Investigators push for more effective treatments for choroidal melanoma

Immunotherapy appears useful and safe for patients with metastatic melanoma, trial results show.

Issue: February 10, 2008

ByJessica Loughery

NEW ORLEANS – Immunotherapy represents a potential new treatment option for patients with metastatic melanoma and appears to pose no increased risk to eyes, according to a speaker here.

Tara A. Young

The problem with choroidal or ocular melanoma is metastatic disease, Tara A. Young, MD, PhD, said at the American Academy of Ophthalmology annual meeting.

“By the time the primary tumor is detected, micrometastasis may already be present,” she said.

“A modern approach to the treatment of patients with choroidal melanoma will involve not only treating the eye, but also looking at better strategies to predict metastasis, detect metastatic lesions early and ultimately treat metastasis successfully,” Dr. Young said.

Although physicians can now predict metastasis with molecular techniques, metastasis is often detected too late. Additionally, systemic radiation, chemotherapy and vaccines have not been shown to prolong the lives of patients with metastatic choroidal melanoma, she said.

Immunotherapy for metastatic disease

“An alternative approach may involve harnessing the immune system, particularly with respect to cytotoxic T-lymphocyte enhancement to help fight metastatic disease,” Dr. Young said.

CP-675,206 (Pfizer), or tremelimumab, is a human monoclonal antibody to cytotoxic T lymphocyte-associated antigen 4 (CTLA4). “CTLA4 plays an essential role in the down-regulation of T-lymphocyte response in the immune system, and CTLA4 also represents a novel drug target,” she said.

“[Tremelimumab] may generate an antimelanoma response by blocking CTLA4, thus enhancing the immune response,” Dr. Young said.

In a prospective trial, she and colleagues at the University of California, Los Angeles, evaluated the safety and efficacy of tremelimumab in the treatment of 20 metastatic melanoma patients. They published their results in the American Journal of Ophthalmology.

The primary melanoma site was the skin in 14 patients, the mucosa in one patient and the eye in one patient. The primary site was unknown in four patients.

Six of the patients received dendritic cell vaccines in combination with immunotherapy as part of a phase 1 trial, and 14 of the patients received tremelimumab alone as part of a phase 1/2 trial.

All patients were followed for at least 2 months.

Patient prior to tremelimumab treatment.

Same patient after tremelimumab treatment.

Images: Young TA

Vision risk

The primary outcome in this study was the potentially toxic effects of CTLA4-blocking antibodies on pigmented and nonpigmented ocular cells. The investigators conducted a full ophthalmic examination, psychophysical and electrophysiological assessment, fundus photography and fluorescein angiography at baseline, 2 months after immunotherapy commenced and thereafter at 2- to 3-month intervals for patients continuing with immunotherapy. They conducted 4 or more months of follow-up with eight patients, 6 or more months follow-up with five patients and 12 or more months follow-up with two patients.

“With respect to ocular findings, none of the 20 patients had any eye or vision problems associated with the drug,” Dr. Young said. Best corrected visual acuity, near vision, Amsler grid interpretation, Pelli-Robson contrast sensitivity and IOP were all stable, the authors found.

Although three patients were found to have bilateral patches of decreased retinal and choroidal pigmentation in the posterior fundus, these findings were not associated with structural or functional problems. One additional patient showed a visual field defect, but this was related to the onset of brain metastasis during the study period.

There were no abnormalities found in 17 patients who underwent color vision, electroretinogram and electrooculogram assessment at baseline and after 2 months. Additionally, all 20 patients reported stable vision with the self-administered National Eye Institute 25-item Visual Function Questionnaire.

For patients examined after the initial study endpoint, no changes or vision deterioration were found.

Antimelanoma response

“There was a 40% antimelanoma response with this drug in this group of patients,” Dr. Young said.

Two of the responding patients received the dendritic cell vaccine in combination with tremelimumab. Of those who received tremelimumab alone, three patients had a complete antitumor response, two had a partial response and one remained stable. None of these patients experienced a relapse during a follow-up period of up to 3 years.

The other eight patients showed tumor progression.

“Although this is a small number of patients and a study of relatively short-term follow-up, it has demonstrated proof of principle for alternative therapy for metastatic melanoma. Our goal is to determine safety and efficacy of this drug and apply this form of immunotherapy to patients with choroidal melanoma with a high risk of metastasis or early metastatic disease,” Dr. Young said.

For more information:

Tara A. Young, MD, PhD, can be reached at Jules Stein Eye Institute, David Geffen School of Medicine, University of California, Los Angeles, 100 Stein Plaza, DS 3–519, Los Angeles, CA 90095; 310-206-7484; fax: 310-794-7904; e-mail: young@jsei.ucla.edu. Dr. Young has no direct financial interest in the products discussed in this article, nor is she a paid consultant for any companies mentioned.

Pfizer, maker of CP-675,206, can be reached at 235 E. 42nd St., New York, NY 10017; 212-733-2323; Web site: www.pfizer.com.

Reference:

Straatsma BR, Nusinowitz S, et al. Surveillance of the eye and vision in clinical trials of CP-675,206 for metastatic melanoma. Am J Ophthalmol. 2007;143:958-969.

Jessica Loughery is an OSN Staff Writer who covers all aspects of ophthalmology.