Patients with cancer are living longer than ever before, with outcomes improving steadily for at least the last decade. Along with improved screening and early diagnosis, this can largely be attributed to novel therapies that have entered physicians’ armamentarium — including not only radiation and chemotherapy, but more the more recent advent of various types of immunotherapies (eg, checkpoint blockade, personalized vaccines, and chimeric antigen receptor T-cells), hormonal therapies and other immune checkpoint inhibitors.
Indeed, the landscape of anti-cancer therapies is expanding rapidly — according to a review from May 2016 to May 2021, it was reported that an astounding 207 new oncology drugs were approved by the FDA.1
While various regimens for each type of drug modality has been validated and deemed “safe” by the FDA, clinicians have also seen an increase in the frequency and significance of drug-related side effects. Ophthalmic related adverse events are among the most prevalent, and while most side effects are mild in severity and transient in nature, many can be severe, debilitating, and irreversible.
One of the largest growing classes of cancer drug development is aimed at harnessing the natural power of the immune system — the most common of which is via immune checkpoint inhibition.
Immune Checkpoint Inhibitor Basics
During an immune response, T-cells become activated to eliminate infected or cancerous cells. However, to prevent excessive inflammation and autoimmune reactions, the immune system has built-in regulatory or “checkpoint” systems to reduce inflammatory activity. Cancer cells exploit this regulatory system by expressing signals on their surface that mimic the natural native signals used to turn off the immune system — thereby masking their presence and reducing the capacity of the immune system to detect and eliminate them. Immune checkpoint inhibitors are an elegant way to “unmask” cancer cells by blocking the cellular regulatory receptors, which allows T-cells to remain active and fight against abnormal cells.
Immune checkpoint inhibitors (ICIs), first approved in 2014, generally classify as antibodies that target specific parts of the T-cell lymphocyte regulatory system. Currently, the most common ICIs target the cytotoxic T-lymphocyte antigen-4- receptor (anti-CTLA-4), the programmed death-1 receptor (anti-PD-1) or its ligand (anti-PD-L1), and more recently lymphocyte-activation gene 3 (LAG-3).
The CTLA-4 receptor typically downregulates activation of the T-cell, while the PD-1 receptor/ligand interactions inhibit T-cell proliferation, cytokine release, and cytotoxicity. LAG3 is the newest target for checkpoint blockade and is known to dampen T-cell activation, which can ultimately limit the T-cell response against cancer cells. Consequently, inhibition of the CTLA-4 receptor, PD-1/PD-L1 and/or the LAG-3 protein has been shown to aid in a durable T-cell response towards cancer cells.
Associated Ocular Complications
The introduction of checkpoint blockade has dramatically transformed the therapeutic landscape for various malignancies and has led to remarkable improvements in patient outcome statistics. However, immune augmentation has also led to multiple types of immune related adverse events (irAEs). While most are self-limited, some irAEs may cause severe and permanent disability. That said, it is important to note that the different Immune checkpoint inhibitors mentioned above tend to differ in both the frequency and severity of irAEs. For instance, research shows ipilimumab (an anti-CTLA4 agent) has an irAE rate of 60% to 65%, with more than 40% of patients developing serious irAEs (ie, grade 3-4).2,3 Alternatively, anti-PD-1/PD-L1 are less frequent and also of lower grade, according to a 2020 study.4 Combination therapy, while gaining popularity for improved outcomes for a number of malignancies above single agent use, consequently results in a further increase in both the frequency and severity of irAEs.5
While the occurrence of ocular irAEs is reported as rare — up to 1% of patients on Immune checkpoint inhibitors — it is likely that many of these events are overlooked and underreported.6,7 Indeed, most reports are retrospective in nature or limited to clinical trial data.8 The most common reports are in patients that develop uveitis (0.3-15%), retinal dysfunction (~10.7%) and dry eye (1.2-24%).9,10 However, ocular disorders extend far beyond these reports and include toxicity of virtually every anatomical structure in the eye (from the eyelids and conjunctiva, to the lens, optic nerve, retina, and choroid).10 Less common ophthalmic irAEs include episcleritis, keratitis, conjunctivitis, myositis, vitritis, retinal detachment, uveal effusion, choroidopathy, and a number of neuro-ophthalmic toxicities.6,11,12 One of the most debilitating side effects that can lead to permanent visual loss is known as Vogt-Koyanagi-Harada (VKH) disease in which there is a T-cell mediated response directed against the pigment containing cells in both the eyes and the skin. This can lead to irreversible vision loss if not managed appropriately.
