43 results on '"check-point inhibitors"'
Search Results
2. Volumetric growth rate of incidentally found meningiomas on immunotherapy.
- Author
-
Berger, Assaf, Mullen, Reed, Bernstein, Kenneth, Mashiach, Elad, Meng, Ying, Silverman, Joshua S., Sulman, Erik P., Golfinos, John G., and Kondziolka, Douglas
- Abstract
Purpose: The expression of PD-L1 in high-grade meningiomas made it a potential target for immunotherapy research in refractory cases. Several prospective studies in this field are still on going. We sought to retrospectively investigate the effects of check-point inhibitors (CI) on meningiomas that had been naïve to either surgical or radiation approaches by following incidental meningiomas found during treatment with CI for various primary metastatic cancers. Methods: We used the NYU Perlmutter Cancer Center Data Hub to find patients treated by CI for various cancers, who also had serial computerized-tomography (CT) or magnetic-resonance imaging (MRI) reports of intracranial meningiomas. Meningioma volumetric measurements were compared between the beginning and end of the CI treatment period. Patients treated with chemotherapy during this period were excluded. Results: Twenty-five patients were included in our study, of which 14 (56%) were on CI for melanoma, 5 (20%) for non-small-cell lung cancer and others. CI therapies included nivolumab (n = 15, 60%), ipilimumab (n = 11, 44%) and pembrolizumab (n = 9, %36), while 9 (36%) were on ipilimumab/nivolumab combination. We did not find any significant difference between tumor volumes before and after treatment with CI (1.31 ± 0.46 vs. 1.34 ± 0.46, p=0.8, respectively). Among patients beyond 1 year of follow-up (n = 13), annual growth was 0.011 ± 0.011 cm
3 /year. Five patients showed minor volume reduction of 0.12 ± 0.10 cm3 (21 ± 6% from baseline). We did not find significant predictors of tumor volume reduction. Conclusion: Check-point inhibitors may impact the natural history of meningiomas. Additional research is needed to define potential clinical indications and treatment goals. [ABSTRACT FROM AUTHOR]- Published
- 2024
- Full Text
- View/download PDF
3. Rationale and design of a multicenter, randomized phase II trial of durvalumab with or without multitarget tyrosine kinase inhibitor as maintenance treatment in extensive‐stage small‐cell lung cancer patients (DURABLE study)
- Author
-
Bo Zhang, Hua Zhong, Chunlei Shi, Zhiqiang Gao, Runbo Zhong, Aiqin Gu, Weimin Wang, Tianqing Chu, Liwen Xiong, Wei Zhang, Huimin Wang, Xueyan Zhang, and Baohui Han
- Subjects
anti‐angiogenesis ,check‐point inhibitors ,ES‐SCLC ,maintenance treatment ,Diseases of the respiratory system ,RC705-779 - Abstract
Abstract Introduction Durvalumab is a check‐point inhibitor against programmed death ligand‐1 (PD‐L1), and anlotinib is a new orally administered multitarget tyrosine kinase inhibitor (TKI). Both agents have been approved in China. Preclinical and clinical trials have suggested that antiangiogenic therapy has the potential to alleviate immunosuppression and showed synergetic effect when combined with ICIs. However, it is unclear that whether this combination is effective when initiated as maintenance treatment in ES‐SCLC patients. Methods This is a multicenter, randomized, phase II study. A total of 64 eligible patients who do not experience disease progression after four cycles platinum‐based chemotherapy combined with durvalumab will be randomized to durvalumab with anlotinib or durvalumab alone until disease progression, withdrawal of consent, or unacceptable toxicity. The primary endpoint is PFS (from randomization); secondary endpoint was OS and PFS (from diagnosis), objective response rate (ORR); disease control rate (DCR) and duration of response (DOR), safety and tolerability assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Discussion We conduct a phase II study to investigate the safety and efficacy of durvalumab combined with anlotinib as maintenance treatment in ES‐SCLC patients.
- Published
- 2023
- Full Text
- View/download PDF
4. Rationale and design of a multicenter, randomized phase II trial of durvalumab with or without multitarget tyrosine kinase inhibitor as maintenance treatment in extensive‐stage small‐cell lung cancer patients (DURABLE study).
- Author
-
Zhang, Bo, Zhong, Hua, Shi, Chunlei, Gao, Zhiqiang, Zhong, Runbo, Gu, Aiqin, Wang, Weimin, Chu, Tianqing, Xiong, Liwen, Zhang, Wei, Wang, Huimin, Zhang, Xueyan, and Han, Baohui
- Subjects
- *
PROTEIN-tyrosine kinase inhibitors , *CANCER patients , *LUNG cancer , *DISEASE progression - Abstract
Introduction: Durvalumab is a check‐point inhibitor against programmed death ligand‐1 (PD‐L1), and anlotinib is a new orally administered multitarget tyrosine kinase inhibitor (TKI). Both agents have been approved in China. Preclinical and clinical trials have suggested that antiangiogenic therapy has the potential to alleviate immunosuppression and showed synergetic effect when combined with ICIs. However, it is unclear that whether this combination is effective when initiated as maintenance treatment in ES‐SCLC patients. Methods: This is a multicenter, randomized, phase II study. A total of 64 eligible patients who do not experience disease progression after four cycles platinum‐based chemotherapy combined with durvalumab will be randomized to durvalumab with anlotinib or durvalumab alone until disease progression, withdrawal of consent, or unacceptable toxicity. The primary endpoint is PFS (from randomization); secondary endpoint was OS and PFS (from diagnosis), objective response rate (ORR); disease control rate (DCR) and duration of response (DOR), safety and tolerability assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Discussion: We conduct a phase II study to investigate the safety and efficacy of durvalumab combined with anlotinib as maintenance treatment in ES‐SCLC patients. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
5. Case report: Heterogenous SMARCA4-deficient thoracic non-small cell lung carcinoma with various responses to nivolumab.
- Author
-
Yun-Tzu Lin, Chien-Feng Li, Hung-Chang Wu, Yi-Hua Jan, and Yu-Hsuan Kuo
- Subjects
NIVOLUMAB ,SMALL cell carcinoma ,IMMUNE checkpoint inhibitors ,CARCINOMA - Abstract
SMARCA4-deficient non-small cell carcinoma is an aggressive neoplasm with poor outcome. Several studies have highlighted its immunochemistry, pathophysiology, and underlying mechanisms, but studies of its definite treatment are few. Here, we report on a 69-year-old male with heterogenous pathological presentations of SMARCA4-deficient non-small cell carcinoma. He initially presented with neck lymphadenopathies. Immunohistochemistry staining and genomic profiling confirmed the diagnosis of SMARCA4-deficient non-small cell carcinoma. The patient responded well to immune checkpoint inhibitors with nivolumab. However, new lesions with various pathological presentations and various responses to nivolumab appeared during the treatment course. The patient survived more than 3 years from the initial diagnosis. This case shows the efficacy of nivolumab to treat SMARCA4-deficient non-small cell lung carcinoma. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
