Discovery of Small Molecules for the Reversal of T Cell Exhaustion
Publication date: 3 December 2019Source: Cell Reports, Volume 29, Issue 10Author(s): Brett S. Marro, Jaroslav Zak, Reza Beheshti Zavareh, John R. Teijaro, Luke L. Lairson, Michael B.A. OldstoneSummaryInhibitory receptors (IRs) function as critical regulators of immune responses by tempering T cell activity. In humans, several persisting viruses as well as cancers exploit IR signaling by upregulating IR ligands, resulting in suppression of T cell function (i.e., exhaustion). This allows escape from immune surveillance and continuation of disease. Here, we report the design, implementation, and results of a phenotypic high-throughput screen for molecules that modulate CD8+ T cell activity. We identify 19 compounds from the ReFRAME drug-repurposing collection that restore cytokine production and enhance the proliferation of exhausted T cells. Analysis of our top hit, ingenol mebutate, a protein kinase C (PKC) inducing diterpene ester, reveals a role for this molecule in overriding the suppressive signaling cascade mediated by IR signaling on T cells. Collectively, these results demonstrate a disease-relevant methodology for identifying modulators of T cell function and reveal new targets for immunotherapy.Graphical Abstract
This study proposes an effective positive control design strategy for cancer treatment by resorting to the combination of immunotherapy and chemotherapy. The treatment objective is to transfer the initial number of tumor cells and immune–competent cells from the malignant region into the region of benign growth where the immune system can inhibit tumor growth. In order to achieve this goal, a new modeling strategy is used that is based on Takagi–Sugeno. A Takagi-Sugeno fuzzy model is derived based on the Stepanova nonlinear model that enables a systematic design of the controller. Then, a positive Parallel Dist...
CONCLUSION: Regulatory T cells play an important role in the pathogenesis of cancer and allergies, and thus represent a therapeutic target. PMID: 31970443 [PubMed - as supplied by publisher]
Palliative care practitioners are increasingly treating patients with comorbid opioid use disorder (OUD), yet guidance is lacking for managing pain in this population. Historically, palliative care clinicians have liberally prescribed opioids to patients with limited prognosis. As medicine has evolved, patients with chronic illnesses, even metastatic cancer, are living longer thanks to immunotherapies and other novel treatments. Thus, palliative care patients are at greater risk of both developing OUD and/or chemical coping while receiving intensive treatments.
Over the past several years, a wave of new cancer immunotherapy agents referred to as immune checkpoint inhibitors (ICIs) have transformed the standard of care for patients with cancer. ICIs are most commonly used in advanced cancers with palliative intent and recently as frontline therapy for some cancers. These new agents have been shown to extend overall survival (OS) and progression free survival (PFS) in patients with lung cancer, melanoma, Hodgkin lymphoma, renal cell carcinoma, urothelial carcinoma, Merkel cell carcinoma, head and neck cancer, and more.
Scientists have successfully destroyed cancer cells in mice by using copper-based nanoparticles and immunotherapy. Importantly, the cancer did not return.
Although rates of cervical cancer in the United States have been declining due to vaccination and screening efforts, it remains the fourth most common cancer in women worldwide and is still far from being eradicated, even in developed nations. This review discusses recent developments in cervical cancer treatment and reviews the literature supporting recent practice changes encompassing staging, surgical management, radiation, chemotherapy, targeted agents including immunotherapy, and imaging.
The role of the immune system in the development of cancer has been a subject of ongoing clinical investigation in recent years. Emerging data demonstrate that tumorigenesis resulting in ovarian, uterine, and cervical cancers is a consequence of impaired host immune responses to cancerous cells. Leveraging the immune system through the use of immune checkpoint inhibitors, therapeutic vaccine therapy, and adoptive cell transfer presents a profound opportunity to revolutionize cancer treatment. This review will encompass the role of the immune system in development of gynecologic cancers and highlight recent data regarding i...
Immune checkpoint inhibitors (ICIs) have become a new standard of care in several cancers but often lead to undesirable immune-related adverse effects, including GI toxicity in up to 1/3 of patients. ICI-related colitis (irColitis) is generally treated with immunosuppressive medications such as steroids, but may be refractory in up to 50% of cases and require further treatments such as infliximab. The role of vedolizumab (VDZ), a newer gut-selective agent approved for inflammatory bowel disease (IBD), remains unclear.
Publication date: Available online 23 January 2020Source: Pharmacological ResearchAuthor(s): Ting Wei, Weijie Zhong, Qingshan LiAbstractRegulatory T cells (Tregs) modulate ongoing immune responses to prevent autoimmunity in healthy bodies and inhibit effective anti-tumor immunity responses in tumor patients, leading to tumor progression. The function of Tregs in tumor immunity suggests that elimination of Tregs in the host may enhance the anti-tumor immune response. Despite the success of strategies for depleting Tregs in tumor-bearing patients, the overall clinical efficacy is limited and accompanied by undesirable side e...
Conclusion: Albeit limited in scope, our data suggest that cytotoxic therapy with nab-paclitaxel and bevacizumab appear to favorably alter systemic parameters of immune function of potential benefit in combination T-cell directed immune checkpoint inhibitor therapy.