Complications’ Mechanisms of Action
The pathophysiology of ophthalmic complications associated with immune checkpoint inhibitor use is not completely understood. However, it is well known that the eyes are a site of “immune-privilege,” meaning there are mechanisms in place to protect against immune system infiltration of the eye. These mechanisms include, but are not limited to, anatomical barriers (the blood-retinal barrier and an absence of lymphatic vasculature leading to the eye) as well as molecular barriers (upregulation of Fas ligand and tumor growth factor-beta (TGF-B), as well as expression of PD-L1 and CTLA-4).13-15 Consequently, researchers have hypothesized that blockades of these regulators via ICIs not only unmasks the cancer cells that mimic these regulatory mechanisms, but it also removes many of the key players that promote immune privilege within the ocular structures. This leaves the ocular structures exposed to T-cell infiltration and manifests as the toxicities mentioned above.
In line with this hypothesis, there have been many reports that suggest that the development of an irAE actually predicts tumor response to ICI treatment.16,17 In one study, 7 out of 15 cases had either partial or complete tumor response after the development of uveitis.18
Maintaining Visual Health
Early recognition and treatment are key to maintaining good visual health in patients undergoing various cancer treatments. Most irAEs can be effectively controlled with topical, periocular, or systemic corticosteroids.9,19 However, treating ophthalmologists should recognize that administration of corticosteroids requires careful consideration, as they may impact the treatment effect of the ICI negatively. Comanagement with the oncology team to determine the relationship between treatment response and severity of irAEs is paramount. It is equally important to weigh the risks of treatment delays in the setting of severe irAEs, and while there are guidelines that recommend management based on the grade of adverse event, this must be established on a personalized patient-by-patient basis.
Further, it must not be lost on the ophthalmologist to consider the vulnerability of the eye to metastasis. There have been few case reports of cutaneous melanoma metastatic to the vitreous while undergoing ICI treatment.20,21 Delays in care of this nature can not only lead to vision loss but may also prevent early transitions to more effective therapies to treat systemic disease.
Lastly, it is important for ophthalmologists to know that while ~70% of ocular irAEs tend to occur within 2 months of initiating ICIs, they may occur at any time during or even after the cessation of treatment.10,22
As new oncologic medications rapidly enter the therapeutic space, patients are benefiting from improved outcomes and longer survival. Immune checkpoint inhibitors have revolutionized cancer treatment by harnessing the immune system’s ability to target and destroy cancer cells. However, the enhanced immune response can lead to irAEs, where the immune system attacks healthy tissues — including any structure within the eye. The unpredictable nature of irAEs possess challenges for medical professionals in balancing the benefits of cancer immunotherapy with the potential risks. Research efforts are focused on identifying biomarkers that can predict the development of irAEs, allowing for personalized treatment plans and risk stratification. Moreover, investigating new immunomodulatory strategies that can mitigate irAEs while preserving anticancer efficacy remains a critical area of interest.
