Browsing by Subject "immunotherapy"

Now showing 1 - 10 of 28
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    Absence of Replication-Competent Lentivirus in the Clinic: Analysis of Infused T Cell Products
    (Elsevier, 2017) Cornetta, Kenneth; Duffy, Lisa; Turtle, Cameron J.; Jensen, Michael; Forman, Stephen; Binder-Scholl, Gwendolyn; Fry, Terry; Chew, Anne; Maloney, David G.; June, Carl H.; Medical and Molecular Genetics, School of Medicine
    Exposure to replication-competent lentivirus (RCL) is a theoretical safety concern for individuals treated with lentiviral gene therapy. For certain ex vivo gene therapy applications, including cancer immunotherapy trials, RCL detection assays are used to screen the vector product as well as the vector-transduced cells. In this study, we reviewed T cell products screened for RCL using methodology developed in the National Gene Vector Biorepository. All trials utilized third-generation lentiviral vectors produced by transient transfection. Samples from 26 clinical trials totaling 460 transduced cell products from 375 subjects were evaluated. All cell products were negative for RCL. A total of 296 of the clinical trial participants were screened for RCL at least 1 month after infusion of the cell product. No research subject has shown evidence of RCL infection. These findings provide further evidence attesting to the safety of third-generation lentiviral vectors and that testing T cell products for RCL does not provide added value to screening the lentiviral vector product.
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    BILITE: A Bayesian randomized phase II design for immunotherapy by jointly modeling the longitudinal immune response and time-to-event efficacy
    (Wiley, 2020-12) Guo, Beibei; Zang, Yong; Biostatistics, School of Public Health
    Immunotherapy—treatments that target a patient's immune system—has attracted considerable attention in cancer research. Its recent success has led to generation of novel immunotherapeutic agents that need to be evaluated in clinical trials. Two unique features of immunotherapy are the immune response and the fact that some patients may achieve long-term durable response. In this article, we propose a two-arm Bayesian adaptive randomized phase II clinical trial design for immunotherapy that jointly models the longitudinal immune response and time-to-event efficacy (BILITE), with a fraction of patients assumed to be cured by the treatment. The longitudinal immune response is modeled using hierarchical nonlinear mixed-effects models with possibly different trajectory patterns for the cured and susceptible groups. Conditional on the immune response trajectory, the time-to-event efficacy data for patients in the susceptible group is modeled via a time-dependent Cox-type regression model. We quantify the desirability of the treatment using a utility function and propose a two-stage design to adaptively randomize patients to treatments and make treatment recommendations at the end of the trial. Simulation studies show that compared with a conventional design that ignores the immune response, BILITE yields superior operating characteristics in terms of the ability to identify promising agents and terminate the trial early for futility.
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    Current Strategies and Novel Therapeutic Approaches for Metastatic Urothelial Carcinoma
    (MDPI, 2020-06-02) Mollica, Veronica; Rizzo, Alessandro; Montironi, Rodolfo; Cheng, Liang; Giunchi, Francesca; Schiavina, Riccardo; Santoni, Matteo; Fiorentino, Michelangelo; Lopez-Beltran, Antonio; Brunocilla, Eugenio; Brandi, Giovanni; Massari, Francesco; Pathology and Laboratory Medicine, School of Medicine
    Urothelial carcinoma (UC) is a frequent cause of cancer-related deaths worldwide. Metastatic UC has been historically associated with poor prognosis, with a median overall survival of approximately 15 months and a 5-year survival rate of 18%. Although platinum-based chemotherapy remains the mainstay of medical treatment for patients with metastatic UC, chemotherapy clinical trials produced modest benefit with short-lived, disappointing responses. In recent years, the better understanding of the role of immune system in cancer control has led to the development and approval of several immunotherapeutic approaches in UC therapy, where immune checkpoint inhibitors have been revolutionizing the treatment of metastatic UC. Because of a better tumor molecular profiling, FGFR inhibitors, PARP inhibitors, anti-HER2 agents, and antibody drug conjugates targeting Nectin-4 are also emerging as new therapeutic options. Moreover, a wide number of trials is ongoing with the aim to evaluate several other alterations and pathways as new potential targets in metastatic UC. In this review, we will discuss the recent advances and highlight future directions of the medical treatment of UC, with a particular focus on recently published data and ongoing active and recruiting trials.
