Project description:As a breakthrough strategy for cancer treatment, immunotherapy mainly consists of immune checkpoint inhibitors (ICIs) and other immunomodulatory drugs that provide a durable protective antitumor response by stimulating the immune system to fight cancer. However, due to the low response rate and unique toxicity profiles of immunotherapy, the strategies of combining immunotherapy with other therapies have attracted enormous attention. These combinations are designed to exert potent antitumor effects by regulating different processes in the cancer-immunity cycle. To date, immune-based combination therapy has achieved encouraging results in numerous clinical trials and has received Food and Drug Administration (FDA) approval for certain cancers with more studies underway. This review summarizes the emerging strategies of immune-based combination therapy, including combinations with another immunotherapeutic strategy, radiotherapy, chemotherapy, anti-angiogenic therapy, targeted therapy, bacterial therapy, and stroma-targeted therapy. Here, we highlight the rationale of immune-based combination therapy, the biomarkers and the clinical progress for these immune-based combination therapies.
Project description:The combination of chemotherapeutic agents with immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment. However, its success is often limited by insufficient immune priming in certain tumors, including pediatric malignancies. In this report, we explore clinical trials currently investigating the use of immunogenic cell death (ICD)-inducing chemotherapies in combination with ICIs for both adult and pediatric cancers. Given the limited clinical data available for pediatric tumors, we focused on recent preclinical studies evaluating the efficacy of these combinations in neuroblastoma (NB). Finally, to address this gap, we propose an innovative strategy to assess the impact of ICD-inducing chemotherapies on antitumor immune responses in NB. Using tumor spheroids derived from a transgenic NB mouse model, we validated our previous in vivo findings concerning how anthracyclines, specifically mitoxantrone and doxorubicin, significantly enhance MHC class I surface expression, stimulate IFNγ and granzyme B production by CD8+ T cells and NK cells, and promote immune cell recruitment. Importantly, these anthracyclines also upregulated PD-L1 expression on NB spheroids. This screening platform yielded results similar to in vivo findings, demonstrating that mitoxantrone and doxorubicin are the most potent immunomodulatory agents for NB. These data suggest that the creation of libraries of ICD inducers to be tested on tumor spheroids could reduce the number of combinations to be tested in vivo, in line with the principles of the 3Rs. Furthermore, these results highlight the potential of chemo-immunotherapy regimens to counteract the immunosuppressive tumor microenvironment in NB, paving the way for improved therapeutic strategies in pediatric cancers. They provide compelling evidence to support further clinical investigations of these combinations to enhance outcomes for children with malignancies.
Project description:Immunotherapies have an established role in the management of several advanced malignancies. Their responses are largely dependent on the presence of PD-L1, microsatellite instability (MSI), and high tumor mutation burden. Sarcomas are heterogenous tumors which comprise over 100 subtypes. They are broadly considered immunologically inert or "cold". Immunotherapy as monotherapy has shown interesting responses in a certain handful of subtypes, such as undifferentiated pleomorphic sarcoma, dedifferentiated and pleomorphic liposarcoma, and alveolar soft part sarcoma. However, the mechanisms of action of immunotherapy agents in several sarcoma subtypes remains unknown. Several sarcoma types such as leiomyosarcoma have been shown to have an immunosuppressive microenvironment. Early clinical studies suggest the emergence of B cell infiltration in sarcoma tumor tissues as well as the role of PD-1 and PD-L1 as biomarkers of response. Immunotherapy combinations with conventional chemotherapies, radiation therapies, tyrosine kinase inhibitors and oncolytic viruses are showing promise in turning these "cold" tumors "hot". Several novel agents as well as repurposing therapies with the potential to enhance immunotherapy responses are undergoing pre-clinical and clinical studies in other tumor types. Herein we review current clinical studies which have explored the use of immunotherapeutic agents in the management of sarcomas and discuss the challenges and future directions.
