<\/p>\n
Immunotherapy and immune checkpoint inhibition in particular present an exciting opportunity for the treatment\u00a0of bladder cancer. Over the last 30 years, bladder cancer\u00a0patients have seen few advances in the treatment of their\u00a0disease. With an estimated 74,000 new cases and 16,000\u00a0deaths from bladder cancer in 2015, the incidence and survival have remained relatively constant. In patients,\u00a0both with muscle-invasive disease undergoing radical cystectomy as well as those with locally advanced or metastatic disease, there have been no new FDA-approved\u00a0therapies for those who cannot tolerate or fail to respond\u00a0to cisplatin-based chemotherapy. However, in the last several years, new insights into tumor immunology have lead\u00a0to the development of a new class of drugs termed immune\u00a0checkpoint inhibitors, several of which have demonstrated\u00a0impressive anti-tumor responses in several malignancies,\u00a0including melanoma, non-small cell lung cancer (NSCLC),\u00a0and renal cell carcinoma (RCC).<\/p>\n
Currently, these immune checkpoint inhibitors<\/a> are being\u00a0actively studied in several treatment settings for bladder\u00a0cancer, including for non-muscle-invasive disease with\u00a0BCG (pembrolizumab<\/a>, NCT02324582) as well as neoadjuvant or adjuvant therapy after cystectomy (atezolizumab<\/a>, NCT02451423, NCT02450331). In June 2014,\u00a0the FDA granted the anti-PD-L1 antibody atezolizumab\u00a0(MPDL3280A) \u201cbreakthrough\u201d status for urothelial carcinoma based on promising results of a phase 1a trial in\u00a0patients with metastatic disease.\u00a0The purpose of this article is to review the basis for\u00a0immune checkpoint inhibition in muscle-invasive bladder\u00a0cancer and discuss the current state of clinical trials to evaluate their safety and efficacy.<\/p>\n Cancer immunotherapy and the role of the<\/b><\/strong>\u00a0<\/b><\/strong>immune checkpoint<\/b><\/strong> The CTLA\u001e4 checkpoint<\/b><\/strong> PD\u001e1 checkpoint<\/b><\/strong> <\/p>\n Reference:<\/p>\n Max Kates<\/b><\/strong>,<\/b><\/strong>\u00a0Nikolai A. Sopko<\/b><\/strong>,<\/b><\/strong>\u00a0Hotaka Matsui<\/b><\/strong>. <\/b><\/strong>World J Urol (2016) 34:49\u201355<\/p>\n Immunotherapy and immune checkpoint inhibition in particular present an exciting opportunity for the treatment\u00a0of bladder cancer. Over the last 30 years, bladder cancer\u00a0patients have seen few advances in the […]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[21],"tags":[287,278,275,288,129,276,277,289,286],"_links":{"self":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/499"}],"collection":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/comments?post=499"}],"version-history":[{"count":1,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/499\/revisions"}],"predecessor-version":[{"id":500,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/499\/revisions\/500"}],"wp:attachment":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/media?parent=499"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/categories?post=499"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/tags?post=499"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}
\nHuman tumors elicit adaptive immune responses, mediated\u00a0primarily by T lymphocytes. T cells have been the primary\u00a0focus of cancer immunotherapy primarily due to their ability to organize diverse immune responses via CD4+ helper\u00a0T cells that have adaptive and innate effector mechanisms.\u00a0Analysis of immune infiltrates suggests that greater infiltration by T lymphocytes is largely associated with a stronger\u00a0anti-tumor activity and chemotherapeutic response.\u00a0Broad cytotoxic CD8+ T cell infiltration in particular has\u00a0been associated with improved survival through its role of\u00a0recognizing tumor-associated antigens (TAA) presented\u00a0by major histocompatibility complex class I (MHC-I)\u00a0molecules. CD4+ T cells also exhibit effector functions against MHC class II molecule-negative tumors and\u00a0produce cytokines that mediate these immune responses.\u00a0These effector T cells are balanced by Foxp3+ regulatory\u00a0Treg (T) cells, which suppress natural killer cells and the\u00a0innate immune response as well as effector T cells and the\u00a0adaptive response. The balance of co-stimulatory and\u00a0inhibitory responses to cancer is a central tenant of cancer\u00a0immunology.<\/p>\n