6. Impact of Epstein Barr Virus Infection on Treatment Opportunities in Patients with Nasopharyngeal Cancer.
- Author
-
Perri, Francesco, Sabbatino, Francesco, Ottaiano, Alessandro, Fusco, Roberta, Caraglia, Michele, Cascella, Marco, Longo, Francesco, Rega, Rosalia Anna, Salzano, Giovanni, Pontone, Monica, Marciano, Maria Luisa, Piccirillo, Arianna, Montano, Massimo, Fasano, Morena, Ciardiello, Fortunato, Della Vittoria Scarpati, Giuseppina, and Ionna, Franco
- Subjects
- *
NASOPHARYNX cancer , *IMMUNE checkpoint inhibitors , *CANCER patients , *CELL cycle , *TUMOR antigens , *EPSTEIN-Barr virus diseases , *IMMUNOTHERAPY , *HISTOCOMPATIBILITY antigens , *DISEASE complications - Abstract
Simple Summary: Epstein Barr virus (EBV) is often responsible for the onset of both solid and hematologic malignancies. In particular, it is implicated in the pathogenesis of nasopharyngeal carcinomas (NPCs). Some viral proteins produced during the latent phase of the virus itself in epithelial cells induce or promote carcinogenesis. These oncoproteins can be used as targets of various immunotherapy strategies. In the past, active or adoptive immunotherapy techniques have been employed. Recently however, the use of check-point inhibitors seems very promising. Some check-point inhibitors are already in use in clinical practice, others will soon receive regulatory approval. Chemical, physical, and infectious agents may induce carcinogenesis, and in the latter case, viruses are involved in most cases. The occurrence of virus-induced carcinogenesis is a complex process caused by an interaction across multiple genes, mainly depending by the type of the virus. Molecular mechanisms at the basis of viral carcinogenesis, mainly suggest the involvement of a dysregulation of the cell cycle. Among the virus-inducing carcinogenesis, Epstein Barr Virus (EBV) plays a major role in the development of both hematological and oncological malignancies and importantly, several lines of evidence demonstrated that nasopharyngeal carcinoma (NPC) is consistently associated with EBV infection. Cancerogenesis in NPC may be induced by the activation of different EBV "oncoproteins" which are produced during the so called "latency phase" of EBV in the host cells. Moreover, EBV presence in NPC does affect the tumor microenvironment (TME) leading to a strongly immunosuppressed status. Translational implications of the above-mentioned statements are that EBV-infected NPC cells can express proteins potentially recognized by immune cells in order to elicit a host immune response (tumor associated antigens). Three immunotherapeutic approaches have been implemented for the treatment of NPC including active, adoptive immunotherapy, and modulation of immune regulatory molecules by use of the so-called checkpoint inhibitors. In this review, we will highlight the role of EBV infection in NPC development and analyze its possible implications on therapy strategies. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
7. Impact of Epstein Barr Virus Infection on Treatment Opportunities in Patients with Nasopharyngeal Cancer
- Author
-
Francesco Perri, Francesco Sabbatino, Alessandro Ottaiano, Roberta Fusco, Michele Caraglia, Marco Cascella, Francesco Longo, Rosalia Anna Rega, Giovanni Salzano, Monica Pontone, Maria Luisa Marciano, Arianna Piccirillo, Massimo Montano, Morena Fasano, Fortunato Ciardiello, Giuseppina Della Vittoria Scarpati, and Franco Ionna
- Subjects
Epstein Barr Virus ,nasopharyngeal carcinoma ,tumor associated antigens ,immunotherapy ,tumor microenvironment ,check-point inhibitors ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Chemical, physical, and infectious agents may induce carcinogenesis, and in the latter case, viruses are involved in most cases. The occurrence of virus-induced carcinogenesis is a complex process caused by an interaction across multiple genes, mainly depending by the type of the virus. Molecular mechanisms at the basis of viral carcinogenesis, mainly suggest the involvement of a dysregulation of the cell cycle. Among the virus-inducing carcinogenesis, Epstein Barr Virus (EBV) plays a major role in the development of both hematological and oncological malignancies and importantly, several lines of evidence demonstrated that nasopharyngeal carcinoma (NPC) is consistently associated with EBV infection. Cancerogenesis in NPC may be induced by the activation of different EBV “oncoproteins” which are produced during the so called “latency phase” of EBV in the host cells. Moreover, EBV presence in NPC does affect the tumor microenvironment (TME) leading to a strongly immunosuppressed status. Translational implications of the above-mentioned statements are that EBV-infected NPC cells can express proteins potentially recognized by immune cells in order to elicit a host immune response (tumor associated antigens). Three immunotherapeutic approaches have been implemented for the treatment of NPC including active, adoptive immunotherapy, and modulation of immune regulatory molecules by use of the so-called checkpoint inhibitors. In this review, we will highlight the role of EBV infection in NPC development and analyze its possible implications on therapy strategies.
- Published
- 2023
- Full Text
- View/download PDF
8. Přístup k nádorům močového měchýře v roce 2021.
- Author
-
Svoboda, Tomáš
- Abstract
Radical cystectomy with pelvic lymphadenectomy is the basic curative treatment for patients with advanced urothelial urinary bladder carcinoma, same as transurethral resection in non‑invasive laesions. Oncological treatment in the form of platinum‑based neoadjuvant chemotherapy is associated with a high number of treatment responses, complete remision incl. and with an overall survival improvement, moreover, there is higher probability of bladder sparing surgery. Radiation therapy also belongs continuously to the treatment armamentarium and modern immunotherapy with check‑point inhibitors plays even more important role today, too. [ABSTRACT FROM AUTHOR]
- Published
- 2021
9. PD-L1 amplification is associated with an immune cell rich phenotype in squamous cell cancer of the lung.
- Author
-
Goldmann, Torsten, Marwitz, Sebastian, Nitschkowski, Dörte, Krupar, Rosemarie, Backman, Max, Elfving, Hedvig, Thurfjell, Viktoria, Lindberg, Amanda, Brunnström, Hans, La Fleur, Linnea, Mezheyeuski, Artur, Mattsson, Johanna Sofia Margareta, Botling, Johan, Micke, Patrick, and Strell, Carina
- Subjects
- *
SQUAMOUS cell carcinoma , *PROGRAMMED death-ligand 1 , *PHENOTYPES , *NON-small-cell lung carcinoma , *BIOMARKERS , *IPILIMUMAB - Abstract
Gene amplification is considered to be one responsible cause for upregulation of Programmed Death Ligand-1 (PD-L1) in non-small cell lung cancer (NSCLC) and to represent a specific molecular subgroup possibly associated with immunotherapy response. Our aim was to analyze the frequency of PD-L1 amplification, its relation to PD-L1 mRNA and protein expression, and to characterize the immune microenvironment of amplified cases. The study was based on two independent NSCLC cohorts, including 354 and 349 cases, respectively. Tissue microarrays were used to evaluate PD-L1 amplification by FISH and PD-L1 protein by immunohistochemistry. Immune infiltrates were characterized immunohistochemically by a panel of immune markers (CD3, CD4, CD8, PD-1, Foxp3, CD20, CD138, CD168, CD45RO, NKp46). Mutational status was determined by targeted sequencing. RNAseq data was available for 197 patients. PD-L1 amplification was detected in 4.5% of all evaluable cases. PD-L1 amplification correlated only weakly with mRNA and protein expression. About 37% of amplified cases were negative for PD-L1 protein. PD-L1 amplification did not show any association with the mutational status. In squamous cell cancer, PD-L1 amplified cases were enriched among patients with high tumoral immune cell infiltration and showed gene expression profiles related to immune exhaustion. In conclusion, PD-L1 amplification correlates with PD-L1 expression in squamous cell cancer and was associated with an immune cell rich tumor phenotype. The correlative findings help to understand the role of PD-L1 amplification as an important immune escape mechanism in NSCLC and suggest the need to further evaluate PD-L1 amplification as predictive biomarker for checkpoint inhibitor therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
10. PD1/PDL1 inhibitors for the treatment of advanced urothelial bladder cancer
- Author
-
Stenehjem DD, Tran D, Nkrumah MA, and Gupta S
- Subjects
Pembrolizumab ,check-point inhibitors ,urothelial cancer ,tumor mutational burden ,bladder cancer ,immunotherapy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
David D Stenehjem,1,2 Dao Tran,1 Michael A Nkrumah,1 Shilpa Gupta2,3 1Department of Pharmacy Practice and Pharmaceutical Sciences, College of Pharmacy, University of Minnesota, 2Masonic Cancer Center, University of Minnesota, 3Division of Hematology, Oncology and Transplantation, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA Introduction: Until recently, systemic chemotherapy was the only option for treating bladder cancer and outcomes remained dismal. After a long gap of no progress for 40 years, immunotherapy with checkpoint inhibitors (PDL1 and PD1) has revolutionized the treatment paradigm of bladder cancer, with five approved agents to treat platinum-refractory bladder cancer since the first approval of atezolizumab in May 2016. Methods: This review summarizes the most recent data on approved checkpoint inhibitors currently used in management of advanced bladder cancer. Early- and late-phase trials of the five checkpoint inhibitors (pembrolizumab, nivolumab, atezolizumab, durvalumab, and avelumab) in advanced bladder cancer are reviewed in detail. This review also describes the potential application of PD1/PDL1 inhibitors in adjuvant and neoadjuvant settings and non-muscle-invasive bladder cancer, as well as with radiation in muscle-invasive bladder cancer treatment. The role of PDL1 and tumor-mutation burden and clinical considerations in choosing a particular immunotherapy are also discussed. Results: The approved checkpoint inhibitors (PD1 and PDL1 inhibitors) have similar efficacy and safety profiles in metastatic platinum-refractory bladder cancer, but they vary in dose and frequency and cost burden. However, only pembrolizumab has shown superiority over standard chemotherapy in a randomized Phase III setting so far. In addition, in the first-line setting for cisplatin-ineligible patients, both pembrolizumab and atezolizumab are US Food and Drug Administration-approved and well tolerated. There is a lack of consensus on the utility of testing for PDL1 as a predictive biomarker, as patients with no PDL1 expression also derive some clinical benefit. Tumor-mutation burden is another predictive biomarker, but needs further validation. Conclusion: Immunotherapy has offered a glimmer of hope to patients with bladder cancer. The current landscape is rapidly evolving, with novel immunotherapy-combination trials to improve outcomes further and evaluate predictive biomarkers to help identify patients most likely to benefit from such therapies. Keywords: pembrolizumab, checkpoint inhibitors, urothelial cancer, tumor-mutation burden, bladder cancer, immunotherapy
- Published
- 2018
11. The Role of TGF-β in Bone Metastases
- Author
-
Trupti Trivedi, Gabriel M. Pagnotti, Theresa A. Guise, and Khalid S. Mohammad
- Subjects
bone metastases ,transforming growth factor-β (TGF-β) ,programmed cell death ligand (PD-L1) ,immune cells ,TGF-β therapeutic targets ,check-point inhibitors ,Microbiology ,QR1-502 - Abstract
Complications associated with advanced cancer are a major clinical challenge and, if associated with bone metastases, worsen the prognosis and compromise the survival of the patients. Breast and prostate cancer cells exhibit a high propensity to metastasize to bone. The bone microenvironment is unique, providing fertile soil for cancer cell propagation, while mineralized bone matrices store potent growth factors and cytokines. Biologically active transforming growth factor β (TGF-β), one of the most abundant growth factors, is released following tumor-induced osteoclastic bone resorption. TGF-β promotes tumor cell secretion of factors that accelerate bone loss and fuel tumor cells to colonize. Thus, TGF-β is critical for driving the feed-forward vicious cycle of tumor growth in bone. Further, TGF-β promotes epithelial-mesenchymal transition (EMT), increasing cell invasiveness, angiogenesis, and metastatic progression. Emerging evidence shows TGF-β suppresses immune responses, enabling opportunistic cancer cells to escape immune checkpoints and promote bone metastases. Blocking TGF-β signaling pathways could disrupt the vicious cycle, revert EMT, and enhance immune response. However, TGF-β’s dual role as both tumor suppressor and enhancer presents a significant challenge in developing therapeutics that target TGF-β signaling. This review presents TGF-β’s role in cancer progression and bone metastases, while highlighting current perspectives on the therapeutic potential of targeting TGF-β pathways.
