Next Article in Journal
A Review of Ocular and Systemic Side Effects in Glaucoma Pharmacotherapy
Previous Article in Journal
Refractive Astigmatism Consistency Pre- and Post-Cycloplegia in Pediatric Population
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JCTO
Volume 3
Issue 1
10.3390/jcto3010001
jcto-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Immunotherapy in Ophthalmic Oncology: Current Trends and Future Directions

by
Mouayad Masalkhi
1,*,
Noura Wahoud
2,
Bridget Moran
3 and
Ezzat Elhassadi
4
1
School of Medicine, University College Dublin, Belfield, D04 C1P1 Dublin, Ireland
2
Faculty of Medicine, American University of Beirut, Beirut 1107, Lebanon
3
Department of Ophthalmology, Mater Misericordiae University Hospital, D07 R2WY Dublin, Ireland
4
Department of Haematology, University Hospital Waterford, X91 ER8E Waterford, Ireland
*
Author to whom correspondence should be addressed.
J. Clin. Transl. Ophthalmol. 2025, 3(1), 1; https://doi.org/10.3390/jcto3010001
Submission received: 19 June 2024 / Revised: 22 November 2024 / Accepted: 30 December 2024 / Published: 7 January 2025
Browse Figures
Versions Notes

Abstract

:
Background: Immunotherapy represents a revolutionary approach in cancer treatment, where it leverages the body’s immune system to target and destroy malignant cells. In ophthalmic oncology, immunotherapeutic agents offer potential for managing traditionally challenging ocular malignancies, such as melanoma and retinoblastoma. In this literature review, we aim to provide a comprehensive and up-to-date review of all current research and trends in this field. Methods: This literature reviews data from recent clinical trials, peer-reviewed articles, and meta-analyses focused on immunotherapeutic interventions for eye-related cancers. Emphasis is placed on the types of immunotherapies being tested, including checkpoint inhibitors, vaccine therapies, and adoptive cell transfer therapies. Results: Recent advancements indicate a growing and significant improvement in survival rates and tumor reduction with minimal adverse effects. Clinical trials focusing on melanoma show significant promise with targeted therapies, while early-stage investigations into retinoblastoma and conjunctival melanoma explore innovative approaches to harness the immune system without harming visual function. Conclusions: Immunotherapy in ophthalmic oncology is evolving rapidly and has demonstrated a remarkable potential as a primary treatment strategy. Although results from various clinical trials are promising, further research is needed to refine these therapies, minimize side effects, and improve overall patient outcomes. The future directions involve more comprehensive clinical trials that integrate immunotherapy with existing treatment modalities to establish more robust treatment protocols.

1. Introduction

Immunotherapy represents a transformative approach in the treatment of cancer via the leveraging of the body’s own immune system to recognize and combat malignant cells [1]. This innovative strategy has dramatically shifted the landscape of oncologic therapeutics, providing new avenues for patients with cancers that were previously difficult to treat. Among the most promising modalities of immunotherapy are immune checkpoint inhibitors (ICIs), which have garnered significant attention for their ability to harness the body’s immune system to combat cancer [1]. ICIs are designed to block proteins such as programmed death protein 1 (PD-1), programmed death protein-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), which are pivotal in maintaining immune homeostasis by negatively regulating T-cell activity [1].
The modern era of immunotherapy began with the discovery of specific immune checkpoints, which are proteins that regulate immune responses to maintain self-tolerance and prevent autoimmunity [1,2]. Among these checkpoints are cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed (PD-1), and its ligand PD-L1 [1,2].
While significant strides have been made in the treatment of various cancers with immunotherapy, the application of these therapies to ocular malignancies presents unique challenges and opportunities. Primary ocular malignancies, although rare, include aggressive forms of cancer, such as uveal melanoma (UM) and conjunctival melanoma (CM), with incidences of 5.1 and 0.46 cases per million worldwide, respectively [3,4]. Due to their distinct genetic and immunological profiles, these ocular malignancies (uveal melanoma more so than conjunctival melanoma) can be more challenging to treat compared to their cutaneous counterparts.
Uveal melanoma, which is the most common primary intraocular malignancy in adults, has shown limited responsiveness to conventional immunotherapies despite their success in the treatment of cutaneous melanoma [5]. This difference in response can be attributed to the unique immunosuppressive microenvironment of the eye and distinct genetic mutations driving these tumors, such as mutations in GNAQ and GNA11 genes [5]. Nonetheless, clinical trials exploring the efficacy of ICIs in uveal melanoma have demonstrated some promising results, highlighting the potential for combination therapies and novel immunotherapeutic strategies to improve patient outcomes [6].
Conjunctival melanoma, a rare and aggressive tumor of the eye surface, has a propensity for local invasion and distant metastasis [7]. Immunotherapy has emerged as a viable treatment option for advanced stages of this disease, especially given its genetic and behavioral similarities to cutaneous melanoma (among many, its infiltrative nature and mutations of BRAF, NRAS, and kit) [8]. The use of ICIs, like nivolumab and pembrolizumab, has shown encouraging results, albeit with manageable immune-related adverse events [8]. In this paper, we aim to provide a comprehensive and thorough review of the current landscape of immunotherapies in the treatment of ocular malignancies, focusing on clinical outcomes, ongoing trials, and future research directions.

