The Effects Of Neoadjuvant Anti Programmed Cell Death Protein 1 Pd 1 Therapy On The Tumor Infiltrating T Cell Compartment And Tumor Microenvironment Immune Composition In Recurrent Glioblastoma Patients
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| Author | : Alexander Hao Lee |
| Publisher | : |
| Total Pages | : 0 |
| Release | : 2023 |
| Genre | : |
| ISBN | : |
Glioblastoma (GBM) is the most common malignant tumor in the central nervous system and has poor patient survival rates. Unlike other cancers, immune checkpoint therapies, such as PD-1 checkpoint blockade, have been largely ineffective in GBMs for several reasons: an immunosuppressive tumor microenvironment, a lack of suitable neoantigens, and poor intratumoral T cell infiltration and activity. However, there is evidence that using anti-PD-1 therapy in the neoadjuvant setting may generate a more robust anti-tumor immune response, though characterizing how the GBM tumor microenvironment changes with such therapy is incomplete. As such, we performed high dimensional analysis using CyTOF mass cytometry and single-cell RNAsequencing to study the intratumoral immune populations in GBM patients treated with or without neoadjuvant anti-PD-1 therapy. Characterizing PD-1 expressing tumor infiltrating T cell populations showed that PD-1 was associated with markers of T cell activation and dysfunction regardless of treatment and that this association existed less strongly in peripheral PD-1 expressing T cells. We studied the effects of neoadjuvant anti-PD-1 therapy on a large patient cohort of tumor infiltrating immune cells and found that neoadjuvant anti-PD-1 therapy significantly increased the proportion of several intratumoral T cell sub-populations, including a TCF7-expressing progenitor exhausted population. Downstream effects of neoadjuvant anti-PD-1 therapy on T cells, namely increased production of IFN-g, included transcriptionally altering the myeloid and dendritic cell populations to be more immune suppressive but also potentially more vulnerable to other immune checkpoint therapies, specifically anti-TIGIT and anti-CTLA-4 therapies. Due to the impact of neoadjuvant anti-PD-1 therapy on intratumoral T cell populations, we examined whether we could detect tumor-reactive T cells by cloning TCRs from transcriptionally defined populations in a patient treated with neoadjuvant anti-PD-1 and testing reactivity to the patient-derived gliomasphereline. Among TCRs cloned, we discovered that T cells arising from the activated and exhausted population showed tumor reactivity, suggesting that utilizing transcriptional phenotypes can guide selection of potential tumor-reactive TCRs in GBM patients treated with neoadjuvant anti-PD-1 therapy. In conclusion, neoadjuvant anti-PD-1 therapies alters the immune landscape in these tumors and can be potentially used in combination with other immunotherapies to more effectively treat this malignancy.
| Author | : Stanley Stylli |
| Publisher | : Mdpi AG |
| Total Pages | : 282 |
| Release | : 2021-12-21 |
| Genre | : |
| ISBN | : 9783036525990 |
This book is a compilation of articles that brings together current knowledge from an international team of contributors who are dedicated investigators exploring novel strategies for the treatment of glioblastoma. These articles describe some of the latest concepts that will provide students, researchers and clinicians with an overview of the therapeutic approaches being developed in the field of neuro-oncology to combat this deadly disease.
| Author | : Michael Grasso III |
| Publisher | : Springer |
| Total Pages | : 0 |
| Release | : 2016-10-15 |
| Genre | : Medical |
| ISBN | : 9783319371429 |
Upper Urinary Tract Urothelial Carcinoma was at one time felt to be a somewhat rare entity. With the success of various treatments for bladder urothelial carcinoma, the incidence of this disease in the uretere and kidney is rising. Many medical subspecialists encounter these complex patients and a multimodality treatment plan is often required for care.
