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Case Reports
. 2009 May;116(5):981-989.e1.
doi: 10.1016/j.ophtha.2008.12.004.

Ocular and Systemic Autoimmunity After Successful Tumor-Infiltrating Lymphocyte Immunotherapy for Recurrent, Metastatic Melanoma

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Free PMC article
Case Reports

Ocular and Systemic Autoimmunity After Successful Tumor-Infiltrating Lymphocyte Immunotherapy for Recurrent, Metastatic Melanoma

Steven Yeh et al. Ophthalmology. .
Free PMC article

Abstract

Objective: To describe the ophthalmic and systemic autoimmune findings after successful adoptive cell transfer of ex vivo expanded, autologous tumor-reactive tumor-infiltrating lymphocytes (TIL) for metastatic melanoma.

Design: Retrospective, interventional case report.

Participant: A 35-year-old man who underwent immunotherapy for metastatic melanoma with adoptive cell transfer of tumor-reactive TIL.

Methods: A 35-year-old man with metastatic melanoma was treated with TIL plus interleukin-2 (IL-2) therapy after a lymphodepleting regimen of cyclophosphamide and fludarabine for metastatic melanoma, which led to a complete and durable remission. Bilateral panuveitis, hearing loss, vitiligo, poliosis, and alopecia developed in the patient, requiring local ophthalmic immunosuppressive therapy. The clinical course, diagnostic testing, and therapeutic interventions over a 2-year period are reviewed.

Main outcome measures: Visual acuity, anterior chamber and vitreous inflammation, optical coherence tomography findings, serial electro-oculograms (EOGs), microperimetry (MP-1) testing, flow cytometric analysis of cells derived from the aqueous humor, and aqueous humor cytokine profiles were evaluated.

Results: After melanoma immunotherapy, complete tumor regression was achieved at 5 months after treatment with a durable, ongoing, complete remission at 24 months. Early in the treatment course, a high fever, a diffuse rash, hearing loss, and bilateral anterior uveitis developed acutely in the patient. Late autoimmune sequelae included the development of alopecia, vitiligo, poliosis, and bilateral panuveitis with diffuse retinal pigment epithelium (RPE) hypopigmentation, reminiscent of Vogt-Koyanagi-Harada (VKH) syndrome. Bilateral cystoid macular edema also developed that was responsive to acetazolamide. Serial EOGs showed alterations in RPE standing potentials in dark conditions, and MP-1 testing revealed diminished foveal and perifoveal sensitivity. An aqueous humor aspirate revealed a high concentration of melanoma tumor antigen-reactive T cells compared with that of peripheral blood samples, as well as a proinflammatory aqueous cytokine profile. At the time of cataract surgery 22 months after immunotherapy, a repeat aqueous humor sample showed the disappearance of the previously seen melanoma differentiation antigen-reactive lymphocytes, but the proinflammatory cytokine profile persisted.

Conclusions: Ocular and systemic autoimmune sequelae resembling VKH may develop after successful melanoma immunotherapy. This report provides insight into the pathogenesis of VKH disease. The patient's clinical course illustrates the fine balance between tumor-specific immunity and loss of self-tolerance.

Financial disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Figures

Figure 1
Figure 1
Computed tomography scans showing (A) bulky supraclavicular lymph nodes (yellow arrows) and (B) an abdominal mass (green arrow) and subcutaneous disease (blue arrow) in July 2006 before tumor-infiltrating lymphocyte (TIL) plus interleukin-2 (IL-2) therapy. Computed tomography scans obtained in December 2006 showing that (C) the supraclavicular lymphadenopathy has regressed (yellow arrows) coincident with (D) the disappearance of the intra-abdominal lesion (green arrow) and subcutaneous lesion (blue arrow). Photographs of the patient (E) obtained at baseline in July 2006 and (F) after therapy in November 2006 showing whitening of the hair and eyebrows. The patient also experienced poliosis in both eyes (not shown).
Figure 2
Figure 2
A and B, Fundus photographs obtained in October 2006 (3 months after tumor-infiltrating lymphocyte therapy) showing normal optic nerves, vessels, and maculae with moderate pigmentation in both eyes. C and D, Repeat fundus photographs obtained 7 months later in May 2007 showing a sunset-glow fundus with diffuse hypopigmentation of the choroid and retinal pigment epithelium in both eyes.
Figure 3
Figure 3
A, Initial electro-oculogram showing Arden ratios of 2.98 in the right eye and 3.02 in the left eye in November 2006. B, Electro-oculogram obtained in May 2007 showing that Arden ratios are elevated to 4.10 in the right eye and 4.51 in the left eye, likely because of a decrease in the dark trough amplitudes in both eyes.
Figure 4
Figure 4
Microperimetry-1 10-2 evaluation obtained in November 2007 showing diffuse perifoveal depression, which was less pronounced in (A) the right eye than in (B) the left eye. C and D, Optical coherence tomography at this time showed no evidence of cystoid macular edema in either eye, suggesting that the decrease in sensitivity may be the result of photoreceptor dysfunction.
Figure 5
Figure 5
T-cell flow cytometry and interferon-γ (IFN-γ) response to antigen stimulation. A, Before adoptive cell transfer (ACT), no CD8+ MART-1 tetramer-positive cells were observed in the peripheral blood lymphocytes (Pre ACT PBL), and 4.5% of the infused treatment (Tx) tumor-infiltrating lymphocyte (TIL) cells were CD8+MART-1 tetramer-positive. After TIL therapy, 2.5% of peripheral blood T cells (Post ACT PBL) were CD8+MART-1 tetramer-positive and 3.9% of ocular-derived T cells (Post ACT Eye) were CD8+MART-1 tetramer-positive. Bar graphs showing that with antigen stimulation on coculture with (B) MART-126-35 and gp100209-217 peptide-bearing target cells or (C) HLA-A2+ melanoma cells, increased human IFN-γ was observed from the patient’s peripheral blood lymphocytes (Post ACT PBL) and ocular-derived cells (Post ACT Eye) compared with 2 normal donor peripheral blood lymphocytes (PBLs) and the patient’s pretreatment PBL.
Figure 6
Figure 6
Optical coherence tomography (OCT) and response of cystoid macular edema (CME) to acetazolamide. A, Spectral-domain OCT scan obtained in September 2007 while receiving acetazolamide therapy showing moderate CME in the left eye with (B) a corresponding retinal contour map with a central retinal thickness of 392 μm. C and D, one month after acetazolamide cessation, an increase in CME to 535 μm was observed with loss of the foveal contour. The foveal contour and CME improved 2 weeks after restarting acetazolamide. E and F, Central retinal thickness was 215 μm.
Figure 7
Figure 7
Flow cytometry from aqueous humor obtained during cataract surgery in May 2008 that differs from the previous sample obtained in June 2006. Cells obtained (left column) from aqueous humor and (right column) after in vitro T-cell expansion were stained with: (A) gp100 tetramer and immunoglobulin G (IgG)-negative antibody controls, (B) MART-1 tetramer and anti-CD3 antibody, (C) and anti-CD8 with anti-CD3 or MART-1 tetramer. None of the ocular infiltrating cells had T-cell receptors that recognized MART-1 or gp100 melanoma tumor antigens.

Comment in

  • Melanoma, vitiligo, and uveitis.
    Albert DM. Albert DM. Ophthalmology. 2010 Mar;117(3):643-4; author reply 644. doi: 10.1016/j.ophtha.2009.12.004. Ophthalmology. 2010. PMID: 20189042 No abstract available.

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