2. Checkpoint Inhibitors in Ocular Oncology

Immune checkpoint inhibitors (ICIs) are antibodies that work by blocking proteins that prevent the immune system from attacking cancer cells [9]. These checkpoint proteins, such as PD-1, PD-L1, and CTLA-4, act as brakes on the immune system, mainly through the negative regulation of T-cell-mediated immune responses, both to maintain self-tolerance and to protect healthy tissues from an overactive immune response [2]. Cancer cells dysregulate these proteins to induce tumor tolerance [10]. T-cells have been the main target of ICIs because of their wide antigen recognition capacity, their direct ability to kill cancer cells (CD-8+), and their organization of different aspects of the immune response (CD-4+) linking both adaptive and innate mechanisms [10].
ICIs exhibit both agonistic and antagonistic activities at checkpoint protein receptors, resulting in either the propagation of stimulatory signals or the suppression of inhibitory signals [10]. A prime example is ipilimumab, which targets the CTLA-4 inhibitory receptors on T-cells [10]. This action serves to counteract the costimulatory effects mediated by the CD28 receptor [10]. Both CTLA-4 and CD28 interact with the same ligands, CD80 and CD86; however, CTLA-4 has a significantly higher affinity for these ligands compared to CD28 [10]. This higher affinity enables CTLA-4 to outcompete CD28, effectively blocking T-cell activation by delivering inhibitory signals [10]. Since 2011, with the approval of CTLA-4 inhibitors for the treatment of metastatic melanoma, many ICIs have been FDA approved for the treatment of multiple cancers, and others continue to be explored [10].
Checkpoint inhibitors have been primarily studied in uveal melanoma (UM), a rare but aggressive form of eye cancer with a 50% rate of both metastasis and mortality [9,11]. The most used checkpoint inhibitors in this context include ipilimumab, nivolumab, and pembrolizumab. Although ICIs have proved their effectiveness in cutaneous melanoma, their efficacy in UM is limited, which can be explained by its complex interactions with the immune system and distinct genetics triggered by mutations in GNAQ or GNA11 as compared to BRAF or NRAS in cutaneous melanoma [5].
In a retrospective study of 39 patients with uveal melanoma undergoing ipilimumab therapy, the median overall survival (OS) was 9.6 months, with manageable toxicities, which included hepatotoxicity, pneumonitis, and colitis [9,12,13]. Additionally, it was found in a systematic review on the use of ICI monotherapy versus dual-ICI regimens for the treatment of metastatic uveal melanoma that dual regimens are superior to ICI monotherapy in terms of the objective response rate, the disease control rate, and progression-free survival [14]. The dual inhibition of the checkpoints lymphocyte-activation gene 3 (LAG-3) and PD-1 in patients with previously untreated metastatic or unresectable melanoma led to greater PFS as compared to inhibition of anti PD-1 alone [15]. A phase II clinical trial is currently studying a combination therapy of nivolumab and relatlimab for metastatic UM (mUM) [16].
Conjunctival melanoma (CM), which comprises about 2% of eye cancers, is a rare tumor of the eye surface, with the potential for local invasion, distant metastasis, and recurrence despite maximal treatment [7]. Early-stage CM can be managed with complete wide-margin excision, brachytherapy, or cryotherapy, locally progressed or metastatic [7]. Since immunotherapy shows significant improvement in the management of metastatic cutaneous melanoma and due to genetic similarities with CM, immunotherapy was speculated to have similar results in CM [17]. In a case series of 5 patients with metastatic CM, the four patients treated with nivolumab (PD-1 inhibitor) had no evidence of disease at 36 months, with half of them developing autoimmune colitis, necessitating stoppage of the immunotherapy. However, the single patient who received pembrolizumab, another PD-1 inhibitor, had stable metastasis at 6 months of treatment but later disease proregression at 11 months, requiring switching to another therapy [13]. In another case series of five patients with local and metastatic CM and receiving therapy with ICIs, including ipilimumab, nivolumab, and pembrolizumab, complete responses were reported in one locally advanced and one metastatic CM patient. Adverse effects experienced by this cohort included adrenal insufficiency, colitis, dermatitis, hepatotoxicity, and pneumonitis [12].
A summary of different immunotherapeutic classes, along with their indications and side effects, is provided in Table 1 and Figure 1. Figure 2 illustrates the current uses of immunotherapy across various ocular tumors.

3. Clinical Trials

Several clinical trials have evaluated the efficacy of checkpoint inhibitors in ocular malignancies (summarized in Table 2). For example, trials on ipilimumab and nivolumab have demonstrated some success in controlling tumor growth and prolonging survival in patients with metastatic UM [11]. However, the response rates are generally lower compared to other types of melanomas, highlighting the need for further research and combination therapies [11].
In a recent phase II clinical trial of pembrolizumab and entinostat, a histone deacetylase, in patients with metastatic uveal melanoma, the median OS was 13.4 months and the OS at one year was 59% [6]. In a phase 1B clinical trial of 10 patients with advanced PD-1-resistant melanoma treated with a combination of ziv-aflibercept, an anti-VEGF, and pembrolizumab, two patients with ocular melanoma developed stable disease [18].
In a single-arm phase IIIb CheckMate study of 533 clinically diverse patients with advanced melanoma, receiving nivolumab plus ipilimumab, followed by nivolumab monotherapy, the OS rate was 36% in the ocular/uveal melanoma subgroup [19]. In a phase 1B trial of avelumab treatment in patients with previously treated metastatic melanoma, the OS of the ocular melanoma subgroup was 17.2 months [19]. Ipilimumab had a limited clinical activity in a multicenter phase II study in patients with metastatic UM, showing 1-year and 2-year OS rates of 22% and 7%, respectively, with a median OS of 6.8 months and progression-free survival (PFS) of 2.8 months [20].
In another trial of 56 mUM patients receiving PD-1 and PD-L1 antibodies, including ipilimumab, pembrolizumab, nivolumab, and atezolizumab, 3 patients had an objective response to ipilimumab, and 8 patients had stable disease as the best response. Objective tumor responses were observed in two patients for an overall response rate of 3.6%. Stable disease (≥6 months) was observed in five patients [21]. The median PFS was 2.6 months, and the median OS was 7.6 months [21]. In a clinical trial of melanoma patients who received nivolumab after progression on prior ipilimumab, the median OS was 12.6 months for ocular melanoma, with an 18-month OS rate of 34.8% [22].
The use of checkpoint inhibitors can lead to various adverse effects, including immune-related ocular adverse events (irOAEs), ranging from mild conditions, such as dry eye, to more severe complications, like uveitis and retinopathy [23]. Dry eye disease, with an incidence rate of 1–4%, and uveitis, with an incidence rate of 1%, are the most frequently reported irOAEs. Nearly all cases of irOAEs are mild to moderate and are resolved spontaneously or with conservative therapy [24]. Mild cases may be treated with oral corticosteroids, while more severe cases might require systemic corticosteroids and the discontinuation of ICIs [23]. Ophthalmoplegia is the most common irOAE (41.5%) reported in the context of lung cancer immunotherapy. The class of ICI influences the risk of certain adverse effects, with ophthalmoplegia being more frequently reported in combination therapies of CTLA-4 and PD-1 [24].