- Published
- 2021
- Full Text
- View/download PDF
12. Immunotherapy in Small Cell Lung Cancer Treatment: a Promising Headway for Future Perspective
- Author
-
Walia, Harleen Kaur, Sharma, Parul, Singh, Navneet, and Sharma, Siddharth
- Published
- 2022
- Full Text
- View/download PDF
13. Immune Check-Point Inhibitors and Standard Chemoradiotherapy in Definitive Head and Neck Cancer Treatment
- Author
-
Francesca De Felice, Daniela Musio, and Vincenzo Tombolini
- Subjects
immunotherapy ,check-point inhibitors ,head neck cancer ,chemoradiotherapy ,HPV ,definitive treatment ,Medicine - Abstract
In head and neck cancer management, there is a need for tailored approaches to optimally implement clinical outcomes. Based on the assumption that efficacy and long-term toxicity are not satisfactory for standard concurrent platinum-based chemoradiotherapy, several trials have been designed to test whether induction immunotherapy and/or concomitant immunotherapy and radiotherapy result in improved survival and toxicity outcomes. Here, we present an overview of the most recent concomitant therapeutic strategies for head and neck cancer, focusing on the knowledge available regarding check-point inhibitors. The aim is to present the characteristics of the main check-point inhibitors and to summarize the clinical trials on the combination of immune check-point inhibitors and (chemo)radiotherapy in the definitive HNC setting, in order to provide a useful clinical tool for further research.
- Published
- 2021
- Full Text
- View/download PDF
14. Germinal immunogenetics as a predictive factor for immunotherapy.
- Author
-
Refae, Sadal, Gal, Jocelyn, Brest, Patrick, and Milano, Gerard
- Subjects
- *
IMMUNOGENETICS , *NANOTECHNOLOGY , *THERAPEUTICS , *IMMUNOTHERAPY , *TUMOR microenvironment - Abstract
Clinical response to checkpoint inhibitors-based (CPIs) therapies can vary among tumor types and between patients according to several factors. Entering host-related parameters (germinal immunogenetics) into the biomarker panel of CPI should provide a valuable strategy for identifying not only factors predictive of treatment efficacy but also of treatment-related toxicity. A major issue concerns the real functional significance of the reported single-nucleotide polymorphisms (SNPs) linked to CPI-treatment outcome. • Most predictors for CPI treatment are centered on tumor and its microenvironment. • The part of the host among predictors for CPI is largely underestimated. • Germinal immunogenetics aim to examine the impact of individual gene polymorphisms on CPI use. Clinical response to checkpoint inhibitors-based (CPIs) therapies can vary among tumor types and between patients. This led to a significant amount of pre-clinical and clinical research into biomarker identification. Biomarkers have been found to cover both the tumor itself and the tumor microenvironment. Entering host-related parameters into the equation should provide a valuable strategy for identifying not only factors predictive of treatment efficacy but also of treatment-related toxicity. It is clear that germline variants can offer efficient and easily-assessable indicators (blood DNA) to enlarge the spectrum of predictive markers for CPI-based treatment. A major issue concerns the real functional significance of the reported single-nucleotide polymorphisms (SNPs) linked to CPI-treatment outcome. Powered calculations should lead to an optimal trade-off between sample size and allele frequency. New molecular technologies and new analytical methods should provide opportunities to bridge the knowledge gap between SNP-CPI treatment associations and the functional impact of these SNPs. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
15. Checkpoint Inhibitors and Engineered Cells: New Weapons for Natural Killer Cell Arsenal Against Hematological Malignancies
- Author
-
Massimo Giuliani and Alessandro Poggi
- Subjects
NK cells ,hematological malignancies ,check-point inhibitors ,CAR NK cells ,antibodies ,immunotherapy ,Cytology ,QH573-671 - Abstract
Natural killer (NK) cells represent one of the first lines of defense against malignant cells. NK cell activation and recognition are regulated by a balance between activating and inhibitory receptors, whose specific ligands can be upregulated on tumor cells surface and tumor microenvironment (TME). Hematological malignancies set up an extensive network of suppressive factors with the purpose to induce NK cell dysfunction and impaired immune-surveillance ability. Over the years, several strategies have been developed to enhance NK cells-mediated anti-tumor killing, while other approaches have arisen to restore the NK cell recognition impaired by tumor cells and other cellular components of the TME. In this review, we summarize and discuss the strategies applied in hematological malignancies to block the immune check-points and trigger NK cells anti-tumor effects through engineered chimeric antigen receptors.
- Published
- 2020
- Full Text
- View/download PDF
16. A Review of the Potential Role of Human Cytomegalovirus (HCMV) Infections in Breast Cancer Carcinogenesis and Abnormal Immunity
- Author
-
Jürgen Geisler, Joel Touma, Afsar Rahbar, Cecilia Söderberg-Nauclér, and Katja Vetvik
- Subjects
cancer ,breast cancer ,triple negative breast cancer ,human cytomegalovirus ,tumor associated macrophages ,t cells ,dendritic cells ,tumor immunology ,check-point inhibitors ,antiviral treatment ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Previously recognized classical human onco-viruses can regulate complex neoplastic events, and are estimated to play a role during carcinogenesis in 15−20% of cancer cases. Although the DNA and gene products of several viruses have been found in breast tumors, none of the classical onco-viruses have definitely been linked to the initiation of breast cancer. However, recent evidence shows that human cytomegalovirus (HCMV) gene products are found in >90% of tumors and metastases of breast cancers, and their increased expression can be correlated to a more aggressive breast cancer phenotype. Supporting the active role of HCMV in breast cancer, a specific HCMV strain, HCMV-DB, was recently shown to exert oncogenic transformational activity in breast epithelial cells in vitro, and to give rise to fast-growing, triple-negative breast tumors when injected into immune deficient mice. The same observation holds true for clinical studies implying increased HCMV protein expression in triple negative breast cancer biopsies. In addition to functionally being able to hijack tumor-promoting cellular events, HCMV is known to exhibit a wide range of immunosuppressive effects, which can have radical impact on the tumor microenvironment. HCMV infected cells can avoid recognition and elimination by the immune system by orchestrating polarization of immunosuppressive type II macrophages, preventing antigen presentation, by expressing T cell inhibitory molecules, and possibly, by the induction of regulatory T (Treg) cell responses. These actions would be especially deleterious for the antigenic activation and proliferation of tumor specific CD8+ cytotoxic T lymphocytes (CTLs), whose effector functions have recently been targeted by successful, experimental immunotherapy protocols. The recognition of alternative causes and drivers of breast cancer is a pivotal research topic for the development of diagnostics and novel, effective preventive and therapeutic strategies targeting both tumor cells and their microenvironments.
- Published
- 2019
- Full Text
- View/download PDF
17. Overview of Immune Checkpoint Inhibitors Therapy for Hepatocellular Carcinoma, and The ITA.LI.CA Cohort Derived Estimate of Amenability Rate to Immune Checkpoint Inhibitors in Clinical Practice
- Author
-
Edoardo G. Giannini, Andrea Aglitti, Mauro Borzio, Martina Gambato, Maria Guarino, Massimo Iavarone, Quirino Lai, Giovanni Battista Levi Sandri, Fabio Melandro, Filomena Morisco, Francesca Romana Ponziani, Maria Rendina, Francesco Paolo Russo, Rodolfo Sacco, Mauro Viganò, Alessandro Vitale, Franco Trevisani, and on behalf of the Associazione Italiana per lo Studio del Fegato (AISF) HCC Special Interest Group
- Subjects
check-point inhibitors ,liver disease ,immunotherapy ,outcome ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Despite progress in our understanding of the biology of hepatocellular carcinoma (HCC), this tumour remains difficult-to-cure for several reasons, starting from the particular disease environment where it arises—advanced chronic liver disease—to its heterogeneous clinical and biological behaviour. The advent, and good results, of immunotherapy for cancer called for the evaluation of its potential application also in HCC, where there is evidence of intra-hepatic immune response activation. Several studies advanced our knowledge of immune checkpoints expression in HCC, thus suggesting that immune checkpoint blockade may have a strong rationale even in the treatment of HCC. According to this background, initial studies with tremelimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, and nivolumab, a programmed cell death protein 1 (PD-1) antibody, showed promising results, and further studies exploring the effects of other immune checkpoint inhibitors, alone or with other drugs, are currently underway. However, we are still far from the identification of the correct setting, and sequence, where these drugs might be used in clinical practice, and their actual applicability in real-life is unknown. This review focuses on HCC immunobiology and on the potential of immune checkpoint blockade therapy for this tumour, with a critical evaluation of the available trials on immune checkpoint blocking antibodies treatment for HCC. Moreover, it assesses the potential applicability of immune checkpoint inhibitors in the real-life setting, by analysing a large, multicentre cohort of Italian patients with HCC.
