prior to and during the course of treatment. Additionally, it can help identify potential therapeutic avenues that can restore normal immune cell function and improve cancer patient outcome.
    MeSH term(s) Humans ; Immunotherapy ; Neoplasms/therapy ; Biopsy ; Cytokines ; Signal Transduction ; Tumor Microenvironment
    Chemical Substances Cytokines
    Language English
    Publishing date 2023-09-23
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 803138-1
    ISSN 1756-9966 ; 0392-9078
    ISSN (online) 1756-9966
    ISSN 0392-9078
    DOI 10.1186/s13046-023-02802-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Blockade of tumor-derived colony-stimulating factor 1 (CSF1) promotes an immune-permissive tumor microenvironment.

    Maldonado, Maria Del Mar / Schlom, Jeffrey / Hamilton, Duane H

    Cancer immunology, immunotherapy : CII

    2023  Volume 72, Issue 10, Page(s) 3349–3362

    Abstract: The macrophage colony-stimulating factor 1 (CSF1) is a chemokine essential for the survival, proliferation, and differentiation of mononuclear phagocytes from hemopoietic stem cells. In addition to its essential physiological role in normal tissues, the ... ...

    Abstract The macrophage colony-stimulating factor 1 (CSF1) is a chemokine essential for the survival, proliferation, and differentiation of mononuclear phagocytes from hemopoietic stem cells. In addition to its essential physiological role in normal tissues, the CSF1/CSF1 receptor axis is known to be overexpressed in many tumor types and associated with poor prognosis. High levels of CSF1 within the tumor microenvironment have been shown to recruit and reeducate macrophages to produce factors that promote tumor invasiveness and accelerate metastasis. In this study, we demonstrate, for the first time, that treating established syngeneic murine colon and breast carcinoma tumors with a CSF1R-blocking antibody also promotes the expansion of neoepitope-specific T cells. To assess the role of tumor-derived CSF1 in these model systems, we generated and characterized CSF1 CRISPR-Cas9 knockouts. Eliminating tumor-derived CSF1 results in decreased tumor growth and enhanced immunity against tumor-associated neoepitopes, potentially promoting an immune permissive tumor microenvironment in tumor-bearing mice. The combination of neoepitope vaccine with anti-PDL1 in the MC38 CSF1-/- tumor model significantly decreased tumor growth in vivo. Moreover, anti-CSF1R therapy combined with the adeno-TWIST1 vaccine resulted in tumor control, decreased metastasis, and a synergistic increase in CD8 T cell infiltration in 4T1 mammary tumors. Analysis of the tumor microenvironment demonstrated greater CD8 T cell infiltration and a reduction in tumor-associated macrophages following CSF1R inhibition in both tumor models. Our findings thus add to the therapeutic potential of CSF1 targeting agents by employing combinations with vaccines to modulate anti-neoepitope responses in the tumor microenvironment.
    MeSH term(s) Mice ; Animals ; Macrophage Colony-Stimulating Factor ; Tumor Microenvironment ; Macrophages ; Neoplasms
    Chemical Substances Macrophage Colony-Stimulating Factor (81627-83-0)
    Language English
    Publishing date 2023-07-28
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 195342-4
    ISSN 1432-0851 ; 0340-7004
    ISSN (online) 1432-0851
    ISSN 0340-7004
    DOI 10.1007/s00262-023-03496-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Preclinical and clinical studies of a tumor targeting IL-12 immunocytokine.

    Minnar, Christine M / Lui, Grace / Gulley, James L / Schlom, Jeffrey / Gameiro, Sofia R

    Frontiers in oncology

    2024  Volume 13, Page(s) 1321318

    Abstract: The clinical success of immune checkpoint inhibitors (ICIs) has demonstrated the promise and challenges of cancer immunotherapy. There is an unmet need to develop novel cancer therapies that can provide clinical benefit for most patients with solid ... ...

    Abstract The clinical success of immune checkpoint inhibitors (ICIs) has demonstrated the promise and challenges of cancer immunotherapy. There is an unmet need to develop novel cancer therapies that can provide clinical benefit for most patients with solid malignancies, which harbor innate or acquired resistance to ICIs. Interleukin-12 (IL-12) is a promising cytokine for cancer therapy given its direct stimulatory effects on innate and adaptive immunity. However, unfavorable pharmacokinetics and a narrow therapeutic index render recombinant IL-12 (rIL-12) less attractive as a cancer therapy. NHS-IL12 is a fusion protein of IL-12 and NHS76 (human IgG1) antibody engineered to target single and double stranded DNA present in necrotic areas solid tumors. In preclinical tumor models, NHS-IL12 elicited significant Th1 immune activation and tumor suppressive effects, primarily mediated by NK and CD8
    Language English
    Publishing date 2024-01-08
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2649216-7
    ISSN 2234-943X
    ISSN 2234-943X
    DOI 10.3389/fonc.2023.1321318
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Immunology of Lynch Syndrome.