4. Vaccine Therapies

Cancer vaccines stimulate the immune system to recognize and attack cancer cells by introducing antigens specific to the tumor [25]. Peptide vaccines, dendritic cell vaccines, and viral vector vaccines all present tumor antigens to the immune system via different mechanisms to induce a targeted immune response [25]. These vaccines can be therapeutic, for the treatment of existing cancers, or prophylactic, with the aim of preventing cancer development [26]. They can also be cell based, including patient-specific tumor cells or dendritic cells, or peptide based, which contain tumor-associated antigens [26]. Dendritic cells are loaded with a tumor-associated antigen to direct the immune system to target that specific antigen [27]. While tumor-associated antigen vaccines are still experimental, one dendritic cell vaccine has been approved for the treatment of advanced prostate cancer [28,29]. A newer type of cancer vaccine is based on oncolytic viruses, which specifically attack and kill cancer cells. Talimogene laherparepvec (T-VEC), used for melanoma refractory to surgery, was the first oncolytic virus therapy to gain FDA approval [30]. It is based on herpes simplex virus type 1, which is killed by normal cells but not cancer cells [28,29].
Viral vaccines like Coxsackievirus A21 (V937) have been used in combination with ipilimumab in patients with mUM; however, no meaningful clinical benefit has been observed [31]. In a study of 14 patients with mUM, receiving dendritic cell vaccines loaded with melanoma antigens gp100 and tyrosinase, tumor-specific immune responses were induced in 4 patients (29%), with a median OS with metastatic disease of 19.2 months, which is longer than the OS in patients with mUM [32]. It was speculated that a high tumor burden might suppress the efficacy of dendritic cell vaccination [32]. Subsequently, a phase II study of dendritic cell vaccination in patients with resected tumors was designed, and it showed a three-year OS rate of 79%, with a median disease-free survival (DFS) of 34.5 months [33]. However, these studies are in early stages, and more research is needed to confirm their efficacy and optimize vaccine formulations. The future of vaccine therapy for ocular cancers lies in the improvement of antigen selection, the enhancement of vaccine delivery methods, and the combination of vaccines with other immunotherapies to boost their effectiveness.

5. Adoptive Cell Transfer Therapies

Adoptive cell transfer (ACT) involves the collection and expansion of a patient’s own immune cells, which are then reintroduced into the body to fight cancer [34]. This method often uses T-cells that are genetically modified to enhance their ability to target cancer cells [31]. Three major models of cellular therapy are tumor-infiltrating lymphocytes (TILs), T-cell receptor (TCR)-modified T-cells, and CAR-T cells [34]. Autologous tumor-infiltrating lymphocytes (TILs) are extracted from the patient by mestastasectom and are then expanded ex vivo and reinfused into the patient with IL-2 after the patient has undergone lymphodepleting chemotherapy [27].
ACT has been explored in the treatment of ocular tumors, particularly uveal melanoma. Techniques such as TIL therapy and chimeric antigen receptor (CAR)-T cell therapy are being investigated for their potential to target and eliminate ocular cancer cells effectively [35]. CAR-T cell therapy involves genetically modifying T-cells to better target cancer cells. For instance, HER2-specific CAR-T cells have shown potential in targeting melanoma cells resistant to other therapies, like TIL and checkpoint inhibitors, offering an additional option for patients who do not respond to standard treatments [36].
In a phase 2 trial, 20 patients with metastatic uveal melanoma were evaluable and received TIL therapy; of them, 7 demonstrated objective tumor regression (35%), and of these 7, 6 patients achieved a partial response (PR). One patient achieved a complete response (CR). Toxic effects were related to chemotherapy and included lymphopenia, neutropenia, and thrombocytopenia [37]. While TIL therapy has demonstrated the ability to induce tumor regression in some patients with metastatic uveal melanoma, the success rates vary, and more research is needed to identify the factors that influence treatment outcomes and to refine the therapeutic protocols [38].
Challenges in ACT include the complexity of cell collection and expansion, the potential for severe immune-related side effects, and the need for personalized treatment approaches. Future research should focused on improving the safety and efficacy of ACT, exploring combination therapies, and developing novel techniques to enhance the anti-tumor activity of transferred cells.

6. Targeted Therapy

6.1. Bispecific T-Cell Engagers

Bispecific T-cell engagers (BiTEs) are antibodies designed to target both cancer cells and T-cells concurrently [39]. BiTEs are made up of two antibody fragments: one binds to a specific tumor antigen on cancer cells, and the other binds to the CD3 receptors on T-cells [39]. This dual binding approximates T-cells to cancer cells, activating and enabling them to efficiently kill the cancer cells [39]. In a phase 1/2 trial of tebentafusp, a bispecific (gp100 × CD3) immune mobilizing monoclonal T-cell receptor against cancer (ImmTAC), 19 uveal melanoma patients received the drug, with a 65% 1-year OS rate and good tolerance [40]. A phase III trial of 378 patients with HLA-A*02:01-metastatic uveal melanoma receiving either tebentafusp or single-agent pembrolizumab, ipilimumab, or dacarbazine (control group) revealed that the OS at 1 year was 73% in the tebentafusp group and 59% in the control group, with PFS of 31% and 19% at 6 months, respectively [38].

6.2. Immunotherapy in Retinoblastoma

Retinoblastoma (RB) is the most common primary intraocular tumor in children, with around 8000 new diagnoses each year [41]. While previously fatal and treated only by enucleation, it is now treated with radiation therapy, laser therapy, and cryotherapy, achieving a survival rate of 95% when diagnosed and treated in its early stages [42]. Newer techniques of treatment include ophthalmic artery chemosurgery (OAC) and intravitreal injections, which have increased chemotherapy delivery to the retina and vitreous body and have aided in the preservation of vision and minimized the probability of tumor dissemination to the brain. The techniques are of no good in disseminated disease; hence, alternative therapies are required [43]. For example, early experiments have shown significant regression in retinoblastoma growth with the EpCAM × CD3 antibody [44]. Furthermore, CAR-T cells with silenced PD-1 have been shown to be effective in retinoblastoma [45].
Vitreous seeding of retinoblastoma cells presents one of the challenges and is associated with poor prognosis. This could be managed with the targeting of the platelet-derived growth factor (PDGF)–PDGFR axis responsible for tumor angiogenesis [46]. In a clinical trial of pediatric neuroectodermal malignancies expressing N-glycosylated gangliosides, including N-glycolyl GM3 (NeuGcGM3), racotumomab, an anti-idiotype vaccine targeting NeuGcGM3, was administered to 14 children, 1 of whom had retinoblastoma. Most patients showed an immune response, with a favorable toxicity profile; however, the response of those with ocular tumors was not explicitly referenced [47].

7. Immunotherapy in Ocular Lymphoma

Ocular adnexal lymphoma (OAL) is a type of systemic lymphoma that affects the orbit, lacrimal glands, eyelids, and conjunctiva. Although it accounts for 1% of non-Hodgkin’s lymphomas, OAL is the most common malignant orbital tumor in adults [48,49]. OAL is a low-grade that has seen important advances in immunotherapy [49]. The discovery of CD20 protein on 90% of malignant B-cells has led to treatments like rituximab, which has shown promising results, particularly when combined with chlorambucil or lenalidomide [49]. A retrospective study of 133 OAL patients showed a 27% response rate to rituximab [50]. In a pilot study, intralesional rituximab resulted in 40% full remission among patients with orbital B-cell lymphoma, with two achieving complete remission and two showing partial responses [51]. In a phase 1 trial of lenalidomide for relapsed CNS lymphoma, including five patients with intraocular involvement, 64% of the patients responded to treatment [52]. Another phase II trial combining lenalidomide with intravenous rituximab for relapsed/refractory primary central nervous system lymphoma (R/R PCNSL) or relapsed/refractory primary vitreoretinal lymphoma (R/R PVRL) saw a 35% complete remission in 17 patients with intraocular lesions [53]. Although immune checkpoint inhibitors (ICIs) have yet to be applied, they hold potential for future treatment of ocular lymphomas. A study of 20 cases revealed increased PD-1, PD-L1, and IDO1 expression in the tumor microenvironment, particularly in the 6 cases with large B-cells, suggesting therapeutic potential [54]. CAR-T cell therapy for ocular lymphoma is still under-researched, with challenges such as limited trafficking across the blood–ocular barrier, as shown in a case where lymphoma persisted in the eye despite systemic control [55,56].