- Published
- 2019
- Full Text
- View/download PDF
18. Cancer immunotherapy in patients with brain metastases.
- Author
-
Caponnetto, Salvatore, Draghi, Arianna, Borch, Troels Holz, Nuti, Marianna, Cortesi, Enrico, Svane, Inge Marie, and Donia, Marco
- Subjects
- *
CANCER immunotherapy , *BRAIN metastasis , *CANCER patients , *IPILIMUMAB , *PEMBROLIZUMAB - Abstract
The exclusion of “real-world” patients from registration clinical trials of cancer immunotherapy represents a significant emerging issue. For instance, a large fraction of cancer patients develops brain metastases during the course of the disease, but results from large prospective clinical trials investigating this considerable proportion of the cancer patient population are currently lacking. To provide a useful tool for the clinician in a “real-world” setting, we have reviewed the available literature regarding the safety and efficacy of immune check-point inhibitors in patients with cancer metastatic to the brain. Overall, these data provide encouraging evidence that these therapeutic agents can induce intracranial objective responses, particularly in patients with asymptomatic and previously untreated brain metastases. Larger prospective studies are needed to confirm these initial results. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
19. Survival of melanoma patients treated with targeted therapy and immunotherapy after systematic upfront control of brain metastases by radiosurgery.
- Author
-
Gaudy-Marqueste, C., Dussouil, A.S., Carron, R., Troin, L., Malissen, N., Loundou, A., Monestier, S., Mallet, S., Richard, M.A., Régis, J.M., and Grob, J.J.
- Subjects
- *
ANTINEOPLASTIC agents , *MELANOMA prognosis , *THERAPEUTIC use of monoclonal antibodies , *IPILIMUMAB , *PROTEIN kinase inhibitors , *TREATMENT effectiveness , *ANTIGENS , *CANCER patients , *BRAIN tumors , *IMMUNOTHERAPY , *MELANOMA , *METASTASIS , *MULTIVARIATE analysis , *RADIOSURGERY , *SURVIVAL analysis (Biometry) , *RETROSPECTIVE studies , *DESCRIPTIVE statistics , *PROGNOSIS , *THERAPEUTICS - Abstract
Background Targeted therapy (TT) and immunotherapies (ITs) have dramatically improved survival in metastatic melanoma (MM). However, their efficacy on brain metastasis (BM) remains limited and poorly documented. Patients and methods Retrospective cohort of consecutive MM patients (pts) with BMs, all systematically upfront treated by Gamma-Knife (GK) at first BM and retreated in case of new BMs, from 2010 to 2015 at the time when ipilimumab BRAF ± MEK inhibitors and anti-PD1 were introduced in practice. Survival after 1st GK (OS GK1 ) according to prognostic factors and treatment. Results Among 179 consecutive pts treated by GK, 109 received IT and/or TT after the 1st GK. Median OS GK1 was 10.95 months and 1- and 2-year survival rates were 49.5% and 27.4%, respectively, versus a median overall survival (OS) of 2.29 months ( p < .001) in those who did not receive IT or TT. In pts who initially had a single BM, median OS and 1- and 2-year survival rates were 14.46 months, 66.7% and 43.4%, respectively; in pts with 2–3 BMs: 8.85 months, 46.4% and 31%, respectively; in pts with >3 BMs: 7.25 months, 37.2% and 11.9%, respectively. Multivariate analysis for OS GK1 confirmed that IT and TT were significantly and highly protective. Best OS GK1 was observed in BRAF–wild-type pts receiving anti-PD1 or in BRAF-mutated pts receiving BRAF-inhibitors and anti-PD1 (12.26 and 14.82 months, respectively). Conclusion In real-life MM pts with BMs, a strategy aiming at controlling BM with GK together with TT and/or TT seems to achieve unprecedented survival rates. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
20. Atlantis exploration: predictive biomarkers to immunotherapy response
- Author
-
A. K. Nosov, N. F. Krotov, and M. V. Berkut
- Subjects
Oncology ,medicine.medical_specialty ,Urology ,medicine.medical_treatment ,03 medical and health sciences ,0302 clinical medicine ,pd-l1 ,Internal medicine ,PD-L1 ,medicine ,Radiology, Nuclear Medicine and imaging ,check-point inhibitors ,Immune gene ,030304 developmental biology ,0303 health sciences ,Bladder cancer ,biology ,business.industry ,Microsatellite instability ,Immunotherapy ,Precision medicine ,medicine.disease ,Clinical trial ,Nephrology ,030220 oncology & carcinogenesis ,biology.protein ,bladder cancer ,biomarker ,Medicine ,Biomarker (medicine) ,Surgery ,immunotherapy ,business - Abstract
The emergence and continuous development of immune checkpoint inhibitors (ICIs) therapy brings a revolution in cancer therapy history including urothelial carcinoma. Early accurate targeting and adequate treatment are critical to patient prognosis and overall survival. To overcome these limitations, two strategies are actively being pursued: identification of predictive biomarkers for clinical response to ICIs and multi-pronged combination therapies. Biomarkers might allow clinicians to practice a precision medicine approach in ICIs (biomarkerbased patient selection). The development of predictive biomarkers is needed to optimize patient benefit, minimize risk of toxicities, and guide combination approaches.The greatest focus in clinical trials and reviews has been on tumor-cell PD-L1 expression. Although PD-L1 positivity enriches for populations with clinical benefit, PD-L1 testing alone is insufficient for patient selection in most malignancies. In this review, we discuss the status of PD-L1 testing and explore emerging data on new biomarker strategies with tumor-infiltrating lymphocytes, mutational burden, immune gene signatures, microsatellite instability and molecular subtypes.
- Published
- 2021
21. PD-L1 amplification is associated with an immune cell rich phenotype in squamous cell cancer of the lung
- Abstract
Gene amplification is considered to be one responsible cause for upregulation of Programmed Death Ligand-1 (PD-L1) in non-small cell lung cancer (NSCLC) and to represent a specific molecular subgroup possibly associated with immunotherapy response. Our aim was to analyze the frequency of PD-L1 amplification, its relation to PD-L1 mRNA and protein expression, and to characterize the immune microenvironment of amplified cases. The study was based on two independent NSCLC cohorts, including 354 and 349 cases, respectively. Tissue microarrays were used to evaluate PD-L1 amplification by FISH and PD-L1 protein by immunohistochemistry. Immune infiltrates were characterized immunohistochemically by a panel of immune markers (CD3, CD4, CD8, PD-1, Foxp3, CD20, CD138, CD168, CD45RO, NKp46). Mutational status was determined by targeted sequencing. RNAseq data was available for 197 patients. PD-L1 amplification was detected in 4.5% of all evaluable cases. PD-L1 amplification correlated only weakly with mRNA and protein expression. About 37% of amplified cases were negative for PD-L1 protein. PD-L1 amplification did not show any association with the mutational status. In squamous cell cancer, PD-L1 amplified cases were enriched among patients with high tumoral immune cell infiltration and showed gene expression profiles related to immune exhaustion. In conclusion, PD-L1 amplification correlates with PD-L1 expression in squamous cell cancer and was associated with an immune cell rich tumor phenotype. The correlative findings help to understand the role of PD-L1 amplification as an important immune escape mechanism in NSCLC and suggest the need to further evaluate PD-L1 amplification as predictive biomarker for checkpoint inhibitor therapy.
- Published
- 2021
- Full Text
- View/download PDF
22. PD-L1 amplification is associated with an immune cell rich phenotype in squamous cell cancer of the lung
- Abstract
Gene amplification is considered to be one responsible cause for upregulation of Programmed Death Ligand-1 (PD-L1) in non-small cell lung cancer (NSCLC) and to represent a specific molecular subgroup possibly associated with immunotherapy response. Our aim was to analyze the frequency of PD-L1 amplification, its relation to PD-L1 mRNA and protein expression, and to characterize the immune microenvironment of amplified cases. The study was based on two independent NSCLC cohorts, including 354 and 349 cases, respectively. Tissue microarrays were used to evaluate PD-L1 amplification by FISH and PD-L1 protein by immunohistochemistry. Immune infiltrates were characterized immunohistochemically by a panel of immune markers (CD3, CD4, CD8, PD-1, Foxp3, CD20, CD138, CD168, CD45RO, NKp46). Mutational status was determined by targeted sequencing. RNAseq data was available for 197 patients. PD-L1 amplification was detected in 4.5% of all evaluable cases. PD-L1 amplification correlated only weakly with mRNA and protein expression. About 37% of amplified cases were negative for PD-L1 protein. PD-L1 amplification did not show any association with the mutational status. In squamous cell cancer, PD-L1 amplified cases were enriched among patients with high tumoral immune cell infiltration and showed gene expression profiles related to immune exhaustion. In conclusion, PD-L1 amplification correlates with PD-L1 expression in squamous cell cancer and was associated with an immune cell rich tumor phenotype. The correlative findings help to understand the role of PD-L1 amplification as an important immune escape mechanism in NSCLC and suggest the need to further evaluate PD-L1 amplification as predictive biomarker for checkpoint inhibitor therapy.
