Browsing by Author "Fecci, Peter E"
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Item Open Access Characterizing and Arresting Bone Marrow T-cell Sequestration in the Setting of Glioblastoma and Other Intracranial Tumors(2020) Chongsathidkiet, PakawatInitiation and maintenance of a productive anti-tumor immune response requires a functional T-cell repertoire. Disruptions to T-cell function contribute to tumor immune escape, and to failure of the anti-tumor immune response in cancer patients. T-cell dysfunction is particularly severe in certain types of cancers such as glioblastoma (GBM), which is the most common primary malignant brain tumor in adults and is extremely lethal. Despite near universal confinement to the intracranial compartment, GBM frequently depletes both the number and function of systemic T-cells. A lack of understanding of the mechanisms underlying T-cell dysfunction poses challenges to the goal of developing appropriate and meaningful therapeutic platforms. Currently available treatments, including immunotherapies, for GBM and other intracranial diseases have proven ineffective in part because of underlying T-cell dysfunction. Thus, there is an unmet need for therapies that effectively address T-cell dysfunction. In this dissertation, we explore bone marrow T-cell sequestration, a novel mode of T-cell dysfunction present in GBM and other intracranial tumors.
Chapter 1 provides a comprehensive review of the epidemiology, clinical manifestation and diagnosis, and current standard of care for GBM. Chapter 2 outlines immunotherapeutic strategies under investigation for GBM. Chapter 3 describes the fading notion of traditional brain immune privilege but provides the current understanding of how the brain remains immunologically distinct. In Chapter 4, we explore bone marrow T-cell sequestration, and how this mechanism is usurped by GBM and other intracranial tumors to prevent anti-tumor efficacy of T-cell based immunotherapeutic modalities. In Chapter 5, we propose β-arrestin 2 (BARR2) depletion as a strategy to overcome bone marrow T-cell sequestration. In summary, this original work provides encouraging insights for the development of strategies to enhance anti-tumor efficacy of T-cell based immunotherapy for GBM, reversal of bone marrow T-cell sequestration.
Item Open Access Gold Nanostars Obviate Limitations to Laser Interstitial Thermal Therapy (LITT) for the Treatment of Intracranial Tumors.(Clinical cancer research : an official journal of the American Association for Cancer Research, 2023-08) Srinivasan, Ethan S; Liu, Yang; Odion, Ren A; Chongsathidkiet, Pakawat; Wachsmuth, Lucas P; Haskell-Mendoza, Aden P; Edwards, Ryan M; Canning, Aidan J; Willoughby, Gavin; Hinton, Joseph; Norton, Stephen J; Lascola, Christopher D; Maccarini, Paolo F; Mariani, Christopher L; Vo-Dinh, Tuan; Fecci, Peter EPurpose
Laser interstitial thermal therapy (LITT) is an effective minimally invasive treatment option for intracranial tumors. Our group produced plasmonics-active gold nanostars (GNS) designed to preferentially accumulate within intracranial tumors and amplify the ablative capacity of LITT.Experimental design
The impact of GNS on LITT coverage capacity was tested in ex vivo models using clinical LITT equipment and agarose gel-based phantoms of control and GNS-infused central "tumors." In vivo accumulation of GNS and amplification of ablation were tested in murine intracranial and extracranial tumor models followed by intravenous GNS injection, PET/CT, two-photon photoluminescence, inductively coupled plasma mass spectrometry (ICP-MS), histopathology, and laser ablation.Results
Monte Carlo simulations demonstrated the potential of GNS to accelerate and specify thermal distributions. In ex vivo cuboid tumor phantoms, the GNS-infused phantom heated 5.5× faster than the control. In a split-cylinder tumor phantom, the GNS-infused border heated 2× faster and the surrounding area was exposed to 30% lower temperatures, with margin conformation observed in a model of irregular GNS distribution. In vivo, GNS preferentially accumulated within intracranial tumors on PET/CT, two-photon photoluminescence, and ICP-MS at 24 and 72 hours and significantly expedited and increased the maximal temperature achieved in laser ablation compared with control.Conclusions
Our results provide evidence for use of GNS to improve the efficiency and potentially safety of LITT. The in vivo data support selective accumulation within intracranial tumors and amplification of laser ablation, and the GNS-infused phantom experiments demonstrate increased rates of heating, heat contouring to tumor borders, and decreased heating of surrounding regions representing normal structures.Item Embargo Intracranial tumors elicit systemic sympathetic hyperactivity that limits immunotherapeutic success(2024) Lorrey, SelenaIntracranial tumors present unique challenges for immunotherapy. These can include both local and systemic modes of immune suppression whose mechanistic underpinnings are incompletely understood. My PhD thesis reveals that intracranial tumors elicit systemic increases in circulating catecholamine levels and that resulting chronic sympathetic hyperactivity drives T cell dysfunction and limits immunotherapeutic success. Further, treatment with beta-adrenergic blockade can partially overcome such chronic sympathetic hypersensitivity, and results in increased NF-kB activity in immune cells, restored T cell polyfunctionality, tumor microenvironment modifications, and extended survival in murine models of glioblastoma (GBM) treated with immune-based therapies. We uncovered that extended survival is also observed in GBM patients that received beta-adrenergic blockade, as well as in patients with melanoma and lung cancer brain metastases who received beta-blockade alongside concomitant immune checkpoint inhibition. While beta-blockade also impacts outcomes in the setting of extracranial disease, the benefits are especially pronounced in patients harboring intracranial disease burdens. These data suggest that sympathetic hyperactivity facilitates systemic immune dysfunction in the setting of intracranial tumors, specifically and advance a role for beta-adrenergic blockade in licensing immunotherapeutic responses within the intracranial compartment.