Project description:One of the major challenges limiting the efficacy of anti-PD-1/PD-L1 therapy in nonresponding patients is the failure of T cells to penetrate the tumor microenvironment. We showed that genetic or pharmacological inhibition of Vps34 kinase activity using SB02024 or SAR405 (Vps34i) decreased the tumor growth and improved mice survival in multiple tumor models by inducing an infiltration of NK, CD8+, and CD4+ T effector cells in melanoma and CRC tumors. Such infiltration resulted in the establishment of a T cell-inflamed tumor microenvironment, characterized by the up-regulation of pro-inflammatory chemokines and cytokines, CCL5, CXCL10, and IFNγ. Vps34i treatment induced STAT1 and IRF7, involved in the up-regulation of CCL5 and CXCL10. Combining Vps34i improved the therapeutic benefit of anti-PD-L1/PD-1 in melanoma and CRC and prolonged mice survival. Our study revealed that targeting Vps34 turns cold into hot inflamed tumors, thus enhancing the efficacy of anti-PD-L1/PD-1 blockade.
Project description:The development of immunotherapies has revolutionized intervention strategies for a variety of primary cancers. Despite this promising progress, treatment options for primary brain cancer and brain metastasis remain limited and still largely depend on surgical resection, radio- and/or chemotherapy. The paucity in the successful development of immunotherapies for brain cancers can in part be attributed to the traditional view of the brain as an immunologically privileged site. The presence of the blood-brain barrier and the absence of lymphatic drainage were believed to restrict the entry of blood-borne immune and inflammatory cells into the central nervous system (CNS), leading to an exclusion of the brain from systemic immune surveillance. However, recent insight from pre-clinical and clinical studies on the immune landscape of brain cancers challenged this dogma. Recruitment of blood-borne immune cells into the CNS provides unprecedented opportunities for the development of tumor microenvironment (TME)-targeted or immunotherapies against primary and metastatic cancers. Moreover, it is increasingly recognized that in addition to genotoxic effects, ionizing radiation represents a critical modulator of tumor-associated inflammation and synergizes with immunotherapies in adjuvant settings. This review summarizes current knowledge on the cellular and molecular identity of tumor-associated immune cells in primary and metastatic brain cancers and discusses underlying mechanisms by which ionizing radiation modulates the immune response. Detailed mechanistic insight into the effects of radiation on the unique immune landscape of brain cancers is essential for the development of multimodality intervention strategies in which immune-modulatory effects of radiotherapy are exploited to sensitize brain cancers to immunotherapies by converting immunologically "cold" into "hot" environments.
Project description:Immunotherapy, represented by immune checkpoint inhibitors (ICIs), has greatly improved the clinical efficacy of malignant tumor therapy. ICI-mediated antitumor responses depend on the infiltration of T cells capable of recognizing and killing tumor cells. ICIs are not effective in "cold tumors", which are characterized by the lack of T-cell infiltration. To realize the full potential of immunotherapy and solve this obstacle, it is essential to understand the drivers of T-cell infiltration into tumors. We present a critical review of our understanding of the mechanisms underlying "cold tumors", including impaired T-cell priming and deficient T-cell homing to tumor beds. "Hot tumors" with significant T-cell infiltration are associated with better ICI efficacy. In this review, we summarize multiple strategies that promote the transformation of "cold tumors" into "hot tumors" and discuss the mechanisms by which these strategies lead to increased T-cell infiltration. Finally, we discuss the application of nanomaterials to tumor immunotherapy and provide an outlook on the future of this emerging field. The combination of nanomedicines and immunotherapy enhances cross-presentation of tumor antigens and promotes T-cell priming and infiltration. A deeper understanding of these mechanisms opens new possibilities for the development of multiple T cell-based combination therapies to improve ICI effectiveness.
Project description:Immune checkpoint inhibitors have limited efficacy in metastatic pancreatic cancer due to the complex tumor immune microenvironment (TIME). Studies have shown that radiotherapy can cause cell lesions to release tumor antigens and then take part in the remodeling of the tumor environment and the induction of ectopic effects via regional and systemic immunoregulation. Here, we reported a case of advanced metastatic pancreatic cancer treated with immunotherapy combined with chemotherapy and radiotherapy and a sharp shift of the TIME from T3 to T2 was also observed. One hepatic metastasis within the planning target volume (PTV) was evaluated complete response (CR), the other one was evaluated partial response (PR) and 2 hepatic metastases outside the PTV were surprisingly considered PR. In the study, we found that immunotherapy combined with chemotherapy and radiotherapy achieved significant therapeutic benefits, which may provide a new strategy for the treatment of advanced pancreatic cancer.