- Published
- 2021
- Full Text
- View/download PDF
23. PD-L1 amplification is associated with an immune cell rich phenotype in squamous cell cancer of the lung
- Abstract
Gene amplification is considered to be one responsible cause for upregulation of Programmed Death Ligand-1 (PD-L1) in non-small cell lung cancer (NSCLC) and to represent a specific molecular subgroup possibly associated with immunotherapy response. Our aim was to analyze the frequency of PD-L1 amplification, its relation to PD-L1 mRNA and protein expression, and to characterize the immune microenvironment of amplified cases. The study was based on two independent NSCLC cohorts, including 354 and 349 cases, respectively. Tissue microarrays were used to evaluate PD-L1 amplification by FISH and PD-L1 protein by immunohistochemistry. Immune infiltrates were characterized immunohistochemically by a panel of immune markers (CD3, CD4, CD8, PD-1, Foxp3, CD20, CD138, CD168, CD45RO, NKp46). Mutational status was determined by targeted sequencing. RNAseq data was available for 197 patients. PD-L1 amplification was detected in 4.5% of all evaluable cases. PD-L1 amplification correlated only weakly with mRNA and protein expression. About 37% of amplified cases were negative for PD-L1 protein. PD-L1 amplification did not show any association with the mutational status. In squamous cell cancer, PD-L1 amplified cases were enriched among patients with high tumoral immune cell infiltration and showed gene expression profiles related to immune exhaustion. In conclusion, PD-L1 amplification correlates with PD-L1 expression in squamous cell cancer and was associated with an immune cell rich tumor phenotype. The correlative findings help to understand the role of PD-L1 amplification as an important immune escape mechanism in NSCLC and suggest the need to further evaluate PD-L1 amplification as predictive biomarker for checkpoint inhibitor therapy.
- Published
- 2021
- Full Text
- View/download PDF
24. PD-L1 amplification is associated with an immune cell rich phenotype in squamous cell cancer of the lung
- Abstract
Gene amplification is considered to be one responsible cause for upregulation of Programmed Death Ligand-1 (PD-L1) in non-small cell lung cancer (NSCLC) and to represent a specific molecular subgroup possibly associated with immunotherapy response. Our aim was to analyze the frequency of PD-L1 amplification, its relation to PD-L1 mRNA and protein expression, and to characterize the immune microenvironment of amplified cases. The study was based on two independent NSCLC cohorts, including 354 and 349 cases, respectively. Tissue microarrays were used to evaluate PD-L1 amplification by FISH and PD-L1 protein by immunohistochemistry. Immune infiltrates were characterized immunohistochemically by a panel of immune markers (CD3, CD4, CD8, PD-1, Foxp3, CD20, CD138, CD168, CD45RO, NKp46). Mutational status was determined by targeted sequencing. RNAseq data was available for 197 patients. PD-L1 amplification was detected in 4.5% of all evaluable cases. PD-L1 amplification correlated only weakly with mRNA and protein expression. About 37% of amplified cases were negative for PD-L1 protein. PD-L1 amplification did not show any association with the mutational status. In squamous cell cancer, PD-L1 amplified cases were enriched among patients with high tumoral immune cell infiltration and showed gene expression profiles related to immune exhaustion. In conclusion, PD-L1 amplification correlates with PD-L1 expression in squamous cell cancer and was associated with an immune cell rich tumor phenotype. The correlative findings help to understand the role of PD-L1 amplification as an important immune escape mechanism in NSCLC and suggest the need to further evaluate PD-L1 amplification as predictive biomarker for checkpoint inhibitor therapy.
- Published
- 2021
- Full Text
- View/download PDF
25. PD-L1 amplification is associated with an immune cell rich phenotype in squamous cell cancer of the lung
- Abstract
Gene amplification is considered to be one responsible cause for upregulation of Programmed Death Ligand-1 (PD-L1) in non-small cell lung cancer (NSCLC) and to represent a specific molecular subgroup possibly associated with immunotherapy response. Our aim was to analyze the frequency of PD-L1 amplification, its relation to PD-L1 mRNA and protein expression, and to characterize the immune microenvironment of amplified cases. The study was based on two independent NSCLC cohorts, including 354 and 349 cases, respectively. Tissue microarrays were used to evaluate PD-L1 amplification by FISH and PD-L1 protein by immunohistochemistry. Immune infiltrates were characterized immunohistochemically by a panel of immune markers (CD3, CD4, CD8, PD-1, Foxp3, CD20, CD138, CD168, CD45RO, NKp46). Mutational status was determined by targeted sequencing. RNAseq data was available for 197 patients. PD-L1 amplification was detected in 4.5% of all evaluable cases. PD-L1 amplification correlated only weakly with mRNA and protein expression. About 37% of amplified cases were negative for PD-L1 protein. PD-L1 amplification did not show any association with the mutational status. In squamous cell cancer, PD-L1 amplified cases were enriched among patients with high tumoral immune cell infiltration and showed gene expression profiles related to immune exhaustion. In conclusion, PD-L1 amplification correlates with PD-L1 expression in squamous cell cancer and was associated with an immune cell rich tumor phenotype. The correlative findings help to understand the role of PD-L1 amplification as an important immune escape mechanism in NSCLC and suggest the need to further evaluate PD-L1 amplification as predictive biomarker for checkpoint inhibitor therapy.
- Published
- 2021
- Full Text
- View/download PDF
26. Case report: Heterogenous SMARCA4-deficient thoracic non-small cell lung carcinoma with various responses to nivolumab.
- Author
-
Lin YT, Li CF, Wu HC, Jan YH, and Kuo YH
- Subjects
- Male, Humans, Aged, Nivolumab therapeutic use, DNA Helicases genetics, Nuclear Proteins genetics, Transcription Factors genetics, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms diagnosis
- Abstract
SMARCA4-deficient non-small cell carcinoma is an aggressive neoplasm with poor outcome. Several studies have highlighted its immunochemistry, pathophysiology, and underlying mechanisms, but studies of its definite treatment are few. Here, we report on a 69-year-old male with heterogenous pathological presentations of SMARCA4-deficient non-small cell carcinoma. He initially presented with neck lymphadenopathies. Immunohistochemistry staining and genomic profiling confirmed the diagnosis of SMARCA4-deficient non-small cell carcinoma. The patient responded well to immune checkpoint inhibitors with nivolumab. However, new lesions with various pathological presentations and various responses to nivolumab appeared during the treatment course. The patient survived more than 3 years from the initial diagnosis. This case shows the efficacy of nivolumab to treat SMARCA4-deficient non-small cell lung carcinoma., Competing Interests: Author Y-HJ was employed by ACT Genomics Co. Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lin, Li, Wu, Jan and Kuo.)
- Published
- 2023
- Full Text
- View/download PDF
27. Emerging role of immune checkpoint inhibitors in the treatment of ovarian cancer
- Abstract
Introduction: In recent years, ovarian cancer (OC) treatment has been enriched with many new target therapies, most of all antiangiogenic drugs and PARP inhibitors (PARPis), which have literally changed the natural history of the disease. The impressive results of immunotherapy in other malignancies, mainly melanoma and lung cancer, and the good signals of activity in gynecological neoplasms like cervical and microsatellite instable (MSI-H) endometrial cancer, opened the space to the introduction of immune-stimulatory drugs in ovarian cancer. Area covered: The goal of this article is to summarize the newest evidence on the use of immune check point inhibitors in OC trying to explain why, at present, this strategy has failed to improve clinical outcome and focusing on the possible strategies to overcome treatment failure. Expert opinion: Although numerous trials have been undertaken, only scanty results have been obtained so far with immune check-point inhibitors (ICIs) in OC either when used as single agents or in combination with antiangiogenic therapy and ongoing trials are exploring the association of ICIs with PARPis and other ICIs. A better knowledge of predictive biomarkers of response and mechanisms of immunotherapy resistance, will help in identifying the most appropriate population to treat with ICIs.