- Benjamin DJ, Xu A, Lythgoe MP, Prasad V. Cancer drug approvals that displaced existing standard-of-care therapies, 2016-2021. JAMA Netw Open. 2022;5(3):e222265. doi:10.1001/jamanetworkopen.2022.2265
- Boutros C, Tarhini A, Routier E, et al. Safety profiles of anti-CTLA- 4 and anti-PD-1 antibodies alone and in combination. Nat Rev Clin Oncol. 2016;13:473–486. doi:10.1038/nrclinonc.2016.58
- Eggermont AMM, Chiarion-sileni V, Grob -J-J, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016;375:1845–1855. doi:10.1056/NEJMoa1611299
- Duan J, Cui L, Zhao X, et al. Use of Immunotherapy with programmed cell death 1 vs programmed cell death ligand 1 inhibitors in patients with cancer: a systematic review and meta-analysis. JAMA Oncol. 2020;6:375. doi:10.1001/jamaoncol.2019.5367
- Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377:1345-1356. doi:10.1056/ NEJMoa1709684
- Antoun J, Titah C, Cochereau I. Ocular and orbital side-effects of checkpoint inhibitors: a review article. Curr Opin Oncol. 2016;28(4):288–294. doi:10.1097/CCO.0000000000000296
- Moorthy RS, Moorthy MS, Cunningham ET. Drug-induced uveitis. Curr Opin Ophthalmol. 2018;29:588–603. doi:10.1097/ICU.0000000000000530
- Bomze D, Meirson T, Hasan Ali OH, Goldman A, Flatz L, Habot-Wilner Z. Ocular adverse events induced by immune checkpoint inhibitors: a comprehensive pharmacovigilance analysis. Ocul Immunol Inflamm. 2022;30(1):191-197. doi:10.1080/09273948.2020.1773867
- Abdel-Rahman O, Oweira H, Petrausch U, et al. Immune-related ocular toxicities in solid tumor patients treated with immune checkpoint inhibitors: a systematic review. Expert Rev Anticancer Ther. 2017;17(4):387-394. doi:10.1080/14737140.2017.1296765
- Dalvin LA, Shields CL, Orloff M, Sato T, Shields JA. Checkpoint inhibitor immune therapy: systemic indications and ophthalmic side effects. Retina. 2018;38(6):1063-1078. doi:10.1097/IAE.0000000000002181
- Theillac C, Straub M, Breton AL, Thomas L, Dalle S. Bilateral uveitis and macular edema induced by Nivolumab: a case report. BMC Ophthalmol. 2017;17(1):227. doi:10.1186/s12886-017-0611-3
- Reddy M, Chen JJ, Kalevar A, Terribilini R, Agarwal A. Immune retinopathy associated with nivolumab administration for metastatic non-small cell lung cancer. Retin Cases Brief Rep. 2020;14(2):120-126. doi:10.1097/ICB.0000000000000675
- de Andrade FA, Fiorot SHS, Benchimol EI, Provenzano J, Martins VJ, Levy RA. The autoimmune diseases of the eyes. Autoimmun Rev. 2016;15(3):258-271. doi:10.1016/j.autrev.2015.12.001
- Zhou R, Caspi RR. Ocular immune privilege. F1000 Biol Rep. Published online January 18, 2010. doi:10.3410/B2-3
- le Fournis S, Gohier P, Urban T, Jeanfaivre T, Hureaux J. Corneal graft rejection in a patient treated with nivolumab for primary lung cancer. Lung Cancer. 2016;102(12):28-29. doi:10.1016/j.lungcan.2016.10.008
- Papavasileiou E, Prasad S, Freitag SK, Sobrin L, Lobo AM. Ipilimumab-induced ocular and orbital inflammation—A case series and review of the literature. Ocul Immunol Inflamm. 2016;24(2):140-146. doi:10.3109/09273948.2014.1001858
- Attia P, Phan GQ, Maker AV, et al. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol. 2005;23(25):6043-6053. doi:10.1200/JCO.2005.06.205
- Wang W, Lam WC, Chen L. Recurrent grade 4 panuveitis with serous retinal detachment related to nivolumab treatment in a patient with metastatic renal cell carcinoma. Cancer Immunol Immunother. 2019;68(1):85-95. doi:10.1007/s00262-018-2260-7
- Davis ME, Francis JH. Cancer therapy with checkpoint inhibitors: establishing a role for ophthalmology. Semin Oncol Nurs. 2017;33(4):415-424. doi:10.1016/j.soncn.2017.08.003
- Manusow JS, Khoja L, Pesin N, Joshua AM, Mandelcorn ED. Retinal vasculitis and ocular vitreous metastasis following complete response to PD-1 inhibition in a patient with metastatic cutaneous melanoma. J Immunother Cancer. 2014;2(1):41. doi:10.1186/s40425-014-0041-1
- Kanavati S, Ottensmeier C, Foria V, Krishnan R. Bilateral metastatic cutaneous melanoma to retina and vitreous after ipilimumab treated with pars plana vitrectomy and radiotherapy. Retin Cases Brief Rep. 2018;12(3):184-187. doi:10.1097/ICB.0000000000000477
- Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378(2):158-168. doi:10.1056/NEJMra1703481