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We also describe the challenges leading to the lack of efficacy with ICI use and discuss potential strategies to overcome those challenges including chimeric antigen receptor T-cell therapy (CAR-T therapy), bispecific T-cell therapy (BiTE), lymphocyte activation gene-3 (LAG-3) inhibitors, T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) inhibitors, vaccines, promotion of inflammatory macrophages, indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors, DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi). Tumor mutational burden and interferon-gamma release assays are potential biomarkers of ICI treatment response beyond PD-L1 expression. Further collaborations between clinicians and scientists are vital to understand the immunopathology in ICI therapy in order to improve clinical outcomes.The advent of chimeric antigen receptor T-cell (CAR T-cell) therapy has revolutionized the treatment paradigm of various hematologic malignancies. Ever since its first approval for treatment of acute lymphoblastic leukemia (ALL) in 2017, CAR T-cell therapy has been found to be efficacious in various other lymphoid malignancies, with recent approvals in diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). Although CAR T-cell therapeutics offer a novel immunotherapeutic approach to treat otherwise refractory malignancies, the plethora of studies/products and complexities in manufacturing and administration have led to several challenges for clinicians and the healthcare system as a whole. Some of the areas of unmet need include manufacturing delays, short persistence of CAR T-cells in circulation, lack of predictive biomarkers for efficacy and toxicity, and high cost of therapy. In this review, we evaluate the existing data on the efficacy and safety of CAR T-cell therapies in mature lymphoid malignancies [lymphomas, chronic lymphocytic leukemia (CLL), and multiple myeloma]. We also provide an in-depth review of the challenges posed by CAR T-cell therapeutics and potential strategies to overcome them. With newer CAR T-cell products and incorporation of measures to mitigate toxicities pertaining to cytokine release and neurological syndromes, there is a potential to overcome several of these challenges in the near future. Finally, as CAR T-cell therapy gains regulatory approval for more indications, there is a need to tackle the financial toxicity posed by this modality to sustain patient access.Immune checkpoint inhibitors have been widely incorporated for cancer treatment in a variety of solid and hematologic malignancies. Multiple clinical trials have demonstrated the efficacy of PD-1/PD-L1 and CTLA-4 axis inhibition in the metastatic and adjuvant settings. Due to the risks of autoimmune toxicity with these agents, stringent inclusion/exclusion criteria were employed in those initial clinical trials. These criteria led to exclusion or underrepresentation of a variety of patient populations with underlying immune dysfunction. These populations included patients with preexisting autoimmune diseases, solid organ or bone marrow transplant recipients, patients with HIV or viral hepatitis infections, patients receiving concurrent chronic steroid therapy, as well as patients who were elderly, pregnant, or had poor performance status. Thus, established guidelines on the use of immune checkpoint inhibitors in these patients are lacking, and evidence to support efficacy or toxicity are overall limited to retrospective studies and case series. Fortunately, ongoing clinical trials are now including these patients and are shedding light on whether these underrepresented populations can also safely benefit from immune checkpoint inhibitor therapies. In this review, we summarize the most clinically relevant available data on the use of checkpoint inhibitors in immunocompromised patient groups with a primary focus on safety.Immunotherapy has led to a paradigm shift in the treatment of several cancers. There have been significant efforts to identify biomarkers that can predict response and toxicities related to immune checkpoint inhibitor (ICPI) therapy. Despite these advances, it has been challenging to tease out why a subset of patients benefit more than others or why certain patients experience immune-related adverse events (irAEs). Although the immune-modulating properties of the human gut bacterial ecosystem are yet to be fully elucidated, there has been growing interest in evaluating the role of the gut microbiome in shaping the therapeutic response to cancer immunotherapy. Considerable research efforts are currently directed to utilizing metagenomic and metabolic profiling of stool microbiota in patients on ICPI-based therapies. Dysbiosis or loss of microbial diversity has been associated with a poor treatment response to ICPIs and worse survival outcomes in cancer patients. Emerging data have shown that certain bacterial strains, such as Faecalibacterium that confer sensitivity to ICPI, also have a higher propensity to increase the risk of irAEs. GS-9973 clinical trial Additionally, the microbiome can modulate the local immune response at the intestinal interface and influence the trafficking of bacterial peptide primed T-cells distally, influencing the toxicity patterns to ICPI. Antibiotic or diet induced alterations in composition of the microbiome can also indirectly alter the production of certain bacterial metabolites such as deoxycholate and short chain fatty acids that can influence the anti-tumor tolerogenesis. Gaining sufficient understanding of the exact mechanisms underpinning the interplay between ICPI induced anti-tumor immunity and the immune modulatory role gut microbiome can be vital in identifying potential avenues of improving outcomes to cancer immunotherapy. In the current review, we have summarized and highlighted the key emerging data supporting the role of gut microbiome in regulating response to ICPIs in cancer.

Patients with pre-existing autoimmune disease (AD) have been largely excluded from clinical trials of immune checkpoint inhibitors (ICI), so data on safety of ICIs among patients with pre-existing AD are relatively limited. There is a need for deeper understanding of the type and management of complications from ICI in patients with pre-existing AD. We sought to investigate the safety of ICIs in patients with pre-existing ADs as well as factors associated with AD flare.

Consecutive patients with pre-existing AD who received monotherapy as well as combination of ICI therapies at our institution from September 2015 through September 1

, 2018 were identified. Clinical information was abstracted via manual chart review. Clinical factors associated with AD flare were determined using multivariable logistic regression.

A total of 42 patients were identified of whom 12 developed AD flare. All flares were treated with oral or topical corticosteroids, while a patient with flare of rheumatoid arthritis was treated with tofacitinib and another patient with Crohn's flare was treated with infliximab.