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    Emerging immunotherapeutic strategies targeting telomerases in genitourinary tumors
    (Elsevier, 2018) Carrozza, Francesco; Santoni, Matteo; Piva, Francesco; Cheng, Liang; Lopez-Beltran, Antonio; Scarpelli, Marina; Montironi, Rodolfo; Battelli, Nicola; Tamberi, Stefano; Pathology and Laboratory Medicine, School of Medicine
    Telomerase activity and telomere length are essential for the pathogenesis of several human diseases, including genitourinary tumors. Telomerase constitutes a complex system that includes human telomerase reverse transcriptase (hTERT), human telomerase RNA component (hTR) and telomerase associated protein 1 (TEP1), which are overexpressed in tumor cells compared to normal cells and are involved in the carcinogenesis and progression of renal cell carcinoma (RCC), bladder (BC) and prostate cancer (PCa). In addition, telomerase degraded peptide fragments expressed on the surface of tumor cells lead to their recognition by immune cells. On this scenario, in vitro and in vivo studies have shown effective anti-tumor activity of hTERT-tailored strategies in genitourinary tumors, including active immunotherapy with hTERT-peptide vaccines and passive immunotherapy with hTERT-transduced T cell infusion. This review emphasizes the role of telomerase in the carcinogenesis and progression of genitourinary tumors, thus underlying the potential of emerging telomerase-tailored immunotherapies in these patients.
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    Erythema annulare centrifugum-type eruption in a patient undergoing cancer vaccine immunotherapy
    (Dermatology Online Journal, 2018-10-15) Tadros, Joseph; Rahnama-Moghadam, Sahand; Dermatology, School of Medicine
    Sipuleucel-T is a cellular immunotherapy approved for the treatment of metastatic castration-resistant prostate cancer. We report a patient developing an immune related adverse effect from sipuleucel-T drug-induced erythema annulare centrifugum-like eruption. A brief review of the mechanism and implications of this eruption are also included.
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    Hereditary diffuse gastric cancer therapeutic roadmap: current and novel approaches in a nutshell
    (Sage, 2020-01) El Rami, Fadi E.; Barsoumian, Hampartsoum B.; Khneizer, Gebran W.; Medicine, School of Medicine
    Hereditary diffuse gastric cancer (HDGC) is a rare malignancy characterized by autosomal dominant inheritance of pathological variants of the CDH1 gene encoding E-cadherin, which is involved in cell–cell adhesion, maintenance of epithelial architecture, tumor suppression, and regulation of intracellular signaling pathways. Late-stage recognition of HDGC is typically associated with a poor clinical outcome due to its metastatic potential and risk of lobular breast cancer (LBC) development. The American College of Gastroenterology issued guidelines to evaluate HDGC, test for CDH1 genetic variants, and recommend prophylactic gastrectomy for carriers of CDH1 mutations. If surgery is not pursued, endoscopy is a surveillance alternative, although it carries a limited ability to detect malignant foci. As part of clinical research efforts, novel endoscopy advances are currently studied, and a center of excellence for HDGC was created for a comprehensive multidisciplinary team approach. Within this review, we cover current conventional treatment modalities such as gastrectomy and chemotherapy, as the mainstay treatments, in addition to Pembrolizumab, an immune checkpoint inhibitor, as the last therapeutic resort. We also shed light on novel and promising approaches with emphasis on immunotherapy to treat HDGC. We further break down the therapeutic paradigms to utilize molecular tools, antibodies against checkpoint inhibitors, TGF-β and tyrosine kinase inhibitors, cell-based adoptive therapies, and oncolytic viral therapies. We aim to expand the understanding on how to modulate the tumor microenvironment to tip the balance towards an anti-tumor phenotype, prevent metastasis of the primary disease, and potentially alter the therapeutic landscape for HDGC.
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    Immunotherapeutic Concepts to Target Acute Myeloid Leukemia: Focusing on the Role of Monoclonal Antibodies, Hypomethylating Agents and the Leukemic Microenvironment
    (MDPI, 2017-07-31) Gbolahan, Olumide Babajide; Zeidan, Amer M.; Stahl, Maximilian; Abu Zaid, Mohammad; Farag, Sherif; Paczesny, Sophie; Konig, Heiko; Medicine, School of Medicine
    Intensive chemotherapeutic protocols and allogeneic stem cell transplantation continue to represent the mainstay of acute myeloid leukemia (AML) treatment. Although this approach leads to remissions in the majority of patients, long-term disease control remains unsatisfactory as mirrored by overall survival rates of approximately 30%. The reason for this poor outcome is, in part, due to various toxicities associated with traditional AML therapy and the limited ability of most patients to tolerate such treatment. More effective and less toxic therapies therefore represent an unmet need in the management of AML, a disease for which therapeutic progress has been traditionally slow when compared to other cancers. Several studies have shown that leukemic blasts elicit immune responses that could be exploited for the development of novel treatment concepts. To this end, early phase studies of immune-based therapies in AML have delivered encouraging results and demonstrated safety and feasibility. In this review, we discuss opportunities for immunotherapeutic interventions to enhance the potential to achieve a cure in AML, thereby focusing on the role of monoclonal antibodies, hypomethylating agents and the leukemic microenvironment.