- Published
- 2020
28. Emerging role of immune checkpoint inhibitors in the treatment of ovarian cancer
- Author
-
Giovanni Scambia, Gennaro Daniele, Antonella Pietragalla, Margherita Muratore, Valentina Ceni, Vanda Salutari, Camilla Nero, Francesca Ciccarone, Vittoria Carbone, and Domenica Lorusso
- Subjects
Check-point inhibitors ,medicine.medical_treatment ,Poly ADP ribose polymerase ,Immune checkpoint inhibitors ,Angiogenesis Inhibitors ,Poly(ADP-ribose) Polymerase Inhibitors ,030226 pharmacology & pharmacy ,03 medical and health sciences ,Mice ,0302 clinical medicine ,medicine ,Animals ,Humans ,Pharmacology (medical) ,Target therapy ,PARP inhibitors ,Immune Checkpoint Inhibitors ,Pharmacology ,Ovarian Neoplasms ,business.industry ,Immunotherapy ,medicine.disease ,ovarian cancer ,Settore MED/40 - GINECOLOGIA E OSTETRICIA ,030220 oncology & carcinogenesis ,Drug Design ,Cancer research ,Female ,sense organs ,Ovarian cancer ,business - Abstract
In recent years, ovarian cancer (OC) treatment has been enriched with many new target therapies, most of all antiangiogenic drugs and PARP inhibitors (PARPis), which have literally changed the natural history of the disease. The impressive results of immunotherapy in other malignancies, mainly melanoma and lung cancer, and the good signals of activity in gynecological neoplasms like cervical and microsatellite instable (MSI-H) endometrial cancer, opened the space to the introduction of immune-stimulatory drugs in ovarian cancer.The goal of this article is to summarize the newest evidence on the use of immune check point inhibitors in OC trying to explain why, at present, this strategy has failed to improve clinical outcome and focusing on the possible strategies to overcome treatment failure.Although numerous trials have been undertaken, only scanty results have been obtained so far with immune check-point inhibitors (ICIs) in OC either when used as single agents or in combination with antiangiogenic therapy and ongoing trials are exploring the association of ICIs with PARPis and other ICIs. A better knowledge of predictive biomarkers of response and mechanisms of immunotherapy resistance, will help in identifying the most appropriate population to treat with ICIs.
- Published
- 2020
29. PD-L1 amplification is associated with an immune cell rich phenotype in squamous cell cancer of the lung
- Author
-
Rosemarie Krupar, Sebastian Marwitz, Carina Strell, Hans Brunnström, Dörte Nitschkowski, Patrick Micke, Viktoria Thurfjell, Amanda Lindberg, Johanna Sofia Margareta Mattsson, Torsten Goldmann, Max Backman, Artur Mezheyeuski, Linnea La Fleur, Hedvig Elfving, and Johan Botling
- Subjects
0301 basic medicine ,Cancer Research ,Lung Neoplasms ,PD-L1 amplification ,medicine.medical_treatment ,Cell ,Gene Expression ,B7-H1 Antigen ,0302 clinical medicine ,Gene Frequency ,Tumor Microenvironment ,Immunology and Allergy ,In Situ Hybridization, Fluorescence ,Tissue microarray ,Clinical Laboratory Medicine ,FOXP3 ,Immunohistochemistry ,Klinisk laboratoriemedicin ,medicine.anatomical_structure ,Phenotype ,Oncology ,030220 oncology & carcinogenesis ,Carcinoma, Squamous Cell ,Original Article ,Immunotherapy ,Lung cancer ,Microenvironment ,Check-point inhibitors ,Immunology ,Biology ,Immunophenotyping ,03 medical and health sciences ,Immune system ,Lymphocytes, Tumor-Infiltrating ,PD-L1 ,medicine ,Biomarkers, Tumor ,Humans ,Cancer och onkologi ,Gene Amplification ,Computational Biology ,medicine.disease ,030104 developmental biology ,Tissue Array Analysis ,Cancer and Oncology ,Mutation ,Cancer research ,biology.protein ,CD8 - Abstract
Gene amplification is considered to be one responsible cause for upregulation of Programmed Death Ligand-1 (PD-L1) in non-small cell lung cancer (NSCLC) and to represent a specific molecular subgroup possibly associated with immunotherapy response. Our aim was to analyze the frequency of PD-L1 amplification, its relation to PD-L1 mRNA and protein expression, and to characterize the immune microenvironment of amplified cases. The study was based on two independent NSCLC cohorts, including 354 and 349 cases, respectively. Tissue microarrays were used to evaluate PD-L1 amplification by FISH and PD-L1 protein by immunohistochemistry. Immune infiltrates were characterized immunohistochemically by a panel of immune markers (CD3, CD4, CD8, PD-1, Foxp3, CD20, CD138, CD168, CD45RO, NKp46). Mutational status was determined by targeted sequencing. RNAseq data was available for 197 patients. PD-L1 amplification was detected in 4.5% of all evaluable cases. PD-L1 amplification correlated only weakly with mRNA and protein expression. About 37% of amplified cases were negative for PD-L1 protein. PD-L1 amplification did not show any association with the mutational status. In squamous cell cancer, PD-L1 amplified cases were enriched among patients with high tumoral immune cell infiltration and showed gene expression profiles related to immune exhaustion. In conclusion, PD-L1 amplification correlates with PD-L1 expression in squamous cell cancer and was associated with an immune cell rich tumor phenotype. The correlative findings help to understand the role of PD-L1 amplification as an important immune escape mechanism in NSCLC and suggest the need to further evaluate PD-L1 amplification as predictive biomarker for checkpoint inhibitor therapy. Supplementary Information The online version contains supplementary material available at 10.1007/s00262-020-02825-z.
- Published
- 2020
30. A Review of the Potential Role of Human Cytomegalovirus (HCMV) Infections in Breast Cancer Carcinogenesis and Abnormal Immunity
- Author
-
Joel Touma, Katja Vetvik, Jürgen Geisler, Afsar Rahbar, and Cecilia Söderberg-Nauclér
- Subjects
0301 basic medicine ,Human cytomegalovirus ,Cancer Research ,medicine.medical_treatment ,T cells ,antiviral treatment ,Review ,medicine.disease_cause ,lcsh:RC254-282 ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Breast cancer ,breast cancer ,medicine ,cancer ,dendritic cells ,tumor immunology ,check-point inhibitors ,Triple-negative breast cancer ,Tumor microenvironment ,business.industry ,tumor associated macrophages ,Cancer ,Immunotherapy ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,030104 developmental biology ,Oncology ,human cytomegalovirus ,030220 oncology & carcinogenesis ,triple negative breast cancer ,Cancer research ,business ,Carcinogenesis - Abstract
Previously recognized classical human onco-viruses can regulate complex neoplastic events, and are estimated to play a role during carcinogenesis in 15–20% of cancer cases. Although the DNA and gene products of several viruses have been found in breast tumors, none of the classical onco-viruses have definitely been linked to the initiation of breast cancer. However, recent evidence shows that human cytomegalovirus (HCMV) gene products are found in >90% of tumors and metastases of breast cancers, and their increased expression can be correlated to a more aggressive breast cancer phenotype. Supporting the active role of HCMV in breast cancer, a specific HCMV strain, HCMV-DB, was recently shown to exert oncogenic transformational activity in breast epithelial cells in vitro, and to give rise to fast-growing, triple-negative breast tumors when injected into immune deficient mice. The same observation holds true for clinical studies implying increased HCMV protein expression in triple negative breast cancer biopsies. In addition to functionally being able to hijack tumor-promoting cellular events, HCMV is known to exhibit a wide range of immunosuppressive effects, which can have radical impact on the tumor microenvironment. HCMV infected cells can avoid recognition and elimination by the immune system by orchestrating polarization of immunosuppressive type II macrophages, preventing antigen presentation, by expressing T cell inhibitory molecules, and possibly, by the induction of regulatory T (Treg) cell responses. These actions would be especially deleterious for the antigenic activation and proliferation of tumor specific CD8+ cytotoxic T lymphocytes (CTLs), whose effector functions have recently been targeted by successful, experimental immunotherapy protocols. The recognition of alternative causes and drivers of breast cancer is a pivotal research topic for the development of diagnostics and novel, effective preventive and therapeutic strategies targeting both tumor cells and their microenvironments.
- Published
- 2019
31. Cancer immunotherapy in patients with brain metastases
- Author
-
Marco Donia, Salvatore Caponnetto, Inge Marie Svane, Marianna Nuti, Troels Holz Borch, Enrico Cortesi, and Arianna Draghi
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Immunology ,monoclonal ,Ipilimumab ,Pembrolizumab ,03 medical and health sciences ,0302 clinical medicine ,Cancer immunotherapy ,brain metastases ,Internal medicine ,antibodies ,Immunology and Allergy ,Medicine ,030212 general & internal medicine ,ipilimumab ,humans ,Prospective cohort study ,check-point inhibitors ,nivolumab ,brain neoplasms ,cancer immunotherapy ,business.industry ,Antibodies, Monoclonal ,Cancer ,Immunotherapy ,medicine.disease ,Clinical trial ,pembrolizumab ,antibodies, monoclonal ,prognosis ,immunotherapy ,030220 oncology & carcinogenesis ,Nivolumab ,business ,medicine.drug - Abstract
The exclusion of "real-world" patients from registration clinical trials of cancer immunotherapy represents a significant emerging issue. For instance, a large fraction of cancer patients develops brain metastases during the course of the disease, but results from large prospective clinical trials investigating this considerable proportion of the cancer patient population are currently lacking. To provide a useful tool for the clinician in a "real-world" setting, we have reviewed the available literature regarding the safety and efficacy of immune check-point inhibitors in patients with cancer metastatic to the brain. Overall, these data provide encouraging evidence that these therapeutic agents can induce intracranial objective responses, particularly in patients with asymptomatic and previously untreated brain metastases. Larger prospective studies are needed to confirm these initial results.