| Author | : Paul D. Rennert |
| Publisher | : Springer |
| Total Pages | : 285 |
| Release | : 2016-05-30 |
| Genre | : Medical |
| ISBN | : 3319298275 |
Cancer care is undergoing a radical transformation as novel technologies are directed toward new treatments and personalized medicine. The most dramatic advances in the treatment of cancer have come from therapeutics that augment the immune response to tumors. The immune checkpoint inhibitors are the best-known and most highly advanced examples of Immune Therapeutics targeting tumor cells and include approved antibody drugs directed at the cell surface proteins CTLA4 and PD-1. These are now considered foundational treatments for several solid tumor indications, and that list of indications is growing quickly. More broadly, antibodies have become workhorse molecules across the entire immunotherapy landscape. Antibodies to novel targets modulate the activity of diverse immune cell regulatory proteins. Engineered antibodies can induce tumor cell death or expose tumor cells to poisonous toxins (ADCC and ADC, respectively). Bi-specific antibodies can engage multiple tumor targets simultaneously, or can redirect lymphocytes to attack tumor cells. The antigen-binding domains within antibodies can be spliced onto cell stimulatory domains and transduced into T cells or NK cells, creating remarkable tumor-specific cellular therapeutics (CAR-T, CAR-NK). Beyond antibody-based therapies there are highly diverse and differentiated technology tool kits being applied to immunotherapy. Small molecule drugs are being developed to attack the tumor microenvironment, novel tumor vaccine approaches are showing great promise, patient lymphocytes are being isolated, expanded and reintroduced to patients, gene-editing techniques are becoming widely deployed, and a vast number of new tumor targets, and mutated tumor proteins (neoantigens), are being discovered. The past decade has seen unprecedented success in the treatment of diverse cancers. The authors of this volume have been asked to not only review progress to date, but importantly, to look ahead, and anticipate the evolution of cancer treatment across diverse Immune Therapeutic approaches. Our hypothesis is that the advances we are seeing across the immunotherapy landscape will further evolve and synergize, leading us finally to outright cures for many cancers.
| Author | : Laurence Zitvogel |
| Publisher | : Springer |
| Total Pages | : 700 |
| Release | : 2017-12-13 |
| Genre | : Medical |
| ISBN | : 3319624318 |
In this book, leading experts in cancer immunotherapy join forces to provide a comprehensive guide that sets out the main principles of oncoimmunology and examines the latest advances and their implications for clinical practice, focusing in particular on drugs with FDA/EMA approvals and breakthrough status. The aim is to deliver a landmark educational tool that will serve as the definitive reference for MD and PhD students while also meeting the needs of established researchers and healthcare professionals. Immunotherapy-based approaches are now inducing long-lasting clinical responses across multiple histological types of neoplasia, in previously difficult-to-treat metastatic cancers. The future challenges for oncologists are to understand and exploit the cellular and molecular components of complex immune networks, to optimize combinatorial regimens, to avoid immune-related side effects, and to plan immunomonitoring studies for biomarker discovery. The editors hope that this book will guide future and established health professionals toward the effective application of cancer immunology and immunotherapy and contribute significantly to further progress in the field.
| Author | : Xuyao Zhang |
| Publisher | : Frontiers Media SA |
| Total Pages | : 520 |
| Release | : 2024-01-15 |
| Genre | : Medical |
| ISBN | : 2832533515 |
Cancer immunotherapy, including immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell (CAR-T) therapy, has revolutionized the paradigm in cancer treatment. However, the clinical outcome of immunotherapy varies considerably among patients and only a minority of patients achieve long-term clinical benefits. This is largely attributed to the fact that existing cancer immunotherapies, which concentrate on several classical targets (CTAL-4, PD-1/PD-L1, etc.) and limited types of immune cell populations (T cells), are insufficient to cope with the complexity of highly heterogeneous tumor microenvironment (TME). This calls for more efforts to not only expand our toolbox for manipulating anticancer immunity but also diversify our combinational strategies. To this end, it is urgent to deeper our understanding of cancer immunotherapy by using both experimental and computational methodologies from multi-scale perspectives: 1) novel targets from either tumor cells or non-tumor cells within TME (e.g., tumor intrinsic resistance drivers, new immune checkpoints, neoantigens), 2) in-depth characterization of more immune cell populations (e.g., macrophages, Tregs, B cells) and their interactions and dynamics within TME, 3) landscape of actionable targets in patient populations for combination design. These efforts will open the avenue of rational design of combinational immunotherapies, allowing researchers and clinicians to design novel targeting therapeutics or to optimally orchestrate combinatory strategies aiming to surmount resistance mechanisms and improve clinical outcomes.
