Corneal pseudomicrocysts following claudin-6 antibody-drug conjugate infusion

Abstract

Purpose

To report a case of bilateral corneal pseudomicrocysts associated with infusions of a novel antibody-drug conjugate targeting claudin-6, called TORL-1-23.

Observations

A 47-year-old female with a history of advanced recurrent serous ovarian cancer presented to a level 1 tertiary care center with ocular irritation, redness, tearing, and light sensitivity following two infusions of TORL-1-23. Patient's past ocular history was unremarkable. The patient was enrolled in a phase 1 clinical trial for TORL-1-23, an antibody-drug conjugate (ADC). Nine days following the second infusion the patient presented to the ophthalmology clinic complaining of two weeks of bilateral eye discomfort, tearing, and photophobia. On examination, the patient had decreased visual acuity with a surface keratopathy associated with a whorled pattern of epithelial pseudomicrocysts in both eyes. Corneal changes were concentrated between the inferior limbus and central cornea. The remainder of the ophthalmic exam was unremarkable. Collagen and silicone punctal plugs were placed and the patient was started on preservative free artificial tears, topical loteprednol 0.5 %, later replaced with topical prednisolone acetate 1 % drops, and brimonidine 0.2 % in both eyes. The patient developed neuropathy which necessitated a decrease in ADC dosage and the patient's symptoms subsequently improved. However, a decrease in visual acuity and increase in corneal pseudomicrocysts was seen after the fifth infusion. Corneal disease improved with the placement of new collagen punctal plugs and addition of cyclosporine 0.05 % eye drops in both eyes. Ocular symptoms and exam findings waxed and waned with continued infusions of the ADC.

Conclusions and importance

This case reports an incidence of corneal pseudomicrocysts associated with TORL-1-23 treatment, which should be recognized as a potential adverse effect of this novel therapy.

1. Introduction

Antibody-drug conjugates (ADCs) are a novel class of drugs used in the treatment of various cancers. ADCs are composed of a monoclonal antibody, a linker molecule, and a cytotoxic payload.¹ Target antigens are selected for expression predominantly in tumor cells and low expressivity in normal tissue. Linker molecules are selected to allow release of cytotoxic payloads at targeted sites while limiting premature release in plasma. TORL-1-23 is an ADC targeting claudin-6 (CLDN6), a component of tight junctions expressed in numerous solid tumors.²

Initial results from the TORL-1-23 phase 1 clinical trial reported treatment-related adverse events including fatigue, peripheral neuropathy, alopecia, nausea, anemia, neutropenia, and arthralgia.³

We present a case of bilateral corneal pseudomicrocysts in an adult being treated with TORL-1-23. Several other ADCs have been reported to cause ocular adverse events, with blurred vision, dry eye, and corneal changes occurring most often.^4,5 As of November 2024, there have been no published ocular adverse events associated with TORL-1-23.

2. Case report

A 47-year-old female with advanced recurrent serous ovarian cancer presented to the acute eye clinic at a level 1 tertiary care center. Patient was referred by oncology for new onset bilateral blurry vision and photophobia following two infusions of TORL-1-23. Past ocular history included myopia with astigmatism in both eyes (OU) and contact lens use. The patient received the first infusion of TORL-1-23 therapy at a dose of 4.0 mg/kg and a second infusion three weeks later.

The patient was first seen in the ophthalmology clinic after two infusions of TORL-1-23, 30 days following the first infusion and nine days following the second. The presenting complaints included ocular irritation, redness, tearing, and light sensitivity OU. Symptoms began prior to the second infusion. Best corrected distance visual acuity (BCDVA) was 20/25 right eye (OD) and 20/25 left eye (OS). Slit lamp examination revealed surface keratopathy and a whorled pattern of epithelial pseudomicrocysts concentrated between the inferior limbus and central cornea OU [Fig. 1]. The remainder of the anterior segment exam and the posterior segment exam were unremarkable. Anterior segment optical coherence tomography (AS-OCT) using the SPECTRALIS HRA + OCT (Heidelberg Engineering, Germany) demonstrated multiple punctate, round, hyperreflective foci within the corneal epithelium [Fig. 2].

Fig. 1.

Slit lamp photography at initial presentation of the right eye (A) and left eye (B), revealing, a whorled pattern of pseudomicrocystic change is seen on each inferior paracentral cornea (arrowheads).

Fig. 2.

AS-OCT of the right eye 30 days after first infusion of TORL-1-23. Multiple punctate, round, hyperreflective foci (red arrows) are seen within the corneal epithelium. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Treatment was initiated using preservative-free artificial tears every 1–2 hours, topical loteprednol 0.5 % four times daily (QID). Punctal plugs were placed using a collagen plug in the right eye and silicone plug in the left eye. The patient was advised to discontinue contact lens use at this time. After one week on this treatment regimen, the patient reported symptomatic improvement; however, the corneal exam still revealed pseudomicrocystic changes. To address the persistent corneal changes, loteprednol was replaced with prednisolone acetate 1 % QID and topical brimonidine 0.2 % was added three times daily (used for its vasoconstrictive effect).