\nCTLA-4<\/a>, which is expressed solely on T cells, primarily\u00a0inactivates T cell activity by competing with the CD28 costimulatory molecule. CD28 and CTLA-4 share the\u00a0identical ligands of CD80 and CD86 on antigen-presenting\u00a0cells (APCs), and thus CTLA-4 competes with CD28 function in T cell survival, proliferation, and recruitment. In particular, CTLA-4 down-modulates CD4+ helper\u00a0T cell activity and enhances Treg immunosuppressive functions. The blockade of CTLA-4 has been in development for\u00a0sometime, since Allison and colleagues used preclinical\u00a0models to show that antibody blockade of CTLA-4-enhanced immune-mediated anti-tumor activity. Ipilimumab<\/a> is a monoclonal antibody targeting CTLA-4 and the\u00a0first therapy to demonstrate a survival benefit for patients\u00a0with metastatic melanoma, and it was quickly FDA approved thereafter (see Fig. 1). More impressive was\u00a0that 18 % of patients survived beyond 2 years, compared\u00a0with a 5 % survival rate with the previous standard of care.\u00a0However, the potent immunomodulatory effects of CTLA-4\u00a0blockade leads to a significant adverse events (AE), which\u00a0occur in >70 % of patients treated with ipilimumab.\u00a0These range from dermatitis, colitis, and hepatitis, to less\u00a0common uveitis, neuropathy, and lupus nephritis.\u00a0Essentially with anti-tumor immune suppression comes a\u00a0component of autoimmune suppression.<\/p>\n
\nIt is in the context of CTLA-4\u2019s dramatic anti-tumor activity with a high burden of AEs that propagated interest in\u00a0the PD-1 pathway. In contrast to CTLA-4, PD-1 expression is induced in peripheral tissues when T cells become\u00a0activated. This cell-surface molecule is activated by two\u00a0ligands\u2014PD-L1 and PD-L2, which share 37 % sequence\u00a0homology and lie within 100 kb of one another in the\u00a0genome. PD-1 is expressed on many different subtypes of tumor infiltrating leukocytes, and is particularly\u00a0overexpressed on intra-tumoral Tregs. Similarly, PD-L1\u00a0has been shown to have high expression in several solid\u00a0organ tumors, including melanoma and lung cancer.\u00a0PD-L2, by contrast, has been less frequently studied but\u00a0is expressed on different types of APCs (monocytes, macrophages, and dendritic cells) and is also up-regulated during T cell activation in tumor.\u00a0PD-L1 and PD-L2 expressions can be up-regulated\u00a0innately via constitutive oncogenic signaling by the tumor\u00a0cells (via activation of the AKT and STAT3 pathways),\u00a0or can be induced by an adaptive means as a response to\u00a0inflammatory signaling. Sustained ligand expression\u00a0of PD-L1 or PD-L2 on tumor cells leads to proliferation\u00a0of Tregs and to a state of exhaustion and ultimately T cell\u00a0anergy and apoptosis. The result is an immunosuppressive state that leads to tumor cell escape and proliferation. Thus far, monoclonal antibodies targeting both PD-1\u00a0(nivolumab<\/a>\/pembrolizumab) and PD-L1 (atezolizumab)\u00a0have been evaluated in human trials. Across multiple histologies, PD-1 and PD-L1 inhibitors\u00a0have shown tumor\u00a0regressions and partial and complete responses. In\u00a0some settings, response was durable beyond 2 years and\u00a0persisted after drug discontinuation.<\/p>\nRelated\u00a0Products:<\/h4>\n
<\/th> <\/th> <\/th> <\/th><\/tr><\/thead> CAS Number <\/td> Product Name <\/td> Target <\/td> Description <\/td><\/tr> 1380723-44-3 <\/td> Atezolizumab<\/a><\/td> PD-L1<\/a><\/td> Atezolizumab binds to PD-L1, blocking its binding to and activation of its receptor programmed death 1 (PD-1) expressed on activated T-cells, which may enhance the T-cell-mediated immune response to neoplasms and reverse T-cell inactivation. In addition, by binding to PD-L1, atezolizumab also prevents binding of this ligand to B7.1 expressed on activated T cells, which further enhances the T-cell-mediated immune response. PD-L1 is overexpressed on many human cancer cell types and on various tumor-infiltrating immune cells. <\/td><\/tr> 477202-00-9 <\/td> Ipilimumab<\/a><\/td> CTLA4<\/a><\/td> Ipilimumab binds to CTLA4 expressed on T-cells and inhibits the CTLA4-mediated downregulation of T-cell activation. This leads to a cytotoxic T-lymphocyte (CTL)-mediated immune response against cancer cells. <\/td><\/tr> 946414-94-4 <\/td> nivolumab<\/a><\/td> PD-1 <\/td> Nivolumab, marketed as Opdivo, is a humanized IgG4 anti-PD-1 monoclonal antibody used to treat cancer. Nivolumab works as a checkpoint inhibitor, blocking a signal that would have prevented activated T cells from attacking the cancer, thus allowing the immune system to clear the cancer. <\/td><\/tr> 1374853-91-4 <\/td> pembrolizumab<\/a><\/td> PD-1 <\/td> Pembrolizumab (formerly MK-3475 and lambrolizumab, trade name Keytruda) is a humanized antibody used in cancer immunotherapy. It targets the programmed cell death 1 (PD-1) receptor. The drug was initially used in treating metastatic melanoma. <\/td><\/tr><\/tbody><\/table><\/div>\n","protected":false},"excerpt":{"rendered":"