- Published
- 2018
32. The Role of TGF-β in Bone Metastases
- Author
-
Theresa A. Guise, Trupti Trivedi, Khalid S. Mohammad, and Gabriel M. Pagnotti
- Subjects
TGF-β therapeutic targets ,Epithelial-Mesenchymal Transition ,Angiogenesis ,transforming growth factor-β (TGF-β) ,Cell ,Bone Neoplasms ,Review ,Microbiology ,Biochemistry ,Bone and Bones ,Bone resorption ,Prostate cancer ,immune cells ,Immune system ,bone metastases ,Transforming Growth Factor beta ,medicine ,Humans ,programmed cell death ligand (PD-L1) ,check-point inhibitors ,Molecular Biology ,business.industry ,Cancer ,medicine.disease ,QR1-502 ,medicine.anatomical_structure ,Cancer cell ,Cancer research ,business ,bone resorption ,Transforming growth factor - Abstract
Complications associated with advanced cancer are a major clinical challenge and, if associated with bone metastases, worsen the prognosis and compromise the survival of the patients. Breast and prostate cancer cells exhibit a high propensity to metastasize to bone. The bone microenvironment is unique, providing fertile soil for cancer cell propagation, while mineralized bone matrices store potent growth factors and cytokines. Biologically active transforming growth factor β (TGF-β), one of the most abundant growth factors, is released following tumor-induced osteoclastic bone resorption. TGF-β promotes tumor cell secretion of factors that accelerate bone loss and fuel tumor cells to colonize. Thus, TGF-β is critical for driving the feed-forward vicious cycle of tumor growth in bone. Further, TGF-β promotes epithelial-mesenchymal transition (EMT), increasing cell invasiveness, angiogenesis, and metastatic progression. Emerging evidence shows TGF-β suppresses immune responses, enabling opportunistic cancer cells to escape immune checkpoints and promote bone metastases. Blocking TGF-β signaling pathways could disrupt the vicious cycle, revert EMT, and enhance immune response. However, TGF-β’s dual role as both tumor suppressor and enhancer presents a significant challenge in developing therapeutics that target TGF-β signaling. This review presents TGF-β’s role in cancer progression and bone metastases, while highlighting current perspectives on the therapeutic potential of targeting TGF-β pathways.
- Published
- 2021
33. The Role of TGF-β in Bone Metastases.
- Author
-
Trivedi, Trupti, Pagnotti, Gabriel M., Guise, Theresa A., and Mohammad, Khalid S.
- Subjects
- *
BONE metastasis , *IMMUNE checkpoint proteins , *TRANSFORMING growth factors , *CELLULAR signal transduction , *PROGNOSIS , *BONE morphogenetic proteins - Abstract
Complications associated with advanced cancer are a major clinical challenge and, if associated with bone metastases, worsen the prognosis and compromise the survival of the patients. Breast and prostate cancer cells exhibit a high propensity to metastasize to bone. The bone microenvironment is unique, providing fertile soil for cancer cell propagation, while mineralized bone matrices store potent growth factors and cytokines. Biologically active transforming growth factor β (TGF-β), one of the most abundant growth factors, is released following tumor-induced osteoclastic bone resorption. TGF-β promotes tumor cell secretion of factors that accelerate bone loss and fuel tumor cells to colonize. Thus, TGF-β is critical for driving the feed-forward vicious cycle of tumor growth in bone. Further, TGF-β promotes epithelial-mesenchymal transition (EMT), increasing cell invasiveness, angiogenesis, and metastatic progression. Emerging evidence shows TGF-β suppresses immune responses, enabling opportunistic cancer cells to escape immune checkpoints and promote bone metastases. Blocking TGF-β signaling pathways could disrupt the vicious cycle, revert EMT, and enhance immune response. However, TGF-β's dual role as both tumor suppressor and enhancer presents a significant challenge in developing therapeutics that target TGF-β signaling. This review presents TGF-β's role in cancer progression and bone metastases, while highlighting current perspectives on the therapeutic potential of targeting TGF-β pathways. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
34. Immune Check-Point Inhibitors and Standard Chemoradiotherapy in Definitive Head and Neck Cancer Treatment.
- Author
-
De Felice, Francesca, Musio, Daniela, Tombolini, Vincenzo, Katsila, Theodora, and Kahlert, Ulf D.
- Subjects
- *
IMMUNE checkpoint inhibitors , *CANCER treatment , *HEAD & neck cancer , *TREATMENT effectiveness , *CHEMORADIOTHERAPY - Abstract
In head and neck cancer management, there is a need for tailored approaches to optimally implement clinical outcomes. Based on the assumption that efficacy and long-term toxicity are not satisfactory for standard concurrent platinum-based chemoradiotherapy, several trials have been designed to test whether induction immunotherapy and/or concomitant immunotherapy and radiotherapy result in improved survival and toxicity outcomes. Here, we present an overview of the most recent concomitant therapeutic strategies for head and neck cancer, focusing on the knowledge available regarding check-point inhibitors. The aim is to present the characteristics of the main check-point inhibitors and to summarize the clinical trials on the combination of immune check-point inhibitors and (chemo)radiotherapy in the definitive HNC setting, in order to provide a useful clinical tool for further research. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
35. Cancer immunotherapy in patients with brain metastases
- Abstract
The exclusion of “real-world” patients from registration clinical trials of cancer immunotherapy represents a significant emerging issue. For instance, a large fraction of cancer patients develops brain metastases during the course of the disease, but results from large prospective clinical trials investigating this considerable proportion of the cancer patient population are currently lacking. To provide a useful tool for the clinician in a “real-world” setting, we have reviewed the available literature regarding the safety and efficacy of immune check-point inhibitors in patients with cancer metastatic to the brain. Overall, these data provide encouraging evidence that these therapeutic agents can induce intracranial objective responses, particularly in patients with asymptomatic and previously untreated brain metastases. Larger prospective studies are needed to confirm these initial results.
- Published
- 2018
36. Acutely induced diabetes mellitus in a 63-year-old female after treatment with ipilimumab for metastatic melanoma
- Author
-
Bisgaard Jørgensen, Line and Yderstræde, Knud Bonnet
- Subjects
diabetes mellitus ,acute ,check-point inhibitors - Abstract
Behandling med immuncheckpointhæmmere ved dissemineret malignt melanom har vundet betydeligt indpas i de seneste par år pga. effekten på overlevelsen hos patienterne med denne lidelse. Der er beskrevet en række endokrinologisk relaterede bivirkninger af behandlingen, herunder hypofysitis og tyroiditis/myksødem. På kasuistisk niveau er der desuden beskrevet få tilfælde af akut opstået diabetes mellitus Immune checkpoint inhibitors have improved survival rate in patients with advanced melanoma, but also have the potential to induce several adverse events. We report on a 63-year-old woman who had advanced melanoma and was admitted with diabetic ketoacidosis, which had occurred upon treatment with ipilimumab. On admission, the C-peptide level was low, and the HbA1c concentration was 50 mmol/l indicating a rapid onset of the disease. The patient had also been diagnosed with thyroiditis. Diabetes mellitus is a rare and serious side effect of treatment with ipilimumab, and we recommend being aware of this due to the rapid course.
- Published
- 2018
37. Checkpoint Inhibitors and Engineered Cells: New Weapons for Natural Killer Cell Arsenal Against Hematological Malignancies.
- Author
-
Giuliani, Massimo and Poggi, Alessandro
- Subjects
- *
HEMATOLOGIC malignancies , *CELLULAR recognition , *CELL anatomy , *CHIMERIC antigen receptors , *KILLER cells , *CELLS - Abstract
Natural killer (NK) cells represent one of the first lines of defense against malignant cells. NK cell activation and recognition are regulated by a balance between activating and inhibitory receptors, whose specific ligands can be upregulated on tumor cells surface and tumor microenvironment (TME). Hematological malignancies set up an extensive network of suppressive factors with the purpose to induce NK cell dysfunction and impaired immune-surveillance ability. Over the years, several strategies have been developed to enhance NK cells-mediated anti-tumor killing, while other approaches have arisen to restore the NK cell recognition impaired by tumor cells and other cellular components of the TME. In this review, we summarize and discuss the strategies applied in hematological malignancies to block the immune check-points and trigger NK cells anti-tumor effects through engineered chimeric antigen receptors. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
38. A Review of the Potential Role of Human Cytomegalovirus (HCMV) Infections in Breast Cancer Carcinogenesis and Abnormal Immunity.