8. Immunotherapy in Ocular Surface Neoplasia

Nonmelanoma tumors affecting the periocular and ocular surfaces, such as basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and ocular surface squamous neoplasia (OSSN), are relatively rare but demand specialized treatment [57]. BCC represents 80% to 96% of periocular malignancies, while SCC accounts for 5% to 10%. These cancers tend to recur more frequently than similar skin tumors. OSSN spans from early squamous dysplasia to conjunctival intraepithelial neoplasia (CIN) or carcinoma in situ, with invasive SCC being the most common ocular malignancy [57]. Interferons (IFNs), glycoproteins with antitumor effects, have shown effectiveness in treating ocular surface neoplasia [58]. A study demonstrated that using both subconjunctival/perilesional and topical interferon-α2b led to complete resolution in six patients with primary or recurrent CIN within six weeks [59]. Similar outcomes were seen in seven eyes treated with topical IFN-α2b for conjunctival and corneal intraepithelial neoplasia [60]. Immune checkpoint inhibitors like anti-PD1 therapy (cemiplimab) have shown promise in managing cutaneous SCC with orbital invasion [61]. In one case series, a 3-month regimen of bevacizumab regimen, an antibody targeting VEGF, reduced the size and vascularity of OSSN [62]. Another series reported significant lesion after the application of topical bevacizumab to 10 eyes over 5 to 14 weeks [63].

9. Variations in the Immune Response of Ocular Tumors and Future Endeavors

As described earlier, certain ocular tumors respond differently to treatments compared to their non-ocular counterparts. For instance, UM exhibits a limited response to standard immunotherapies, like ICIs, unlike cutaneous melanoma [5]. This variation may stem from genetic differences between the tumors [5]. UM often carries GNAQ and GNA11 mutations, while cutaneous melanoma typically involves BRAF or NRAS mutations [5]. CM, which has a superior immune response compared to UM, shares genetic traits with cutaneous melanoma, including mutations in BRAF, NRAS, and KIT [64].
The distinct immune behavior of ocular tumors is linked to the eye’s unique immunosuppressive microenvironment [65]. The eye’s immune privilege is maintained by a specialized blood–ocular barrier and the absence of direct lymphatic drainage, both of which minimize inflammation and protect the delicate ocular compartment [65]. The ocular environment is also rich in immunosuppressive factors that affect immune cell activity [65]. When foreign antigens are introduced into the eye, they may trigger systemic tolerance via anterior-chamber-associated immune deviation (ACAID), weakening the efficacy of immune-based therapies [65]. Additionally, the blood–ocular barrier complicates drug delivery [55].
Future research should prioritize developing targeted therapies through the genetic profiling of ocular cancers. Efforts to overcome the eye’s immunosuppressive environment, such as modulating ACAID, need exploration. Improving drug delivery across the blood–ocular barrier and evaluating combination therapies are crucial. Advanced preclinical models and biomarkers will help guide therapy selection, and clinical trials should test novel therapies specifically for ocular tumors. Comparative studies of ocular and non-ocular tumors could further clarify immune response mechanisms and treatment outcomes.

10. Conclusions

Overall, the development of immunotherapy has revolutionized cancer treatment and offers new hope for patients with ocular malignancies that were once considered challenging to manage. While immune checkpoint inhibitors (ICIs) have reshaped the therapeutic landscape for many cancers, their application in ocular oncology presents unique challenges. The unique immunosuppressive microenvironment of the eye, which is characterized by the blood–ocular barrier and anterior-chamber-associated immune deviation (ACAID), significantly influences the efficacy of immune-based therapies. While studies on ICIs, such as ipilimumab, nivolumab, and pembrolizumab, have yielded varying results in UM and CM, combination therapies and novel approaches, like adoptive cell transfer (ACT) and vaccine therapies, are emerging as potential strategies to enhance therapeutic outcomes.
Additionally: advancements in targeted therapies, including bispecific T-cell engagers (BiTEs) and antibody–drug conjugates (ADCs), offer new avenues for managing ocular malignancies. However, the limited success rates and variability in response highlight the need for further research. Moving forward, research should focus on understanding the genetic and immune variations in ocular tumors to enhance the efficacy of immunotherapy. Overcoming the ocular immunosuppressive environment, optimizing drug delivery methods across the blood–ocular barrier, and developing combination therapies tailored to ocular cancers are essential for advancing treatment outcomes. Comparative studies between ocular and non-ocular tumors may provide further insights into therapeutic mechanisms and guide future endeavors. As our understanding of immunotherapy in ocular oncology evolves, personalized and targeted approaches hold the promise of improving patient survival and quality of life.

Funding

This research received no external funding.