    Pastor, Danielle M / Schlom, Jeffrey

    Current oncology reports

    2021  Volume 23, Issue 8, Page(s) 96

    Abstract: Purpose of review: Patients with Lynch syndrome have a high probability of developing colorectal and other carcinomas. This review provides a comprehensive assessment of the immunologic aspects of Lynch syndrome pathogenesis and provides an overview of ... ...

    Abstract Purpose of review: Patients with Lynch syndrome have a high probability of developing colorectal and other carcinomas. This review provides a comprehensive assessment of the immunologic aspects of Lynch syndrome pathogenesis and provides an overview of potential immune interventions for patients with Lynch syndrome polyps and Lynch syndrome-associated carcinomas.
    Recent findings: Immunogenic properties of the majority of Lynch syndrome polyps and associated cancers include microsatellite instability leading to a high mutational burden and the development of novel frameshift peptides, i.e., neoantigens. In addition, patients with Lynch syndrome develop T cell responses in the periphery and in the tumor microenvironment (TME) to tumor-associated antigens, and a proinflammatory cytokine TME has also been identified. However, Lynch syndrome lesions also possess immunosuppressive entities such as alterations in MHC class I antigen presentation, TGFβ receptor mutations, regulatory T cells, and upregulation of PD-L1 on tumor-associated lymphocytes. The rich immune microenvironment of Lynch syndrome polyps and associated carcinomas provides an opportunity to employ the spectrum of immune-mediating agents now available to induce and enhance host immune responses and/or to also reduce immunosuppressive entities. These agents can be employed in the so-called prevention trials for the treatment of patients with Lynch syndrome polyps and for trials in patients with Lynch syndrome-associated cancers.
    MeSH term(s) Antibodies/immunology ; Colorectal Neoplasms, Hereditary Nonpolyposis/immunology ; Humans ; Microsatellite Instability ; Microsatellite Repeats/immunology ; Tumor Microenvironment
    Chemical Substances Antibodies
    Language English
    Publishing date 2021-06-14
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Intramural ; Review
    ZDB-ID 2057359-5
    ISSN 1534-6269 ; 1523-3790
    ISSN (online) 1534-6269
    ISSN 1523-3790
    DOI 10.1007/s11912-021-01085-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: The Importance of Cellular Immunity in the Development of Vaccines and Therapeutics for COVID-19.

    Schlom, Jeffrey / Donahue, Renee N

    The Journal of infectious diseases

    2020  Volume 222, Issue 9, Page(s) 1435–1438

    Abstract: It is important to develop vaccines that can also mediate T-cell responses to SARS-CoV-2 to limit severity of infections, and to analyze the cellular immunome in the use of anti-SARS-CoV-2 therapeutics. ...

    Abstract It is important to develop vaccines that can also mediate T-cell responses to SARS-CoV-2 to limit severity of infections, and to analyze the cellular immunome in the use of anti-SARS-CoV-2 therapeutics.
    MeSH term(s) Aging/immunology ; Antigens, CD/blood ; Betacoronavirus/immunology ; COVID-19 ; COVID-19 Vaccines ; Coronavirus Infections/drug therapy ; Coronavirus Infections/immunology ; Coronavirus Infections/prevention & control ; Drug Development ; Flow Cytometry ; Humans ; Immunity, Cellular ; Leukocytes, Mononuclear/immunology ; Pandemics/prevention & control ; Pneumonia, Viral/drug therapy ; Pneumonia, Viral/immunology ; Pneumonia, Viral/prevention & control ; SARS-CoV-2 ; Viral Vaccines
    Chemical Substances Antigens, CD ; COVID-19 Vaccines ; Viral Vaccines
    Keywords covid19
    Language English
    Publishing date 2020-07-10
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Intramural
    ZDB-ID 3019-3
    ISSN 1537-6613 ; 0022-1899
    ISSN (online) 1537-6613
    ISSN 0022-1899
    DOI 10.1093/infdis/jiaa415
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Exploiting an Interleukin-15 Heterodimeric Agonist (N803) for Effective Immunotherapy of Solid Malignancies.

    Lui, Grace / Minnar, Christine M / Soon-Shiong, Patrick / Schlom, Jeffrey / Gameiro, Sofia R

    Cells

    2023  Volume 12, Issue 12

    Abstract: Identifying effective immunotherapies for solid tumors remains challenging despite the significant clinical responses observed in subsets of patients treated with immune checkpoint inhibitors. Interleukin-15 (IL-15) is a promising cytokine for the ... ...

    Abstract Identifying effective immunotherapies for solid tumors remains challenging despite the significant clinical responses observed in subsets of patients treated with immune checkpoint inhibitors. Interleukin-15 (IL-15) is a promising cytokine for the treatment of cancer as it stimulates NK and CD8
    MeSH term(s) Humans ; BCG Vaccine ; Interleukin-15 ; Nivolumab ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Immune Checkpoint Inhibitors ; Lung Neoplasms/drug therapy ; Urinary Bladder Neoplasms/pathology ; Mycobacterium bovis ; Immunotherapy
    Chemical Substances BCG Vaccine ; Interleukin-15 ; Nivolumab (31YO63LBSN) ; Immune Checkpoint Inhibitors
    Language English
    Publishing date 2023-06-12
    Publishing country Switzerland
    Document type Journal Article ; Review ; Research Support, N.I.H., Intramural
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells12121611
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Generation of murine tumor models refractory to αPD-1/-L1 therapies due to defects in antigen processing/presentation or IFNγ signaling using CRISPR/Cas9.