| Author | : Manmeet Ahluwalia |
| Publisher | : Springer Nature |
| Total Pages | : 421 |
| Release | : 2019-11-05 |
| Genre | : Medical |
| ISBN | : 3030234177 |
This book provides a comprehensive overview of brain metastases, from the molecular biology aspects to therapeutic management and perspectives. Due to the increasing incidence of these tumors and the urgent need to effectively control brain metastatic diseases in these patients, new therapeutic strategies have emerged in recent years. The volume discusses all these innovative approaches combined with new surgical techniques (fluorescence, functional mapping, integrated navigation), novel radiation therapy techniques (stereotactic radiosurgery) and new systemic treatment approaches such as targeted- and immunotherapy. These combination strategies represent a new therapeutic model in brain metastatic patients in which each medical practitioner (neurosurgeon, neurologist, medical oncologist, radiation oncologist) plays a pivotal role in defining the optimal treatment in a multidisciplinary approach. Written by recognized experts in the field, this book is a valuable tool for neurosurgeons, neuro-oncologists, neuroradiologists, medical oncologists, radiation oncologists, cognitive therapists, basic scientists and students working in the area of brain tumors.
| Author | : Raymond John S Lim |
| Publisher | : |
| Total Pages | : 126 |
| Release | : 2022 |
| Genre | : |
| ISBN | : |
Lung cancer remains the most common cause of cancer death worldwide with approximately 85% of patients having non-small cell lung cancer (NSCLC). Checkpoint blockade immunotherapy has evolved the current treatment landscape with robust and durable responses in approximately 20% of patients with progressive, locally advanced, or metastatic NSCLC, as well as in treatment-naïve advanced disease. Inefficient tumor antigen presentation, diminished T cell infiltration into tumor and LKB1-inactivating mutations contribute to the mechanisms of resistance to programmed death-ligand 1 (PD-L1) or programmed cell death protein 1 (PD-1) blockade in NSCLC. One approach to overcome this immunosuppressive tumor microenvironment (TME) is to utilize in situ vaccination with gene-modified functional antigen presenting cells (APCs) to enhance tumor antigen presentation and promote tumor-specific T cell activation. Here I address two potential therapies: 1) CCL21-genetically engineered dendritic cells (CCL21-DC) and 2) CXCL9/10-genetically engineered dendritic cells (CXCL9/10-DC), which are shown to remodel the tumor immune microenvironment and promote an anti-tumor immune response. In addition, the pre-clinical studies detailed here investigate the mechanisms of how these potential therapies can potentiate checkpoint blockade immunotherapy. These preclinical models serve as a platform to enhance our understanding of the molecular mechanisms of response and resistance to immunotherapy. In addition, these studies provide insights to anti-tumor immunity mediated by in situ DC vaccination and may in turn facilitate the improvement of novel vaccine therapies. The final chapter addresses the pressing need for the development of innovative approaches to detect and intercept lung cancer at its earliest stages of development. Using spatial multiplex immunofluorescence, this chapter highlights the efforts to understand the immune landscape in the tumor microenvironment associated with early-stage lung carcinogenesis and provides further understanding of the mechanism of lung cancer evolution. Research focusing on the development of novel strategies for cancer interception prior to the progression to advanced stages will potentially lead to a paradigm shift in the treatment of lung cancer and have a major impact on clinical outcomes.