Data Availability Statement

No new data was created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Masalkhi, M.; Wahoud, N.; Moran, B.; Elhassadi, E. Impact of immune checkpoint inhibitors on vision and eye health. Eye 2024, 38, 2854–2856. [Google Scholar] [CrossRef]
  2. Pardoll, D.M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 2012, 12, 252–264. [Google Scholar] [CrossRef] [PubMed]
  3. Kaliki, S.; Shields, C.L. Uveal melanoma: Relatively rare but deadly cancer. Eye 2017, 31, 241–257. [Google Scholar] [CrossRef] [PubMed]
  4. Virgili, G.; Parravano, M.; Gatta, G.; Capocaccia, R.; Mazzini, C.; Mallone, S.; Botta, L. Incidence and Survival of Patients With Conjunctival Melanoma in Europe. JAMA Ophthalmol. 2020, 138, 601–608. [Google Scholar] [CrossRef] [PubMed]
  5. Sorrentino, F.S.; De Rosa, F.; Di Terlizzi, P.; Toneatto, G.; Gabai, A.; Finocchio, L.; Salati, C.; Spadea, L.; Zeppieri, M. Uveal melanoma: Recent advances in immunotherapy. World J. Clin. Oncol. 2024, 15, 23–31. [Google Scholar] [CrossRef]
  6. Ny, L.; Jespersen, H.; Karlsson, J.; Alsén, S.; Filges, S.; All-Eriksson, C.; Andersson, B.; Carneiro, A.; Helgadottir, H.; Levin, M.; et al. The PEMDAC phase 2 study of pembrolizumab and entinostat in patients with metastatic uveal melanoma. Nat. Commun. 2021, 12, 5155. [Google Scholar] [CrossRef]
  7. Wong, J.R.; Nanji, A.A.; Galor, A.; Karp, C.L. Management of conjunctival malignant melanoma: A review and update. Expert Rev. Ophthalmol. 2014, 9, 185–204. [Google Scholar] [CrossRef]
  8. Brouwer, N.J.; Verdijk, R.M.; Heegaard, S.; Marinkovic, M.; Esmaeli, B.; Jager, M.J. Conjunctival melanoma: New insights in tumour genetics and immunology, leading to new therapeutic options. Prog. Retin. Eye Res. 2022, 86, 100971. [Google Scholar] [CrossRef]
  9. Luke, J.J.; Callahan, M.K.; Postow, M.A.; Romano, E.; Ramaiya, N.; Bluth, M.; Giobbie-Hurder, A.; Lawrence, D.P.; Ibrahim, N.; Ott, P.A.; et al. Clinical activity of ipilimumab for metastatic uveal melanoma. Cancer 2013, 119, 3687–3695. [Google Scholar] [CrossRef]
  10. Lee, J.B.; Kim, H.R.; Ha, S.J. Immune Checkpoint Inhibitors in 10 Years: Contribution of Basic Research and Clinical Application in Cancer Immunotherapy. Immune Netw. 2022, 22, e2. [Google Scholar] [CrossRef]
  11. Tan, Y.; Lu, Y.; Chen, S.; Zou, C.; Qin, B. Immunotherapy for ocular melanoma: A bibliometric and visualization analysis from 1991 to 2022. Front. Oncol. 2023, 13, 1161759. [Google Scholar] [CrossRef] [PubMed]
  12. Finger, P.T.; Pavlick, A.C. Checkpoint inhibition immunotherapy for advanced local and systemic conjunctival melanoma: A clinical case series. J. Immunother. Cancer 2019, 7, 83. [Google Scholar] [CrossRef] [PubMed]
  13. Sagiv, O.; Thakar, S.D.; Kandl, T.J.; Ford, J.; Sniegowski, M.C.; Hwu, W.J.; Esmaeli, B. Immunotherapy with Programmed Cell Death 1 Inhibitors for 5 Patients With Conjunctival Melanoma. JAMA Ophthalmol. 2018, 136, 1236–1241. [Google Scholar] [CrossRef]
  14. Yamada, K.; Takeuchi, M.; Fukumoto, T.; Suzuki, M.; Kato, A.; Mizuki, Y.; Yamada, N.; Kaneko, T.; Mizuki, N.; Horita, N. Immune checkpoint inhibitors for metastatic uveal melanoma: A meta-analysis. Sci. Rep. 2024, 14, 7887. [Google Scholar] [CrossRef]
  15. Tawbi, H.A.; Schadendorf, D.; Lipson, E.J.; Ascierto, P.A.; Matamala, L.; Gutiérrez, E.C.; Rutkowski, P.; Gogas, H.J.; Lao, C.D.; De Menezes, J.J.; et al. Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. N. Engl. J. Med. 2022, 386, 24–34. [Google Scholar] [CrossRef]
  16. Lutzky, J.; Feun, L.; Harbour, W. 430 A phase II study of nivolumab + BMS-986016 (relatlimab) in patients with metastatic uveal melanoma(UM) (CA224–094). J. ImmunoTherapy Cancer 2020, 8, A261–A262. [Google Scholar] [CrossRef]
  17. Cohen, V.M.L.; O’Day, R.F. Management Issues in Conjunctival Tumours: Conjunctival Melanoma and Primary Acquired Melanosis. Ophthalmol. Ther. 2019, 8, 501–510. [Google Scholar] [CrossRef]
  18. Baginska, J.; Nau, A.; Gomez Diaz, I.; Giobbie-Hurder, A.; Weirather, J.; Vergara, J.; Abrecht, C.; Hallisey, M.; Dennis, J.; Severgnini, M.; et al. Ziv-aflibercept plus pembrolizumab in patients with advanced melanoma resistant to anti-PD-1 treatment. Cancer Immunol. Immunother. 2024, 73, 17. [Google Scholar] [CrossRef]
  19. Dummer, R.; Corrie, P.; Gutzmer, R.; Meniawy, T.M.; Del Vecchio, M.; Lebbé, C.; Guida, M.; Dutriaux, C.; Dreno, B.; Meyer, N.; et al. First-Line, Fixed-Duration Nivolumab Plus Ipilimumab Followed by Nivolumab in Clinically Diverse Patient Populations With Unresectable Stage III or IV Melanoma: CheckMate 401. J. Clin. Oncol. 2023, 41, 3917–3929. [Google Scholar] [CrossRef]
  20. Zimmer, L.; Vaubel, J.; Mohr, P.; Hauschild, A.; Utikal, J.; Simon, J.; Garbe, C.; Herbst, R.; Enk, A.; Kämpgen, E.; et al. Phase II DeCOG-Study of Ipilimumab in Pretreated and Treatment-Naïve Patients with Metastatic Uveal Melanoma. PLoS ONE 2015, 10, e0118564. [Google Scholar] [CrossRef]
  21. Algazi, A.P.; Tsai, K.K.; Shoushtari, A.N.; Munhoz, R.R.; Eroglu, Z.; Piulats, J.M.; Ott, P.A.; Johnson, D.B.; Hwang, J.; Daud, A.I.; et al. Clinical outcomes in metastatic uveal melanoma treated with PD-1 and PD-L1 antibodies. Cancer 2016, 122, 3344–3353. [Google Scholar] [CrossRef] [PubMed]