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    Immunotherapy in Lung Cancer: Current Landscape and Future Directions
    (Frontiers, 2022-02-08) Mamdani, Hirva; Matosevic, Sandro; Khalid, Ahmed Bilal; Durm, Gregory; Jalal, Shadia I.; Medicine, School of Medicine
    Over the past decade, lung cancer treatment has undergone a major paradigm shift. A greater understanding of lung cancer biology has led to the development of many effective targeted therapies as well as of immunotherapy. Immune checkpoint inhibitors (ICIs) have shown tremendous benefit in the treatment of non-small cell lung cancer (NSCLC) and are now being used as first-line therapies in metastatic disease, consolidation therapy following chemoradiation in unresectable locally advanced disease, and adjuvant therapy following surgical resection and chemotherapy in resectable disease. Despite these benefits, predicting who will respond to ICIs has proven to be difficult and there remains a need to discover new predictive immunotherapy biomarkers. Furthermore, resistance to ICIs in lung cancer is frequent either because of a lack of response or disease progression after an initial response. The utility of ICIs in the treatment of small cell lung cancer (SCLC) remains limited to first-line treatment of extensive stage disease in combination with chemotherapy with modest impact on overall survival. It is thus important to explore and exploit additional targets to reap the full benefits of immunotherapy in the treatment of lung cancer. Here, we will summarize the current state of immunotherapy in lung cancer, discuss novel targets, and explore the intersection between DNA repair defects and immunotherapy.
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    Is There a Role for Immunotherapy in Prostate Cancer?
    (MDPI, 2020-09-08) Rizzo, Alessandro; Mollica, Veronica; Cimadamore, Alessia; Santoni, Matteo; Scarpelli, Marina; Giunchi, Francesca; Cheng, Liang; Lopez-Beltran, Antonio; Fiorentino, Michelangelo; Montironi, Rodolfo; Massari, Francesco; Pathology and Laboratory Medicine, School of Medicine
    In the last decade, immunotherapy has revolutionized the treatment landscape of several hematological and solid malignancies, reporting unprecedented response rates. Unfortunately, this is not the case for metastatic castration-resistant prostate cancer (mCRPC), as several phase I and II trials assessing programmed death receptor 1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors have shown limited benefits. Moreover, despite sipuleucel-T representing the only cancer vaccine approved by the Food and Drug Administration (FDA) for mCRPC following the results of the IMPACT trial, the use of this agent is relatively limited in everyday clinical practice. The identification of specific histological and molecular biomarkers that could predict response to immunotherapy represents one of the current challenges, with an aim to detect subgroups of mCRPC patients who may benefit from immune checkpoint monoclonal antibodies as monotherapy or in combination with other anticancer agents. Several unanswered questions remain, including the following: is there—or will there ever be—a role for immunotherapy in prostate cancer? In this review, we aim at underlining the failures and promises of immunotherapy in prostate cancer, summarizing the current state of art regarding cancer vaccines and immune checkpoint monoclonal antibodies, and discussing future research directions in this immunologically “cold” malignancy.
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    Knowledge Gaps and Research Priorities in Immune Checkpoint Inhibitor–related Pneumonitis. An Official American Thoracic Society Research Statement
    (American Thoracic Society - AJRCCM, 2019-09-15) Sears, Catherine R.; Peikert, Tobias; Possick, Jennifer D.; Naidoo, Jarushka; Nishino, Mizuki; Patel, Sandip P.; Camus, Philippe; Gaga, Mina; Garon, Edward B.; Gould, Michael K.; Limper, Andrew H.; Montgrain, Philippe R.; Travis, William D.; Rivera, M. Patricia; Medicine, School of Medicine
    Rationale: Immune checkpoint inhibitors (ICIs) have revolutionized cancer care but are associated with unique adverse events, including potentially life-threatening pneumonitis. The diagnosis of ICI-pneumonitis is increasing; however, the biological mechanisms, clinical and radiologic features, and the diagnosis and management have not been well defined. Objectives: To summarize evidence, identify knowledge and research gaps, and prioritize topics and propose methods for future research on ICI-pneumonitis. Methods: A multidisciplinary group of international clinical researchers reviewed available data on ICI-pneumonitis to develop and refine research questions pertaining to ICI-pneumonitis. Results: This statement identifies gaps in knowledge and develops potential research questions to further expand knowledge regarding risk, biologic mechanisms, clinical and radiologic presentation, and management of ICI-pneumonitis. Conclusions: Gaps in knowledge of the basic biological mechanisms of ICI-pneumonitis, coupled with a precipitous increase in the use of ICIs alone or combined with other therapies, highlight the importance in triaging research priorities for ICI-pneumonitis.