CTLA-4 offers promise to melanoma patients

"Although CTLA-4 has been associated with some serious autoimmune phenomena, the interesting thing is that steroids can be used to control the 'side effects' without adversely impacting the efficacy of the monoclonal antibodies," she says.

Phan and colleagues used serial administration of CTLA-4 antibody in conjunction with vaccination with two modified peptides from melanoma-associated antigen to treat metastatic melanoma in 14 patients (Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA. 100:8372-8377, 2003). The blockade of CTLA-4 induced grade III/IV autoimmune manifestations in six patients, or 43 percent, including dermatitis, enterocolitis, hepatitis and hypophysitis.

Methods and outcomes

All patients in the trial had stage IV melanoma; 12, or 86 percent, had visceral metastases. All had undergone excision of the primary lesion, and six patients, or 43 percent, had received prior chemotherapy. Eleven patients, or 79 percent, had received prior immunotherapy that included IFN-alpha, low-dose IL-2, high-dose IL-2, whole-cell melanoma vaccines, NY-ESO-1 peptide vaccine or granulocyte-macrophage colony-stimulating factor.

Two patients experienced complete tumor responses, and one had a partial response, i.e., shrinkage of a solitary lung lesion after two treatment cycles and complete resolution of a lung mass. Two patients had mixed responses: disappearance of several lung nodules after four cycles, but progression of mediastinal lymph nodes, and substantial shrinkage of a large hilar mass and several lung nodules after two cycles, but growth in other lung lesions.

Adverse reactions included diarrhea, skin rash, pulmonary infiltrates associated with mild pleuritic chest pain and vitiligo. Autoimmune screening blood tests were normal except for two patients who developed antinuclear Ab. Six patients, or 43 percent, developed seven grade III/IV autoimmune toxicities, including three patients with dermatitis, two with colitis/enterocolitis and one each with hypophysitis and hepatitis.

Biologic overview

"CTLA-4 is in several phase 3 FDA clinical trials, and I think it is the most exciting new therapeutic development - biologic or nonbiologic - that we have going on for melanoma," Dr. Spitler says. "I'm very optimistic that one or more of these studies will pan out. The question is going to be, can we balance the therapeutic benefits against the autoimmune side effects."

In direct contrast to the promise shown with CTLA-4 is the failure of numerous clinical trials exploring the safety and efficacy of melanoma vaccines, according to Dr. Spitler.

"There's a lot of 'buzz' about vaccines, but there are six large, randomized phase 3 trials of vaccines for adjuvant therapy of melanoma that have all been negative studies," she says. "I believe that that says a lot about the potential for vaccines. It seems to me that we're missing something; that we have to do something different with the vaccines than what's been done so far."

Two biologics are currently approved for therapy of melanoma: interleukin-2 (IL-2), approved for therapy of metastatic disease, and alpha interferon, approved for adjuvant therapy of high-risk melanoma. IL-2 has been used alone or in combination with chemotherapy, lymphokine activity killer cells (LAK) or tumor infiltrating lymphocytes (TIL) or biologics such as interferon, according to Dr. Spitler. It is administered in high doses, low doses and by various infusion schedules such as bolus and continuous infusion.