  22. Nathan, P.; Ascierto, P.A.; Haanen, J.; Espinosa, E.; Demidov, L.; Garbe, C.; Guida, M.; Lorigan, P.; Chiarion-Sileni, V.; Gogas, H.; et al. Safety and efficacy of nivolumab in patients with rare melanoma subtypes who progressed on or after ipilimumab treatment: A single-arm, open-label, phase II study (CheckMate 172). Eur. J. Cancer 2019, 119, 168–178. [Google Scholar] [CrossRef] [PubMed]
  23. Antoun, J.; Titah, C.; Cochereau, I. Ocular and orbital side-effects of checkpoint inhibitors: A review article. Curr. Opin. Oncol. 2016, 28, 288. [Google Scholar] [CrossRef] [PubMed]
  24. Zhou, L.; Wei, X. Ocular Immune-Related Adverse Events Associated with Immune Checkpoint Inhibitors in Lung Cancer. Front. Immunol. 2021, 12, 701951. [Google Scholar] [CrossRef]
  25. Le, I.; Dhandayuthapani, S.; Chacon, J.; Eiring, A.M.; Gadad, S.S. Harnessing the Immune System with Cancer Vaccines: From Prevention to Therapeutics. Vaccines 2022, 10, 816. [Google Scholar] [CrossRef]
  26. Tian, Y.; Hu, D.; Li, Y.; Yang, L. Development of therapeutic vaccines for the treatment of diseases. Mol. Biomed. 2022, 3, 40. [Google Scholar] [CrossRef]
  27. Schank, T.E.; Hassel, J.C. Immunotherapies for the Treatment of Uveal Melanoma—History and Future. Cancers 2019, 11, 1048. [Google Scholar] [CrossRef]
  28. Kaczmarek, M.; Poznańska, J.; Fechner, F.; Michalska, N.; Paszkowska, S.; Napierała, A.; Mackiewicz, A. Cancer Vaccine Therapeutics: Limitations and Effectiveness—A Literature Review. Cells 2023, 12, 2159. [Google Scholar] [CrossRef]
  29. Bartlett, D.L.; Liu, Z.; Sathaiah, M.; Ravindranathan, R.; Guo, Z.; He, Y.; Guo, Z.S. Oncolytic viruses as therapeutic cancer vaccines. Mol. Cancer 2013, 12, 103. [Google Scholar] [CrossRef]
  30. Ferrucci, P.F.; Pala, L.; Conforti, F.; Cocorocchio, E. Talimogene Laherparepvec (T-VEC): An Intralesional Cancer Immunotherapy for Advanced Melanoma. Cancers 2021, 13, 1383. [Google Scholar] [CrossRef]
  31. Lutzky, J.; Sullivan, R.J.; Cohen, J.V.; Ren, Y.; Li, A.; Haq, R. Phase 1b study of intravenous coxsackievirus A21 (V937) and ipilimumab for patients with metastatic uveal melanoma. J. Cancer Res. Clin. Oncol. 2023, 149, 6059–6066. [Google Scholar] [CrossRef] [PubMed]
  32. Bol, K.F.; Mensink, H.W.; Aarntzen, E.H.J.G.; Schreibelt, G.; Keunen, J.E.E.; Coulie, P.G.; de Klein, A.; Punt, C.J.; Paridaens, D.; Figdor, C.G.; et al. Long Overall Survival After Dendritic Cell Vaccination in Metastatic Uveal Melanoma Patients. Am. J. Ophthalmol. 2014, 158, 939–947.e5. [Google Scholar] [CrossRef] [PubMed]
  33. Bol, K.F.; Bosch, T.v.d.; Schreibelt, G.; Mensink, H.W.; Keunen, J.E.E.; Kiliç, E.; Japing, W.J.; Geul, K.W.; Westdorp, H.; Boudewijns, S.; et al. Adjuvant Dendritic Cell Vaccination in High-Risk Uveal Melanoma. Ophthalmology 2016, 123, 2265–2267. [Google Scholar] [CrossRef] [PubMed]
  34. Barbari, C.; Fontaine, T.; Parajuli, P.; Lamichhane, N.; Jakubski, S.; Lamichhane, P.; Deshmukh, R.R. Immunotherapies and Combination Strategies for Immuno-Oncology. Int. J. Mol. Sci. 2020, 21, 5009. [Google Scholar] [CrossRef]
  35. Rohaan, M.W.; Berg, J.H.v.d.; Kvistborg, P.; Haanen, J.B.A.G. Adoptive transfer of tumor-infiltrating lymphocytes in melanoma: A viable treatment option. J. Immunother. Cancer 2018, 6, 102. [Google Scholar] [CrossRef]
  36. Forsberg, E.M.V.; Lindberg, M.F.; Jespersen, H.; Alsén, S.; Bagge, R.O.; Donia, M.; Svane, I.M.; Nilsson, O.; Ny, L.; Nilsson, L.M.; et al. HER2 CAR-T Cells Eradicate Uveal Melanoma and T-cell Therapy–Resistant Human Melanoma in IL2 Transgenic NOD/SCID IL2 Receptor Knockout Mice. Cancer Res. 2019, 79, 899–904. [Google Scholar] [CrossRef]
  37. Chandran, S.S.; Somerville, R.P.; Yang, J.C.; Sherry, R.M.; Klebanoff, C.A.; Goff, S.L.; Wunderlich, J.R.; Danforth, D.N.; PharmD, D.Z.; Paria, B.C.; et al. Treatment of metastatic uveal melanoma with adoptive transfer of tumour-infiltrating lymphocytes: A single-centre, two-stage, single-arm, phase 2 study. Lancet Oncol. 2017, 18, 792–802. [Google Scholar] [CrossRef]
  38. Nathan, P.; Hassel, J.C.; Rutkowski, P.; Baurain, J.-F.; Butler, M.O.; Schlaak, M.; Ryan, J.S.; John, M.K.; Anthony, M.J.; Joseph, J.S.; et al. Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma. N. Engl. J. Med. 2021, 385, 1196–1206. [Google Scholar] [CrossRef]
  39. Tian, Z.; Liu, M.; Zhang, Y.; Wang, X. Bispecific T cell engagers: An emerging therapy for management of hematologic malignancies. J. Hematol. Oncol. 2021, 14, 75. [Google Scholar] [CrossRef]
  40. Middleton, M.R.; McAlpine, C.; Woodcock, V.K.; Corrie, P.; Infante, J.R.; Steven, N.M.; Thomas, R.; Alan, A.; Alexander, N.S.; Omid, H.; et al. Tebentafusp, A TCR/Anti-CD3 Bispecific Fusion Protein Targeting gp100, Potently Activated Antitumor Immune Responses in Patients with Metastatic Melanoma. Clin. Cancer Res. 2020, 26, 5869–5878. [Google Scholar] [CrossRef]
  41. Cruz-Gálvez, C.C.; Ordaz-Favila, J.C.; Villar-Calvo, V.M.; Cancino-Marentes, M.E.; Bosch-Canto, V. Retinoblastoma: Review and new insights. Front. Oncol 2022, 12, 963780. [Google Scholar] [CrossRef] [PubMed]
