Horowitzcohen7361

Reviewed topics include immune-related adverse events (irAEs), toxicities on combining immunotherapy with other agents, disease reactivation such as tuberculosis (TB) and sarcoid-like granulomatosis, tumor hyperprogression (HPD), financial toxicity, challenges in special patient populations such as solid organ transplant recipients and those with auto-immune diseases. We also reviewed reports of worse or even lethal outcomes compared to other oncologic therapies in certain scenarios and summarized biomarkers predicting adverse events.Immune checkpoint inhibitors (ICPIs) have revolutionized the treatment paradigm of a wide range of malignancies with durable responses seen in even advanced, refractory cancers. Unfortunately, only a small proportion of patients with cancer derive meaningful benefit to ICPI therapy, and its use is also limited by significant immune and financial toxicities. Thus, there is a critical need for the development of biomarkers to reliably predict response to ICPI therapy. Only a few biomarkers are validated and approved for use with currently Food and Drug administration (FDA)-approved ICPIs. The development and broad application of biomarkers is limited by the lack of complete understanding of the complex interactions of tumor-host environment, the effect of immunotherapies on these already complex interactions, a lack of standardization and interpretation of biomarker assays across tumor types. Despite these challenges, the field of identifying predictive biomarkers is evolving at an unprecedented pace leaving the clinician responsible for identifying the patients that may derive optimal benefit from ICPIs. In this review, we provide clinicians with a current and practical update on the key, clinically relevant biomarkers of response to ICPIs. We categorize the current and emerging biomarkers of response to ICPIs in four major categories that govern anticancer response-the inflamed tumor, tumor antigens, immune suppression, and overall host environment.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.Prognosis of metastatic melanoma has undergone substantial improvement with the discovery of checkpoint inhibitors. Immunotherapies and targeted therapies have improved the median overall survival (OS) of metastatic melanoma from 6 months to more than 3 years. However, still about half of the patients die due to uncontrolled disease. Emricasan Therefore, multiple strategies are currently being investigated to improve outcomes. One such strategy is intralesional/intratumoral (IT) therapies which can either directly kill the tumor cells or make the tumor more immunogenic to be recognized by the immune system. Talimogene laherparepvec (T-VEC), an oncolytic virus, is the first FDA approved IT therapy. This review focuses on the current status of IT agents currently under clinical trials in melanoma. Reviewed therapies include T-VEC, T-VEC with immune checkpoint inhibitors including ipilimumab and pembrolizumab or other agents, RP1, OrienX010, Canerpaturev (C-REV, HF10), CAVATAK (coxsackievirus A21, CVA21) alone or in combination with checkpoint inhibitors, oncolytic polio/rhinovirus recombinant (PVSRIPO), MAGE-A3-expressing MG1 Maraba virus, VSV-IFNbetaTYRP1, suicide gene therapy, ONCOS-102, OBP-301 (Telomelysin), Stimulation of Interferon Genes Pathway (STING agonists) including DMXAA, MIW815 (ADU-S100) and MK-1454, PV-10, toll-like receptors (TLRs) agonists including TLR-9 agonists (SD-101, CMP-001, IMO-2125 or tilsotolimod, AST-008 or cavrotolimod, MGN1703 or lefitolimod), CV8102, NKTR-262 plus NKTR-214, LHC165, G100, intralesional interleukin-2, Daromun (L19IL2 plus L19TNF), Hiltonol (poly-ICLC), electroporation including calcium electroporation and plasmid interleukin-12 electroporation (pIL-12 EP), IT ipilimumab, INT230-6 (cisplatin and vinblastine with an amphiphilic penetration enhancer), TTI-621 (SIRPαFc), CD-40 agonistic antibodies (ABBV-927 and APX005M), antimicrobial peptide LL37 and other miscellaneous agents.Immune checkpoint inhibitors (ICIs) are immunomodulatory antibodies that intensify the host immune response, thereby leading to cytotoxicity. The primary targets for checkpoint inhibition have included cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death receptor-1 (PD-1) or programmed cell death ligand-1 (PD-L1). ICIs have resulted in a change in treatment landscape of various neoplasms. Among hematologic malignancies, ICIs have been most successful in certain subtypes of lymphomas such as classic Hodgkin lymphoma (cHL) and primary mediastinal B-cell lymphoma (PMBCL). However, there have been several challenges in harnessing the host immune system through ICI use in other lymphomas. The underlying reasons for the low efficacy of ICI monotherapy in most lymphomas may include defects in antigen presentation, non-inflamed tumor microenvironment (TME), immunosuppressive metabolites, genetic factors, and an overall lack of predictive biomarkers of response. In this review, we outline the existing and ongoing studies utilizing ICI therapy in various lymphomas.