Cancer is primarily a disease of the older adult with more than 50 % of new cases occurring in adults older than 65 years. The care of older adults with cancer can be complicated by multiple issues such as comorbidity, age-related organ dysfunction, and decreased functional status. This “vulnerable” profile underlines the importance of understanding the role of different treatment modalities in the geriatric population. Immune checkpoint inhibition is a novel treatment modality that is being explored in multiple malignancies.
Immune system activation begins when T cells recognize peptide fragments of intracellular proteins that are expressed on the surface of antigen presenting cells (APCs) bound to specific mixed histocompatibility complex (MHC) molecules. This interaction requires the presence of a costimulatory molecule (B7) and it results in the in upregulation of cytotoxic Tlymphocyte antigen 4 (CTLA-4) on the surface of T lymphocytes. CTLA-4 is a negative regulator of T cell activation. It exerts its downregulating activity by forming a bond with B7 that outcompetes CD28, thus serving as a physiologic “brakeof” immune function. The programmed cell death 1 receptor (PD-1) is another inhibitory receptor on activated T cells. The ability of activated T cells to produce an effective immune response is decreased when PD-1 binds to its ligand PD-L1. PD-L1 is often present on tumor cells.
Ipilimumab is an antibody directed against CTLA-4. Antibodies against PD-L1 include nivolumab and pembrolizumab. These antibodies restore the antitumor immune response of the immune system, thereby producing a therapeutic effect in a variety of malignancies. These immune checkpoint inhibitors are novel agents in oncology. Their improved efficacy and better safety profile make them an attractive treatment option especially in older patients where treatment tolerance can be a major issue. While there are no elderly specific trials, this review attempts to look at the current available data from a geriatric oncology perspective. Multiple trials looking at checkpoint inhibitors have been published. In this paper, we will focus on agents that have both mature data as well as FDA approved indications in common malignancies such as non-small lung cancer, melanoma, and renal cancer (Table 1).
Immunologic checkpoint inhibitors have showed superior efficacy and a favorable safety profile in comparison to previous, standard cytotoxic therapy. This has transformed the management of many malignancies. Studies published by the time this review was written were not sufficient to draw a definitive conclusion regarding the role of these agents among different age groups, but it seems that their profile is similar in both younger and older adults. This is mostly true in patients aged between 65 and 75 years but it is not as clear in patients older than 75 years. This issue could be related to the low accrual of patients in this age group; however, there is still a theoretical concern about the efficacy of immune mediated therapies in older adults due to immunosenescence. It is not clear at this time how the aging of the immune system and the associated dysfunction in T cells affects the response to immunotherapy in general and to checkpoint inhibition in particular. Checkpoint inhibitors are favorable because of efficacy with an improved safety profile. Across all trials, they were associated with lower rates of AEs of any grade compared to the control arm. Treatment with checkpoint inhibitors can be particularly associated with immune-related AEs, and it is recommended that all patients receiving these agents routinely have thyroid function studies, complete blood counts, liver function tests, and metabolic panels checked. This is of particular concern in older adults as the incidence of autoimmune antibodies increases with age. Current data does not show an increase in toxicity rates with checkpoint inhibitors in older patients. The most significant immune AEs include dermatological manifestations (maculopapular rash), diarrhea, colitis, thyroiditis (hypo- or hyperthyroidism), and elevation in transaminases. Less common (<5 %) but potentially more serious AEs include pneumonitis, adrenal insufficiency, nephritis, and hypophysitis. Select side effects of particular interest in the geriatric population due to their potential impact on quality of life and/or functional status are observed at lower rates with checkpoint inhibitors compared to other systemic treatment options. Side effects are more common with the anti-CTLA-4 antibody ipilimumab than with the anti-PD-1 agents, and dual checkpoint inhibition is associated with greater toxicity compared to monotherapy.
Although the role of immune checkpoint inhibitors in older patients has yet to be well explored, they remain at this time a highly recommended treatment option. Many questions remain to be answered about immunotherapy in older patients and the effect of immunosenescence on tumor-targeted inflammatory response.
Rawad Elias & Joshua Morales & Yasser Rehman & Humera Khurshid. Curr Oncol Rep (2016) 18: 47
|CAS Number||Product Name||Target||Description|
|1374853-91-4||pembrolizumab||PD-1||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.|
|946414-94-4||nivolumab||PD-1||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.|
|477202-00-9||Ipilimumab||CTLA4||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.|