  42. Byroju, V.V.; Nadukkandy, A.S.; Cordani, M.; Kumar, L.D. Retinoblastoma: Present scenario and future challenges. Cell Commun. Signal. 2023, 21, 226. [Google Scholar] [CrossRef] [PubMed]
  43. Wang, L.; Li, S.; Mei, J.; Ye, L. Immunotherapies of retinoblastoma: Effective methods for preserving vision in the future. Front. Oncol. 2022, 12, 949193. [Google Scholar] [CrossRef] [PubMed]
  44. Mitra, M.; Kandalam, M.; Harilal, A.; Verma, R.S.; Krishnan, U.M.; Swaminathan, S.; Krishnakumar, S. EpCAM is a putative stem marker in retinoblastoma and an effective target for T-cell-mediated immunotherapy. Mol. Vis. 2012, 18, 290–308. [Google Scholar]
  45. Ghassemi, S.; Martinez-Becerra, F.J.; Master, A.M.; Richman, S.A.; Heo, D.; Leferovich, J.; Tu, Y.; García-Cañaveras, J.C.; Ayari, A.; Lu, Y.; et al. Enhancing Chimeric Antigen Receptor T Cell Anti-tumor Function through Advanced Media Design. Mol. Ther. Methods Clin. Dev. 2020, 18, 595–606. [Google Scholar] [CrossRef]
  46. Wilson, M.W.; Goldsmith, Z.; Coppess, W.; Gao, B.; McEwen, M.; Irvine, A.; Brennan, R.C.; Morales, V.M. PDGF-PDGFR Signaling Sustain Angiogenesis in an Autocrine and Paracrine Fashion in Retinoblastoma. Investig. Ophthalmol. Vis. Sci. 2016, 57. Available online: https://iovs.arvojournals.org/article.aspx?articleid=2560037 (accessed on 18 June 2024).
  47. Cacciavillano, W.; Sampor, C.; Venier, C.; Gabri, M.R.; de Dávila, M.T.G.; Galluzzo, M.L.; Guthmann, M.D.; Fainboim, L.; Alonso, D.F.; Chantada, G.L.; et al. A Phase I Study of the Anti-Idiotype Vaccine Racotumomab in Neuroblastoma and Other Pediatric Refractory Malignancies. Pediatr. Blood Cancer 2015, 62, 2120–2124. [Google Scholar] [CrossRef]
  48. Eckardt, A.M.; Lemound, J.; Rana, M.; Gellrich, N.C. Orbital lymphoma: Diagnostic approach and treatment outcome. World J. Surg. Oncol. 2013, 11, 73. [Google Scholar] [CrossRef]
  49. Lee Boniao, E.; Allen, R.C.; Sundar, G. Targeted therapy and immunotherapy for orbital and periorbital tumors: A major review. Orbit 2023, 43, 656–673. [Google Scholar] [CrossRef]
  50. Fernández, C.A.; Henry, R.K.; Shields, C.L.; Bilyk, J.R.; Lally, S.E.; Eagle, R.C.; Milman, T. Ocular adnexal lymphoma: A single-institution retrospective study. Saudi J. Ophthalmol. 2022, 35, 230–238. [Google Scholar] [CrossRef]
  51. Savino, G.; Battendieri, R.; Balia, L.; Colucci, D.; Larocca, L.M.; Laurenti, L.; De Padua, L.; Blasi, M.A.; Balestrazzi, E. Evaluation of intraorbital injection of rituximab for treatment of primary ocular adnexal lymphoma: A pilot study. Cancer Sci. 2011, 102, 1565–1567. [Google Scholar] [CrossRef] [PubMed]
  52. Rubenstein, J.L.; Geng, H.; Fraser, E.J.; Formaker, P.; Chen, L.; Sharma, J.; Killea, P.; Choi, K.; Ventura, J.; Kurhanewicz, J.; et al. Phase 1 investigation of lenalidomide/rituximab plus outcomes of lenalidomide maintenance in relapsed CNS lymphoma. Blood Adv. 2018, 2, 1595–1607. [Google Scholar] [CrossRef]
  53. Ghesquieres, H.; Chevrier, M.; Laadhari, M.; Chinot, O.; Choquet, S.; Moluçon-Chabrot, C.; Beauchesne, P.; Gressin, R.; Morschhauser, F.; Schmitt, A.; et al. Lenalidomide in combination with intravenous rituximab (REVRI) in relapsed/refractory primary CNS lymphoma or primary intraocular lymphoma: A multicenter prospective ‘proof of concept’ phase II study of the French Oculo-Cerebral lymphoma (LOC) Network and the Lymphoma Study Association (LYSA). Ann. Oncol. 2019, 30, 621–628. [Google Scholar]
  54. Craig, A.; Güney, E.; Pekmezci, M.; Bloomer, M.; Laszik, Z.; Ohgami, R.S.; Toland, A.; Vogel, H.; Forns, T.; Wang, E.; et al. Utility of PD-1, PD-L1, and IDO-1 Stains in Ocular Extranodal Marginal Zone Lymphoma (MZL) and Diffuse Large B-cell Lymphoma (DLBCL). Appl. Immunohistochem. Mol. Morphol. 2024, 32, 395–399. [Google Scholar] [CrossRef] [PubMed]
  55. Taher, A.; Abadir, E.; McCluskey, P.; Hamad, N.; Lo, T.H.; Heydon, P. Presumptive recurrence of intraocular lymphoma despite chimeric antigen receptor T-cell therapy. Retin. Cases Brief Rep. 2023, 17, 562–566. [Google Scholar] [CrossRef] [PubMed]
  56. Masalkhi, M.; Wahhoud, N.; Elhassadi, E. Next-gen oncology: The role of CAR-T cells against ocular lymphoma and myeloma. Eye 2024, 38, 3416–3417. [Google Scholar] [CrossRef] [PubMed]
  57. Hooper, J.; Shao, K.; Feng, P.W.; Falcone, M.; Feng, H. Periocular and ocular surface nonmelanoma skin cancer. Clin. Dermatol. 2024, 42, 71–77. [Google Scholar] [CrossRef]
  58. Basti, S.; Macsai, M.S. Ocular Surface Squamous Neoplasia: A Review. Cornea 2003, 22, 687. [Google Scholar] [CrossRef]
  59. Vann, R.R.; Karp, C.L. Perilesional and topical interferon alfa-2b for conjunctival and corneal neoplasia. Ophthalmology 1999, 106, 91–97. [Google Scholar] [CrossRef]
  60. Schechter, B.A.; Schrier, A.; Nagler, R.S.; Smith, E.F.; Velasquez, G.E. Regression of presumed primary conjunctival and corneal intraepithelial neoplasia with topical interferon alpha-2b. Cornea 2002, 21, 6–11. [Google Scholar] [CrossRef]
  61. Nägeli, M.; Mangana, J.; Chaloupka, K.; Dummer, R. Cutaneous SCC with orbital invasion: Case series. J. Eur. Acad. Dermatol. Venereol. 2022, 36 (Suppl. S1), 59–62. [Google Scholar] [CrossRef] [PubMed]