Project description:Reprogramming the tumor microenvironment to increase immune-mediated responses is currently of intense interest. Patients with immune-infiltrated "hot" tumors demonstrate higher treatment response rates and improved survival. However, only the minority of tumors are hot, and a limited proportion of patients benefit from immunotherapies. Innovative approaches that make tumors hot can have immediate impact particularly if they repurpose drugs with additional cancer-unrelated benefits. The seasonal influenza vaccine is recommended for all persons over 6 mo without prohibitive contraindications, including most cancer patients. Here, we report that unadjuvanted seasonal influenza vaccination via intratumoral, but not intramuscular, injection converts "cold" tumors to hot, generates systemic CD8+ T cell-mediated antitumor immunity, and sensitizes resistant tumors to checkpoint blockade. Importantly, intratumoral vaccination also provides protection against subsequent active influenza virus lung infection. Surprisingly, a squalene-based adjuvanted vaccine maintains intratumoral regulatory B cells and fails to improve antitumor responses, even while protecting against active influenza virus lung infection. Adjuvant removal, B cell depletion, or IL-10 blockade recovers its antitumor effectiveness. Our findings propose that antipathogen vaccines may be utilized for both infection prevention and repurposing as a cancer immunotherapy.
Project description:BackgroundClear cell renal cell carcinoma (ccRCC) is the most frequently occurring malignant tumor within the kidney cancer subtype. It has low sensitivity to traditional radiotherapy and chemotherapy, the optimal treatment for localized ccRCC has been surgical resection, but even with complete resection the tumor will be eventually developed into metastatic disease in up to 40% of localized ccRCC. For this reason, it is crucial to find early diagnostic and treatment markers for ccRCC.MethodsWe obtained anoikis-related genes (ANRGs) integrated from Genecards and Harmonizome dataset. The anoikis-related risk model was constructed based on 12 anoikis-related lncRNAs (ARlncRNAs) and verified by principal component analysis (PCA), Receiver operating characteristic (ROC) curves, and T-distributed stochastic neighbor embedding (t-SNE), and the role of the risk score in ccRCC immune cell infiltration, immune checkpoint expression levels, and drug sensitivity was evaluated by various algorithms. Additionally, we divided patients based on ARlncRNAs into cold and hot tumor clusters using the ConsensusClusterPlus (CC) package.ResultsThe AUC of risk score was the highest among various factors, including age, gender, and stage, indicating that the model we built to predict survival was more accurate than the other clinical features. There was greater sensitivity to targeted drugs like Axitinib, Pazopanib, and Sunitinib in the high-risk group, as well as immunotherapy drugs. This shows that the risk-scoring model can accurately identify candidates for ccRCC immunotherapy and targeted therapy. Furthermore, our results suggest that cluster 1 is equivalent to hot tumors with enhanced sensitivity to immunotherapy drugs.ConclusionCollectively, we developed a risk score model based on 12 prognostic lncRNAs, expected to become a new tool for evaluating the prognosis of patients with ccRCC, providing different immunotherapy strategies by screening for hot and cold tumors.
Project description:We discuss how small-molecule inhibitors of the tryptophan (Trp) catabolic enzyme indoleamine 2,3-dioxygenase (IDO) represent a vanguard of new immunometabolic adjuvants to safely enhance the efficacy of cancer immunotherapy, radiotherapy, or 'immunogenic' chemotherapy by leveraging responses to tumor neoantigens. IDO inhibitors re-program inflammatory processes to help clear tumors by blunting tumor neovascularization and restoring immunosurveillance. Studies of regulatory and effector pathways illuminate IDO as an inflammatory modifier. Recent work suggests that coordinate targeting of the Trp catabolic enzymes tryptophan 2,3-dioxygenase (TDO) and IDO2 may also safely broaden efficacy. Understanding IDO inhibitors as adjuvants to turn immunologically 'cold' tumors 'hot' can seed new concepts in how to improve the efficacy of cancer therapy while limiting collateral damage.