{"id":501,"date":"2016-08-17T21:56:23","date_gmt":"2016-08-18T02:56:23","guid":{"rendered":"http:\/\/www.bocsci.com\/blog\/?p=501"},"modified":"2016-08-17T22:01:24","modified_gmt":"2016-08-18T03:01:24","slug":"immune-checkpoint-inhibitors-in-older-adults","status":"publish","type":"post","link":"https:\/\/www.bocsci.com\/blog\/immune-checkpoint-inhibitors-in-older-adults\/","title":{"rendered":"Immune Checkpoint Inhibitors in Older Adults"},"content":{"rendered":"

Cancer is primarily a disease of the older adult with more than\u00a050 % of new cases occurring in adults older than 65 years.\u00a0The care of older adults with cancer can be complicated by\u00a0multiple issues such as comorbidity, age-related organ dysfunction, and decreased functional status. This \u201cvulnerable\u201d\u00a0profile underlines the importance of understanding the role of\u00a0different treatment modalities in the geriatric population.\u00a0Immune checkpoint inhibition<\/a> is a novel treatment modality\u00a0that is being explored in multiple malignancies.<\/p>\n

Immune system activation begins when T cells recognize\u00a0peptide fragments of intracellular proteins that are expressed\u00a0on the surface of antigen presenting cells (APCs) bound to\u00a0specific mixed histocompatibility complex (MHC) molecules.\u00a0This interaction requires the presence of a costimulatory molecule (B7) and it results in the in upregulation of cytotoxic Tlymphocyte antigen 4 (CTLA-4<\/a>) on the surface of T lymphocytes. CTLA-4 is a negative regulator of T cell activation. It\u00a0exerts its downregulating activity by forming a bond with B7\u00a0that outcompetes CD28, thus serving as a physiologic \u201cbrakeof\u201d\u00a0immune function. The programmed cell death 1 receptor (PD-1<\/a>) is another inhibitory receptor on activated T cells.\u00a0The ability of activated T cells to produce an effective immune\u00a0response is decreased when PD-1 binds to its ligand PD-L1<\/a>.\u00a0PD-L1 is often present on tumor cells.<\/p>\n

Ipilimumab<\/a> is an antibody directed against CTLA-4.\u00a0Antibodies against PD-L1 include nivolumab<\/a> and\u00a0pembrolizumab<\/a>. These antibodies restore the antitumor immune response of the immune system, thereby producing a\u00a0therapeutic effect in a variety of malignancies. These\u00a0immune checkpoint inhibitors are novel agents in oncology.\u00a0Their improved efficacy and better safety profile make them\u00a0an attractive treatment option especially in older patients\u00a0where treatment tolerance can be a major issue. While there\u00a0are no elderly specific trials, this review attempts to look at the\u00a0current available data from a geriatric oncology perspective.\u00a0Multiple trials looking at checkpoint inhibitors have been published. In this paper, we will focus on agents that have both\u00a0mature data as well as FDA approved indications in common\u00a0malignancies such as non-small lung cancer, melanoma, and\u00a0renal cancer (Table 1).<\/p>\n

Immunologic checkpoint inhibitors have showed superior efficacy and a favorable safety\u00a0profile in comparison to previous, standard cytotoxic therapy. This has transformed the\u00a0management of many malignancies. Studies published by\u00a0the time this review was written were not sufficient to draw\u00a0a definitive conclusion regarding the role of these agents\u00a0among different age groups, but it seems that their profile is\u00a0similar in both younger and older adults. This is mostly true in\u00a0patients aged between 65 and 75 years but it is not as clear in\u00a0patients older than 75 years. This issue could be related to the\u00a0low accrual of patients in this age group; however, there is still\u00a0a theoretical concern about the efficacy of immune mediated\u00a0therapies in older adults due to immunosenescence. It is not\u00a0clear at this time how the aging of the immune system and the\u00a0associated dysfunction in T cells affects the response to immunotherapy in general and to checkpoint inhibition in particular. Checkpoint\u00a0inhibitors are favorable because\u00a0of efficacy with an improved safety profile. Across all trials,\u00a0they were associated with lower rates of AEs of any grade\u00a0compared to the control arm. Treatment with checkpoint inhibitors can be particularly associated with immune-related\u00a0AEs, and it is recommended that all patients receiving these\u00a0agents routinely have thyroid function studies, complete blood\u00a0counts, liver function tests, and metabolic panels checked. This is of particular concern in older adults as the incidence of autoimmune antibodies increases with age.\u00a0Current data does not show an increase in toxicity rates with\u00a0checkpoint inhibitors in older patients. The most significant\u00a0immune AEs include dermatological manifestations\u00a0(maculopapular rash), diarrhea, colitis, thyroiditis (hypo- or\u00a0hyperthyroidism), and elevation in transaminases. Less common (<5 %) but potentially more serious AEs include pneumonitis,\u00a0adrenal insufficiency, nephritis, and hypophysitis.\u00a0Select side effects of particular interest in the geriatric population due to their potential impact on quality of life and\/or\u00a0functional status are observed at lower rates with checkpoint\u00a0inhibitors compared to other systemic treatment options. Side\u00a0effects are more common with the anti-CTLA-4 antibody\u00a0ipilimumab than with the anti-PD-1 agents, and dual checkpoint inhibition is associated with greater toxicity compared to\u00a0monotherapy.
\nAlthough the role of immune checkpoint inhibitors in older\u00a0patients has yet to be well explored, they remain at this time a\u00a0highly recommended treatment option. Many questions remain to be answered about immunotherapy in older patients\u00a0and the effect of immunosenescence on tumor-targeted inflammatory response.<\/p>\n

 <\/p>\n

Reference:<\/p>\n

Rawad Elias & Joshua Morales & Yasser Rehman & Humera Khurshid. Curr Oncol Rep (2016) 18: 47<\/p>\n

 <\/p>\n

Related Products:<\/p>\n

<\/div>
<\/th><\/th><\/th><\/th><\/tr><\/thead>
CAS Number <\/td>Product Name <\/td>Target <\/td>Description <\/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>
946414-94-4 <\/td>nivolumab<\/a><\/td>PD-1<\/a><\/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>
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><\/tbody><\/table><\/div>\n","protected":false},"excerpt":{"rendered":"

Cancer is primarily a disease of the older adult with more than\u00a050 % of new cases occurring in adults older than 65 years.\u00a0The care of older adults with cancer can […]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[21],"tags":[278,275,288,129,276,277,286],"_links":{"self":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/501"}],"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=501"}],"version-history":[{"count":2,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/501\/revisions"}],"predecessor-version":[{"id":503,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/501\/revisions\/503"}],"wp:attachment":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/media?parent=501"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/categories?post=501"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/tags?post=501"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}