  62. Faramarzi, A.; Feizi, S. Subconjunctival bevacizumab injection for ocular surface squamous neoplasia. Cornea 2013, 32, 998–1001. [Google Scholar] [CrossRef] [PubMed]
  63. Özcan, A.A.; Çiloğlu, E.; Esen, E.; Şimdivar, G.H. Use of topical bevacizumab for conjunctival intraepithelial neoplasia. Cornea 2014, 33, 1205–1209. [Google Scholar] [CrossRef] [PubMed]
  64. van Poppelen, N.M.; van Ipenburg, J.A.; van den Bosch, Q.; Vaarwater, J.; Brands, T.; Eussen, B.; Magielsen, F.; Dubbink, H.J.; Paridaens, D.; Brosens, E.; et al. Molecular Genetics of Conjunctival Melanoma and Prognostic Value of TERT Promoter Mutation Analysis. Int. J. Mol. Sci. 2021, 22, 5784. [Google Scholar] [CrossRef]
  65. Taylor, A.W. Ocular immune privilege. Eye 2009, 23, 1885–1889. [Google Scholar] [CrossRef]
Jcto 03 00001 g001
Figure 1. Graphical representation of overall survival and one-year overall survival rate by therapy.
Figure 1. Graphical representation of overall survival and one-year overall survival rate by therapy.
Jcto 03 00001 g001
Jcto 03 00001 g002
Figure 2. The current uses of immunotherapy across various ocular tumors. Adapted with permission from “T-cell Deactivation vs. Activation” and “Cancer Vaccine Principle”. 2025, by BioRender.com. Retrieved from https://app.biorender.com/biorender-templates (accessed on 18 June 2024).
Figure 2. The current uses of immunotherapy across various ocular tumors. Adapted with permission from “T-cell Deactivation vs. Activation” and “Cancer Vaccine Principle”. 2025, by BioRender.com. Retrieved from https://app.biorender.com/biorender-templates (accessed on 18 June 2024).
Jcto 03 00001 g002
Table 1. Clinical trials of ICIs, cancer vaccines, and ACT in selected eye tumors.
Table 1. Clinical trials of ICIs, cancer vaccines, and ACT in selected eye tumors.
Type of ImmunotherapyCancer TypeOverall Survival (OS)One-Year OS RateTwo-Year OS RatePFSStable Disease RateOther Response RatesReferences
Pembrolizumab + entinostatMetastatic uveal melanoma13.4 months59%N/A *N/AN/AN/A[1]
Ziv-aflibercept + pembrolizumabOcular melanomaN/AN/AN/AN/AStable disease in both patientsN/A[2]
Nivolumab + ipilimumab, followed by nivolumabOcular/uveal melanoma15.3 months63%36%N/AN/AN/A[3]
AvelumabOcular melanoma17.2 monthsN/AN/AN/AN/AN/A[4]
IpilimumabMetastatic uveal melanoma6.8 months22%7%2.8 monthsN/AN/A[5]
Ipilimumab, pembrolizumab, nivolumab + atezolizumabMetastatic uveal melanoma7.6 monthsN/AN/A2.6 months14.3%N/A[6]
NivolumabOcular melanoma12.6 monthsN/AN/AN/AN/A18-month OS rate = 34.8%[7]
Coxsackievirus A21 (V937) vaccine + ipilimumabMetastatic uveal melanomaN/AN/AN/AN/ANo meaningful clinical benefitN/A[8]
Dendritic-cell-based vaccines/gp100 + tyrosinaseMetastatic uveal melanoma19.2 monthsN/AN/AN/AN/AN/A[9]
TIL therapyMetastatic uveal melanomaN/AN/AN/AN/AN/APartial response = 30%, objective tumor regression = 35%, complete response = 5%[10]
TebentafuspUveal melanomaN/A65%N/AN/AN/AN/A[11]
TebentafuspHLA-A*0201 uveal melanoma16.8 months62%N/A2.8 months45%N/A[12]
TebentafuspHLA-A*02:01-metastatic uveal melanomaN/A73%N/AN/AN/A6-month PFS = 31%[13]
Pembrolizumab, ipilimumab, or dacarbazineHLA-A*02:01-metastatic uveal melanomaN/A59%N/AN/AN/A6-month PFS = 19%[13]
RacotumomabN-glycolyl GM3 neuroectodermal malignanciesN/AN/AN/AN/AN/AImmune response with favorable toxicity profile[14]
* N/A stands for not announced.
Table 2. Classes of immunotherapy, their uses, and adverse effects.
Table 2. Classes of immunotherapy, their uses, and adverse effects.
Drug ClassClinical UseAdverse Effects
Immune checkpoint inhibitorsMetastatic melanoma, non-small-cell lung cancer, renal cell carcinoma [15]Dry eye disease, uveitis [16], retinopathy [17],
ophthalmoplegia [13]
Vaccine therapiesRefractory melanoma [18], prostate cancer [18]Injection site pain, headache, influenza-like illness [19]
Adoptive cell transfer therapiesMetastatic melanoma, cervical SCC, cholangiocarcinoma [20], Epstein–Barr virus (EBV)-induced post-transplant lymphoproliferative disease [21]Cytokine release syndrome and prolonged B-cell depletion [22], capillary leak syndrome [20]
Bispecific T-cell engagersUveal melanoma [11]Rash, pruritis, pyrexia, periorbital edema, fatigue, nausea [11]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Masalkhi, M.; Wahoud, N.; Moran, B.; Elhassadi, E. Immunotherapy in Ophthalmic Oncology: Current Trends and Future Directions. J. Clin. Transl. Ophthalmol. 2025, 3, 1. https://doi.org/10.3390/jcto3010001

AMA Style

Masalkhi M, Wahoud N, Moran B, Elhassadi E. Immunotherapy in Ophthalmic Oncology: Current Trends and Future Directions. Journal of Clinical & Translational Ophthalmology. 2025; 3(1):1. https://doi.org/10.3390/jcto3010001

Chicago/Turabian Style

Masalkhi, Mouayad, Noura Wahoud, Bridget Moran, and Ezzat Elhassadi. 2025. "Immunotherapy in Ophthalmic Oncology: Current Trends and Future Directions" Journal of Clinical & Translational Ophthalmology 3, no. 1: 1. https://doi.org/10.3390/jcto3010001

APA Style

Masalkhi, M., Wahoud, N., Moran, B., & Elhassadi, E. (2025). Immunotherapy in Ophthalmic Oncology: Current Trends and Future Directions. Journal of Clinical & Translational Ophthalmology, 3(1), 1. https://doi.org/10.3390/jcto3010001

Article Metrics

Back to TopTop