Four weeks following the second infusion, the patient was given a third infusion of TORL-1-23 with a dose adjustment down to 2.4 mg/kg due to patient reported adverse effects of neuropathy. Following the third infusion, the patient reported ocular symptoms resolved OD and nearly resolved OS. On exam, BCDVA improved to 20/20 OD and 20/25 OS. Anterior segment exam was relatively stable with improvement in surface keratopathy bilaterally [Fig. 3].

Fig. 3.

Slit lamp photography of the right eye (A) and left eye (B) three weeks after initiation of treatment with punctal plugs, preservative-free artificial tears, topical steroids, and brimonidine. Photos reveal decreased density and severity of corneal lesions (arrowheads).

Future TORL-1-23 infusions were continued at the 2.4 mg/kg dose. The patient was instructed to use topical phenylephrine 2.5 % 20–30 minutes prior to future infusions for vasoconstrictive effects to limit possible corneal exposure to the drug. Additionally, a tapered steroid approach was considered for future infusions: QID during the week of the infusion followed by a TID, BID, then once daily weekly taper.

Two weeks after a fourth infusion, the patient was asymptomatic with persistent corneal pseudomicrocysts. However, after the fifth infusion, her vision decreased and slit lamp examination showed progression of pseudomicrocysts centrally OU. Collagen punctal plugs were placed in both eyes and cyclosporine 0.05 % BID OU was added to the treatment plan. Vision was stable at the next follow up with improvement of examination findings.

Final management of the patient's symptoms and corneal findings consisted of punctal plugs, prednisolone acetate 1 %, cyclosporine 0.05 %, and brimonidine 0.2 % in both eyes, with additional use of topical phenylephrine 2.5 % prior to infusions.

3. Discussion

Corneal pseudomicrocysts or microcyst-like epithelial changes have been reported in the literature secondary to multiple antibody-drug conjugates.⁴ TORL-1-23 is a new chemotherapeutic ADC undergoing Phase I clinical trials. TORL-1-23 is a humanized IgG1 linked to Monomethyl auristatin E (MMAE).⁶ TORL-1-23 targets claudin-6 (CLDN6), a component of tight junction strands expressed in numerous solid tumors. Prior literature has shown expression of CLDN6 in the cornea,⁷ perhaps suggesting the mechanism of toxicity. However, ADC toxicity is thought to be largely target-independent, due to similar adverse events occurring in ADCs with differing targets.⁸ Another plausible cause of ocular toxicity is off-target cytotoxin release. Proposed mechanisms for off-target effects of ADCs include premature release of the cytotoxic payload in circulation, associated with insufficient linker stability, and uptake of intact ADCs into healthy cells through endocytosis or passive diffusion.⁸ Endocytosis of ADCs could be receptor-dependent or independent, as in macropinocytosis.

No treatment regimen for ADC-associated pseudomicrocysts has been proven to effectively treat or prevent corneal changes.⁹ However, dry eye treatment, topical corticosteroids, and vasoconstrictors can be considered to ameliorate symptoms and reduce corneal reactivity to the chemotherapeutic. For dry eye symptoms and ocular irritation, treatment can be pursued using artificial tears, punctal plugs, and medications such as cyclosporine eye drops. Autologous serum tears have been used to treat other ADC-related keratitis^10,11 and can be considered in cases refractive to less invasive treatment. It is also important to consider weighing the benefit of punctal plugs versus the potential risk of increased exposure or concentration of a medication to the ocular surface. In patients who use contact lenses, consider avoiding use while symptomatic or if corneal lesions are present. Regular follow up is important to track changes and adjust treatment according to exam findings or patient concerns. Fortunately, spontaneous resolution of corneal toxicity often occurs with reduction in dose or discontinuation of the offending chemotherapeutic, although clinical improvement can vary.^4,5

In this patient, corneal toxicity began after the first infusion of TORL-1-23. Corneal changes persisted despite topical ocular treatments and dose reduction of the ADC. Treatment aimed at symptomatic improvement did have reported benefits, but further infusions caused periodic recurrences. Changes on clinical examination did not always align with reported change in symptoms. Physicians caring for patients taking novel ADCs or ADCs with known corneal toxicities should consider an approach to address both corneal findings and patient symptoms.

4. Conclusions

TORL-1-23, like other ADCs, may cause dose-related pseudomicrocystic corneal toxicity. Providers involved in oncological treatments using ADCs should be aware of the potential for ocular adverse events. In the exploration of new ADCs, such as TORL-1-23, ocular complaints should be promptly addressed by referral to an ophthalmologist. A multi-faceted treatment approach may be necessary to address symptoms and dose reduction may be considered for refractory symptoms or corneal changes.

CRediT authorship contribution statement

Laura Matuszewska: Writing – review & editing, Formal analysis, Writing – original draft, Data curation. Caitlynn Cooper: Writing – original draft, Writing – review & editing, Data curation. Victoria Sattarova: Writing – original draft, Conceptualization, Writing – review & editing, Data curation. Wassef Chanbour: Writing – original draft, Conceptualization, Writing – review & editing, Data curation. Evan Meyer: Writing – review & editing, Supervision, Conceptualization, Writing – original draft, Data curation. Vania Rashidi: Writing – original draft, Data curation, Writing – review & editing, Supervision, Conceptualization.

Patient consent

Written consent to publish this case has not been obtained. This report does not contain any personal identifying information.

Authorship

All authors attest that they meet the current ICMJE criteria for Authorship.

Funding

No funding or grant support.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.