    Chariou, Paul L / Minnar, Christine M / Tandon, Mayank / Guest, Mary R / Chari, Raj / Schlom, Jeffrey / Gameiro, Sofia R

    PloS one

    2024  Volume 19, Issue 3, Page(s) e0287733

    Abstract: Immune checkpoint blockade (ICB) targeting the programmed cell death protein 1 (PD-1) and its ligand 1 (PD-L1) fails to provide clinical benefit for most cancer patients due to primary or acquired resistance. Drivers of ICB resistance include tumor ... ...

    Abstract Immune checkpoint blockade (ICB) targeting the programmed cell death protein 1 (PD-1) and its ligand 1 (PD-L1) fails to provide clinical benefit for most cancer patients due to primary or acquired resistance. Drivers of ICB resistance include tumor antigen processing/presentation machinery (APM) and IFNγ signaling mutations. Thus, there is an unmet clinical need to develop alternative therapies for these patients. To this end, we have developed a CRISPR/Cas9 approach to generate murine tumor models refractory to PD-1/-L1 inhibition due to APM/IFNγ signaling mutations. Guide RNAs were employed to delete B2m, Jak1, or Psmb9 genes in ICB-responsive EMT6 murine tumor cells. B2m was deleted in ICB-responsive MC38 murine colon cancer cells. We report a detailed development and validation workflow including whole exome and Sanger sequencing, western blotting, and flow cytometry to assess target gene deletion. Tumor response to ICB and immune effects of gene deletion were assessed in syngeneic mice. This workflow can help accelerate the discovery and development of alternative therapies and a deeper understanding of the immune consequences of tumor mutations, with potential clinical implications.
    MeSH term(s) Animals ; Mice ; Antigen Presentation ; B7-H1 Antigen ; Cell Line, Tumor ; CRISPR-Cas Systems/genetics ; Programmed Cell Death 1 Receptor/genetics ; RNA, Guide, CRISPR-Cas Systems ; Signal Transduction
    Chemical Substances B7-H1 Antigen ; Programmed Cell Death 1 Receptor ; RNA, Guide, CRISPR-Cas Systems
    Language English
    Publishing date 2024-03-01
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0287733
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article: NHS-IL12, a Tumor-Targeting Immunocytokine.

    Greiner, John W / Morillon, Y Maurice / Schlom, Jeffrey

    ImmunoTargets and therapy

    2021  Volume 10, Page(s) 155–169

    Abstract: NHS-IL12 is a novel immunocytokine designed for delivery of IL-12 to the tumor microenvironment (TME). NHS-IL12 consists of two molecules of IL-12 fused to a human IgG1 (NHS76) recognizing DNA/histone complexes, which are often exposed in the necrotic ... ...

    Abstract NHS-IL12 is a novel immunocytokine designed for delivery of IL-12 to the tumor microenvironment (TME). NHS-IL12 consists of two molecules of IL-12 fused to a human IgG1 (NHS76) recognizing DNA/histone complexes, which are often exposed in the necrotic portions of tumors. Preclinical studies demonstrated the tumor-targeting ability and longer plasma half-life for NHS-IL12 when compared with recombinant IL-12 (rIL-12). NHS-IL12 outperformed rIL-12 in enhancing the proliferation and activation of immune as well as antigen-presenting cells, resulting in a more robust primary immune response. NHS-IL12 also reduced the number and function of suppressive myeloid cells (myeloid derived suppressor cells/macrophages) within the TME. In a murine bladder tumor model, NHS-IL12 administration led to a coordinated increase in host immunity with a reduction of immunosuppressive myeloid cells in the TME resulting in substantial reduction in tumor growth. Several preclinical studies have demonstrated increased overall anti-tumor efficacy when NHS-IL12 was combined with either immune-based therapeutics or chemotherapeutic approaches.
    Language English
    Publishing date 2021-05-27
    Publishing country New Zealand
    Document type Journal Article ; Review
    ISSN 2253-1556
    ISSN 2253-1556
    DOI 10.2147/ITT.S306150
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Vaccines as an Integral Component of Cancer Immunotherapy.

    Schlom, Jeffrey / Gulley, James L

    JAMA

    2018  Volume 320, Issue 21, Page(s) 2195–2196

    MeSH term(s) Cancer Vaccines/therapeutic use ; Humans ; Immunotherapy ; Neoplasms/immunology ; Neoplasms/therapy
    Chemical Substances Cancer Vaccines
    Language English
    Publishing date 2018-11-12
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2958-0
    ISSN 1538-3598 ; 0254-9077 ; 0002-9955 ; 0098-7484
    ISSN (online) 1538-3598
    ISSN 0254-9077 ; 0002-9955 ; 0098-7484
    DOI 10.1001/jama.2018.9511
    Database MEDical Literature Analysis and Retrieval System OnLINE

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