Bilateral Optic Neuropathy Secondary to Toxicity From Tumor-Infiltrating Lymphocytes Therapy Combined With Checkpoint Blockade

We present a unique case of immune-mediated optic neuropathy presenting after immunotherapy with adoptive cell therapy (ACT) with tumor- infiltrating lymphocytes (TILs) and single dose of check- point inhibitor for metastatic melanoma.

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD Bilateral Optic Neuropathy Secondary to Toxicity From Tumor-Infiltrating Lymphocytes Therapy Combined With Checkpoint Blockade Anna Kabanovski, BS, Trishal Jeeva-Patel, MD, Sam Saibil, MD, PhD, Edward Margolin, MD W e present a unique case of immune-mediated optic neuropathy presenting after immunotherapy with adoptive cell therapy (ACT) with tumorinfiltrating lymphocytes (TILs) and single dose of checkpoint inhibitor for metastatic melanoma. A 60-year-old woman with a history of metastatic malignant melanoma presented with 2 days history of blurry vision. She was diagnosed with acral lentiginous melanoma of the nailbed 6 years ago and subsequently presented with metastatic disease in the lungs and chest wall 3 years later. She was treated with pembrolizumab (antiprogrammed cell death [PD-1] antibody) but experienced progressive disease. Treatment with nivolumab (another anti–PD-1 antibody) and an antilymphocyte activator gene3 antibody commenced as part of a clinical trial. Unfortunately, she again experienced progressive disease and was treated with ipilimumab (anticytotoxic T-lymphocyte– associated antigen antibody) and intralesional injections with toll-like receptor agonist. Shortly after this regimen started, she developed symptoms of adrenal insufficiency and was found to have immune-mediated hypophysitis and panhypopituitarism requiring chronic hormonal replacement. She was then switched to a clinical trial of pembrolizumab and lenvatinib, a multiple-kinase inhibitor. Despite this, the disease continued to progress radiologically and this treatment was discontinued after 5 months. She was then treated with ACT using TILs therapy after receiving lymphodepleting chemotherapy with fludarabine and cyclophosphamide. This was followed by one infusion of pembrolizumab a month later. Four days after this injection, the patient noticed blurry vision in both eyes. On examination, vision was 20 of 50 in each eye, there was minimal left relative afferent pupillary defect, and both optic nerves were swollen with multiple peripapillary Department of Ophthalmology and Vision Sciences, Faculty of Medicine (AK), University of Toronto, Toronto, Canada; and Departments of Ophthalmology and Vision Sciences (TJ-P, EM), and Medicine (SS, EM), Faculty of Medicine, University of Toronto, Canada. The authors report no conflicts of interest. Address correspondence to Edward Margolin, MD, Division of Neurology, Department of Ophthalmology and Visual Sciences, and Medicine, Neuro-Ophthalmology, University of Toronto, 801 Eglinton Avenue West, Suite 301, Toronto, ON M5N 1E3, Canada; E-mail: [e-mail] e720 hemorrhages (Fig. 1A). There were nerve fiber bundle defects (NFBDs) in each eye on formal visual field testing (Fig. 1B). Urgent MRI of the brain and orbits with gadolinium demonstrated subtle perineural enhancement of the intracanalicular portion of the left optic nerve extending to chiasm (Fig. 2). High volume lumbar puncture demonstrated normal opening pressure and cerebrospinal fluid composition with cytology negative for malignancy. A presumed diagnosis of immune-mediated optic neuritis was made and treatment with high dose intravenous steroids for 3 days commenced. Two months later, central vision improved to 20 of 25 in each eye, there was no relative afferent pupillary defect, and optic nerve head edema completely resolved with mild residual NFBD on formal visual fields. Immune checkpoint inhibitors (ICIs) and ACT with TILs are 2 different therapeutic approaches in cancer immunotherapy. ICIs work by blocking negative regulatory signals to T-cells (1). Ligation of negative-regulatory receptors, such as cytotoxic T-lymphocyte–associated-4 (CTLA-4), PD-1 and lymphocyte-activation gene 3 (LAG3), by their cognate ligands causes downregulation of T-cells, allowing the tumor to grow. ICIs work by blocking this interaction and preventing the inhibition of T-cells, thereby allowing T-cells to remain activated and attack tumor cells (1). The first ICI was approved for treatment of metastatic melanoma in 2011, followed by the emergence of many new drugs, combinations, and indications. As expected with their mechanism of action, ICIs can cause immune-related adverse events that affect many organs and tissues, most commonly the skin, gastrointestinal tract (diarrhea, colitis), and endocrine system (thyroid dysfunction, hypophysitis, and adrenal crisis) side effects (1). The rate of severe adverse events (grade 3 or higher) is up to 52% in monotherapy, with higher risk in combination anti–CTLA4 and PD-1 blockade (1). ACT with TILs therapy is another immunotherapy modality for which clinical trials are ongoing. ACT with TILs involves extraction of CD8+ and CD4+ T-cells from the tumor material, expansion ex vivo with interleukin-2 (IL-2), and transfer back to the patient after a lymphodepleting preparatory chemotherapy regimen (2). The T-cell growth factor IL-2 is then given after cell infusion. Cell therapy with TILs has shown to have clinical benefit as Kabanovski et al: J Neuro-Ophthalmol 2021; 41: e720-e722 