Item Open Access T Cell Exhaustion in Glioblastoma(2020) Woroniecka, KarolinaGlioblastoma (GBM) is the most common primary malignant brain tumor. Despite standard of care treatment GBM remains universally lethal, demonstrating a significant need for newer treatment strategies such as immunotherapy. Immune checkpoint blockade is a type of immunotherapy which seeks to perpetuate T cell activity by blocking inhibitory immune checkpoints. This strategy has gained FDA approval in several solid tumors, yet has failed in GBM. Severe T cell dysfunction such as T cell exhaustion is a known contributor to failures of immune checkpoint blockade, yet has not been thoroughly described in GBM. In this dissertation, we explore T cell exhaustion as a contributor to immune checkpoint blockade failure in GBM. Chapters 1-3 provide a comprehensive review of several distinct modes of T cell dysfunction in GBM including the importance of T cell exhaustion. In Chapter 4 we demonstrate severe bona fide T cell exhaustion in patients with GBM. In Chapter 5 we explore 4-1BB agonism as a means to prevent T cell exhaustion and thus sensitize GBM to immunotherapeutic strategies. In Chapter 6 we describe the mechanism driving T cell exhaustion and reveal a novel mechanism by which T cell based immunotherapies may recognize and kill tumor cells. In summary, this original work provides several encouraging insights for the development and evaluation of immunotherapeutic strategies, particularly immune checkpoint blockade, in GBM.
Item Open Access Temozolomide lymphodepletion enhances CAR abundance and correlates with antitumor efficacy against established glioblastoma.(Oncoimmunology, 2018-01) Suryadevara, Carter M; Desai, Rupen; Abel, Melissa L; Riccione, Katherine A; Batich, Kristen A; Shen, Steven H; Chongsathidkiet, Pakawat; Gedeon, Patrick C; Elsamadicy, Aladine A; Snyder, David J; Herndon, James E; Healy, Patrick; Archer, Gary E; Choi, Bryan D; Fecci, Peter E; Sampson, John H; Sanchez-Perez, LuisAdoptive transfer of T cells expressing chimeric antigen receptors (CARs) is an effective immunotherapy for B-cell malignancies but has failed in some solid tumors clinically. Intracerebral tumors may pose challenges that are even more significant. In order to devise a treatment strategy for patients with glioblastoma (GBM), we evaluated CARs as a monotherapy in a murine model of GBM. CARs exhibited poor expansion and survival in circulation and failed to treat syngeneic and orthotopic gliomas. We hypothesized that CAR engraftment would benefit from host lymphodepletion prior to immunotherapy and that this might be achievable by using temozolomide (TMZ), which is standard treatment for these patients and has lymphopenia as its major side effect. We modelled standard of care temozolomide (TMZSD) and dose-intensified TMZ (TMZDI) in our murine model. Both regimens are clinically approved and provide similar efficacy. Only TMZDI pretreatment prompted dramatic CAR proliferation and enhanced persistence in circulation compared to treatment with CARs alone or TMZSD + CARs. Bioluminescent imaging revealed that TMZDI + CARs induced complete regression of 21-day established brain tumors, which correlated with CAR abundance in circulation. Accordingly, TMZDI + CARs significantly prolonged survival and led to long-term survivors. These findings are highly consequential, as it suggests that GBM patients may require TMZDI as first line chemotherapy prior to systemic CAR infusion to promote CAR engraftment and antitumor efficacy. On this basis, we have initiated a phase I trial in patients with newly diagnosed GBM incorporating TMZDI as a preconditioning regimen prior to CAR immunotherapy (NCT02664363).