- Author
-
Geisler, Jürgen, Touma, Joel, Rahbar, Afsar, Söderberg-Nauclér, Cecilia, and Vetvik, Katja
- Subjects
- *
BREAST tumor risk factors , *CELL proliferation , *BIOPSY , *BREAST tumors , *CELL lines , *CYTOMEGALOVIRUS diseases , *IMMUNE system , *IMMUNOSUPPRESSION , *PROTEINS , *RISK assessment , *DISEASE complications - Abstract
Previously recognized classical human onco-viruses can regulate complex neoplastic events, and are estimated to play a role during carcinogenesis in 15–20% of cancer cases. Although the DNA and gene products of several viruses have been found in breast tumors, none of the classical onco-viruses have definitely been linked to the initiation of breast cancer. However, recent evidence shows that human cytomegalovirus (HCMV) gene products are found in >90% of tumors and metastases of breast cancers, and their increased expression can be correlated to a more aggressive breast cancer phenotype. Supporting the active role of HCMV in breast cancer, a specific HCMV strain, HCMV-DB, was recently shown to exert oncogenic transformational activity in breast epithelial cells in vitro, and to give rise to fast-growing, triple-negative breast tumors when injected into immune deficient mice. The same observation holds true for clinical studies implying increased HCMV protein expression in triple negative breast cancer biopsies. In addition to functionally being able to hijack tumor-promoting cellular events, HCMV is known to exhibit a wide range of immunosuppressive effects, which can have radical impact on the tumor microenvironment. HCMV infected cells can avoid recognition and elimination by the immune system by orchestrating polarization of immunosuppressive type II macrophages, preventing antigen presentation, by expressing T cell inhibitory molecules, and possibly, by the induction of regulatory T (Treg) cell responses. These actions would be especially deleterious for the antigenic activation and proliferation of tumor specific CD8+ cytotoxic T lymphocytes (CTLs), whose effector functions have recently been targeted by successful, experimental immunotherapy protocols. The recognition of alternative causes and drivers of breast cancer is a pivotal research topic for the development of diagnostics and novel, effective preventive and therapeutic strategies targeting both tumor cells and their microenvironments. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
39. Overview of Immune Checkpoint Inhibitors Therapy for Hepatocellular Carcinoma, and The ITA.LI.CA Cohort Derived Estimate of Amenability Rate to Immune Checkpoint Inhibitors in Clinical Practice.
- Author
-
Giannini, Edoardo G., Aglitti, Andrea, Borzio, Mauro, Gambato, Martina, Guarino, Maria, Iavarone, Massimo, Lai, Quirino, Levi Sandri, Giovanni Battista, Melandro, Fabio, Morisco, Filomena, Ponziani, Francesca Romana, Rendina, Maria, Russo, Francesco Paolo, Sacco, Rodolfo, Viganò, Mauro, Vitale, Alessandro, and Trevisani, Franco
- Subjects
- *
ANTIGENS , *ANTINEOPLASTIC agents , *HEPATOCELLULAR carcinoma , *IMMUNOTHERAPY , *EVALUATION of medical care , *GUT microbiome , *BLOCKING antibodies , *PHARMACODYNAMICS - Abstract
Despite progress in our understanding of the biology of hepatocellular carcinoma (HCC), this tumour remains difficult-to-cure for several reasons, starting from the particular disease environment where it arises—advanced chronic liver disease—to its heterogeneous clinical and biological behaviour. The advent, and good results, of immunotherapy for cancer called for the evaluation of its potential application also in HCC, where there is evidence of intra-hepatic immune response activation. Several studies advanced our knowledge of immune checkpoints expression in HCC, thus suggesting that immune checkpoint blockade may have a strong rationale even in the treatment of HCC. According to this background, initial studies with tremelimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, and nivolumab, a programmed cell death protein 1 (PD-1) antibody, showed promising results, and further studies exploring the effects of other immune checkpoint inhibitors, alone or with other drugs, are currently underway. However, we are still far from the identification of the correct setting, and sequence, where these drugs might be used in clinical practice, and their actual applicability in real-life is unknown. This review focuses on HCC immunobiology and on the potential of immune checkpoint blockade therapy for this tumour, with a critical evaluation of the available trials on immune checkpoint blocking antibodies treatment for HCC. Moreover, it assesses the potential applicability of immune checkpoint inhibitors in the real-life setting, by analysing a large, multicentre cohort of Italian patients with HCC. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
40. Pembrolizumab-induced diabetes.
- Author
-
Banatwalla R, Kirresh OZ, and Ahmed FW
- Subjects
- Antibodies, Monoclonal, Humanized adverse effects, Humans, Antibodies, Monoclonal, Humanized therapeutic use, Diabetes Mellitus, Type 1
- Abstract
Not required for Clinical Vignette.
- Published
- 2021
- Full Text
- View/download PDF
41. Emerging role of immune checkpoint inhibitors in the treatment of ovarian cancer.
- Author
-
Lorusso D, Ceni V, Muratore M, Salutari V, Nero C, Pietragalla A, Ciccarone F, Carbone V, Daniele G, and Scambia G
- Subjects
- Angiogenesis Inhibitors administration & dosage, Angiogenesis Inhibitors pharmacology, Animals, Drug Design, Female, Humans, Immune Checkpoint Inhibitors pharmacology, Mice, Ovarian Neoplasms immunology, Ovarian Neoplasms pathology, Poly(ADP-ribose) Polymerase Inhibitors administration & dosage, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, Immune Checkpoint Inhibitors administration & dosage, Immunotherapy methods, Ovarian Neoplasms drug therapy
- Abstract
Introduction: In recent years, ovarian cancer (OC) treatment has been enriched with many new target therapies, most of all antiangiogenic drugs and PARP inhibitors (PARPis), which have literally changed the natural history of the disease. The impressive results of immunotherapy in other malignancies, mainly melanoma and lung cancer, and the good signals of activity in gynecological neoplasms like cervical and microsatellite instable (MSI-H) endometrial cancer, opened the space to the introduction of immune-stimulatory drugs in ovarian cancer., Area Covered: The goal of this article is to summarize the newest evidence on the use of immune check point inhibitors in OC trying to explain why, at present, this strategy has failed to improve clinical outcome and focusing on the possible strategies to overcome treatment failure., Expert Opinion: Although numerous trials have been undertaken, only scanty results have been obtained so far with immune check-point inhibitors (ICIs) in OC either when used as single agents or in combination with antiangiogenic therapy and ongoing trials are exploring the association of ICIs with PARPis and other ICIs. A better knowledge of predictive biomarkers of response and mechanisms of immunotherapy resistance, will help in identifying the most appropriate population to treat with ICIs.
- Published
- 2020
- Full Text
- View/download PDF
42. Monoclonal antibodies in newly diagnosed and smoldering multiple myeloma: an updated review of current clinical evidence.
- Author
-
Musto P and La Rocca F
- Subjects
- Humans, Antineoplastic Agents, Immunological therapeutic use, Smoldering Multiple Myeloma diagnosis, Smoldering Multiple Myeloma drug therapy
- Abstract
Introduction : Monoclonal antibodies (MoAbs) are rapidly changing the therapeutic scenario of multiple myeloma. Most of the available data, however, come from studies performed in patients with relapsed or refractory disease. Area covered : Here, the most recent results from clinical trials that have investigated (or are investigating) efficacy and safety of MoAbs as front-line treatments in both transplant-eligible and not-eligible patients with newly diagnosed multiple myeloma, as well as in smoldering myeloma, are reviewed. PubMed reported articles before 28 March 2020, and abstracts presented at the last ASCO, ASH, EHA, and IMW meetings were considered. Among others, pertinent data regarding daratumumab, isatuximab, elotuzumab, and pembrolizumab will be analyzed. Expert opinion : Introduction of MoAbs as first-line therapy will likely provide a significant improvement in the clinical outcome of patients with multiple myeloma. This will also require an appropriate re-positioning of salvage therapies. The role of MoAbs in smoldering myeloma appears to be promising, but adequate follow-up is needed.
- Published
- 2020
- Full Text
- View/download PDF
43. Monoclonal antibodies in relapsed/refractory myeloma: updated evidence from clinical trials, real-life studies, and meta-analyses.
- Author
-
Musto P and La Rocca F
- Subjects
- Antibodies, Monoclonal adverse effects, Antibodies, Neoplasm adverse effects, Clinical Trials as Topic, Female, Humans, Male, Antibodies, Monoclonal therapeutic use, Antibodies, Neoplasm therapeutic use, Multiple Myeloma drug therapy
- Abstract
Introduction : In the last few years, monoclonal antibodies have rapidly modified the therapeutic strategies for treating patients with multiple myeloma. Areas covered : In this review, the most recent literature data regarding indications for which monoclonal antibodies are currently or will be shortly approved as salvage therapies in relapsed/refractory myeloma are discussed. In particular, updated results until March 22, 2020 of antibodies directed against CD38 (daratumumab and isatuximab), SLAMF7 (elotuzumab), BCMA (GSK2857916/belantamab mafodotin), and PD-1/PD-1 L axis (nivolumab and pembrolizumab) will be analyzed in detail. Expert opinion : Monoclonal antibodies represent a new, very effective approach that will open novel and dynamic treatment scenarios for myeloma patients in the coming years. Optimal positioning and selection of different antibodies that are or will be soon available, appropriate combinations and careful evaluation of possible new toxicities should be considered in the future management of these patients.
- Published
- 2020
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.