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. Fundus photographs demonstrating bilateral optic disc swelling with peripapillary disc hemorrhages seen on initial presentation (A), formal visual fields demonstrating left more than right diffuse nerve fiber bundle defect on initial presentation (B). monotherapy and potentially as combination with checkpoint inhibitors (2). Toxicities are usually associated with the lymphodepleting preparatory regimens and IL-2 (2). TIL itself although can also lead to autoimmune complications if the infused T-cells target antigens that are expressed by some normal tissues in addition to the target tumor cells (“on target, off tumor” autoimmunity) or if off-target toxicities occur (2). In patients treated for melanoma, autoimmune melanocyte destruction often manifests as vitiligo and/or uveitis (3). Although there are several reports describing optic nerve head swelling in patients on ICI (4), TIL has only very rarely been associated with ocular side effects and only anterior uveitis has been previously described. One previous case described a 35-year-old man with metastatic melanoma who FIG. 2. MRI T1 post-contrast imaging demonstrates subtle left optic nerve perineural enhancement seen on coronal view (A) along with subtle perineural enhancement involving the intracanalicular segment of the left optic nerve tracking back to the level of the optic chiasm on the axial view (B). Kabanovski et al: J Neuro-Ophthalmol 2021; 41: e720-e722 developed fever, rash, vitiligo, hearing loss, and recurrent bilateral anterior uveitis and cystoid macular edema after TIL therapy (3). Another report described uveitis in 5 of 35 patients undergoing TIL treatment for melanoma (3). There are no previous reports of immune-mediated optic neuritis as a result of TIL therapy. We believe our patient’s bilateral optic neuritis was most likely the consequence of TIL or possibly its potentiation by ICI as she was previously treated multiple times with the same ICI without any vision-related complications, and optic nerve head swelling developed very shortly after TIL was completed and only a few days after her rechallenge with pembrolizumab. Investigations for other etiologies of infiltrative causes of optic neuropathy were negative, and the patient demonstrated rapid resolution of optic nerve head swelling with improvement of central acuities after therapy with intravenous steroids and no recurrence on follow-up. The precise pathophysiological mechanism resulting in the patients’ vision loss, however, remains unclear. It is possible that the infused T-cells could have initiated an acute inflammatory demyelination of the retrobulbar optic nerves resulting in conduction block and vision loss. As the patient previously had severe immune-related side effects after PD-1 therapy, it is possible that although TIL have caused an onset of optic neuropathy, one infusion of PD-1 antibody might have potentiated this toxicity. Another possible etiology of optic neuropathy in this case could have been neurosarcoidosis which has been associated with ICI therapy (5). Although the exact pathophysiology of ICI inducing neurosarcoidosis remains unknown, it has been shown that they increase levels of Th17 CD4+ cells in peripheral e721 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence blood and in tissue samples (5). These are pathological findings seen in sarcoidosis, suggesting that the pathophysiology may involve infiltration of the involved tissues by Th17 CD4+ cells (5). We believe that although sarcoidosis was unlikely a culprit in our case because of the acute presentation of visual loss and absence of any other findings consistent with sarcoidosis on chest imaging. This is the first case presentation of acute optic neuropathy as a possible consequence of a synergistic toxicity between TIL and ICI therapy. This case highlights the importance of prudent monitoring for ocular complications in patients receiving immunotherapy, particularly those receiving novel combinations for which the potential toxicities remain undefined. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: E. Margolin, A. Kabanovski, T. Jeeva-Patel, and S. Saibil; b. Acquisition of data: E. Margolin, A. Kabanovski, T. Jeeva-Patel, and S. Saibil; c. Analysis and interpretation of data: E. Margolin, A. Kabanovski, T. Jeeva-Patel, and S. Saibil. Category 2: a. Drafting the manuscript: E. Margolin, A. Kabanovski, T. Jeeva-Patel, and S. Saibil; b. Revising it for intellectual content: E. Margolin, A. Kabanovski, T. Jeeva-Patel, and S. Saibil. e722 Category 3: a. Final approval of the completed manuscript: E. Margolin, A. Kabanovski, T. Jeeva-Patel, and S. Saibil. REFERENCES 1. Simeone E, Grimaldi AM, Festino L, Trojaniello C, Vitale MG, Vanella V, Palla M, Ascierto PA. Immunotherapy in metastatic melanoma: a novel scenario of new toxicities and their management. Melanoma Manag. 2019;6:MMT30. 2. Wolf B, Zimmermann S, Arber C, Irving M, Trueb L, Coukos G. Safety and tolerability of adoptive cell therapy in cancer. Drug Saf. 2019;42:315–334. 3. Yeh S, Karne NK, Kerkar SP, Heller CK, Palmer DC, Johnson LA, Li Z, Bishop RJ, Wong WT, Sherry RM, Yang JC, Dudley ME, Restifo NP, Rosenberg SA, Nussenblatt RB. Ocular and systemic autoimmunity after successful tumor-infiltrating lymphocyte immunotherapy for recurrent, metastatic melanoma. Ophthalmology. 2009;116:981–989.e1. 4. 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