| Author | : James H. Finke |
| Publisher | : Springer Science & Business Media |
| Total Pages | : 392 |
| Release | : 2003-11-24 |
| Genre | : Medical |
| ISBN | : 1592597432 |
Leading investigators and clinicians detail the different mechanisms used by tumors to escape and impair the immune system and then spell out possible clinical strategies to prevent or reverse tumor-induced immune dysfunction. The authors review the mechanisms of immune dysfunction and evasion mechanisms in histologically diverse human tumors, focusing on tumor-induced molecular defects in T cells and antigen-presenting cells (dendritic cells and tumors), that may serve as biomarkers for patient prognosis. They discuss the means by which these immune functions may be protected or restored in order to more effectively support the process of tumor rejection in situ. Cutting-edge techniques are outlined with the capacity to monitor the strength and quality of patients' immune responses using immunocytometry, MHC-peptide tetramers combined with apoptosis assay, ELISPOT assay, and detection of MHC-TAA peptide complexes on tumor cells.
| Author | : Yeni Romero |
| Publisher | : |
| Total Pages | : |
| Release | : 2020 |
| Genre | : |
| ISBN | : |
Tumors consist of a diverse population of cancer cells as well as various tumor-infiltrating immune cells, soluble factors, and extracellular matrix proteins, which are collectively known as the tumor immune microenvironment (TIME). The interactions between cancer cells and their microenvironment heavily influence tumor progression and therapeutic responses, often leading to tumor immune evasion and therapeutic resistance. Understanding these complex interactions will help develop novel strategies to target tumor cells or improve the efficacy of existing therapies. The goal of my research was to explore the role of two regulators of the tumor immune microenvironment, PD-L1 and regulatory T cells, in triple negative breast cancer (TNBC). Programmed death-ligand 1 (PD-L1) is a negative regulator of the immune system that acts as a "brake" to keep the body's immune responses under control. However, in cancer, PD-L1 expression leads to immune evasion and poor disease outcomes. In breast cancer, PD-L1 expression is most upregulated in the TNBC subtype. Under certain circumstances, transmembrane PD-L1 can be cleaved, generating a soluble form containing an intact receptor-binding domain. In my research, I investigated the cleavage of PD-L1 expressed on the surface of tumor cells. I found that a ~37-kDa N-terminal cleavage product of PD-L1 is released to the culture media. Analysis of the ~18-kDa C-terminal PD-L1 fragment demonstrated that this fragment is unstable and readily eliminated by lysosomal degradation. Furthermore, I identified ADAM10 and ADAM17, two members of the cell surface family of ADAM metalloproteases, as mediators of the cleavage of transmembrane PD-L1. Regulatory T cells (Tregs) are a subset of T cells that play a role in regulating or suppressing other immune cells. Tregs regulate the immune response to self and foreign antigens and help prevent autoimmune diseases by maintaining immune homeostasis. In cancer, Tregs are involved in tumor development and progression by inhibiting effector cells and reducing anti-tumor immunity. In TNBC, infiltration of Tregs into the TIME is often associated with resistance to anti-PD-L1 therapy and poor patient survival. Therefore, a better understanding of the mechanisms regulating the numbers of Tregs in the TIME of TNBC is necessary to tackle the problem of immunotherapy resistance. Claudin-low breast tumors are known to have increased numbers of tumor-infiltrating lymphocytes, specifically Tregs, as well as upregulated expression levels of ADAM12, an active ADAM metalloprotease. My goal was to investigate the role of ADAM12 in T cell accumulation to the tumor microenvironment in vivo using a mouse transplantation model of claudin-low breast cancer. Specifically, I investigated the accumulation of Tregs and other T cell subsets to tumors with or without expression of ADAM12. I found that the frequency of Tregs in tumor immune infiltrates was increased in tumors that lacked ADAM12 expression. Collectively, these findings give insight into the complex regulatory roles that PD-L1 and Tregs play in the breast cancer TIME.
