Novel Treatment Approaches For Patients With Metastatic Melanoma (Page 4 of 5)

New Immunomodulatory Agents in Development

Four types of new immunomodulatory agents are in development for use in patients with malignant melanoma, including STA-4783, a heat shock protein inducer; PD-1 antagonistic antibody; anti-41-BB (CD137) antagonistic antibody; and CD40 agonistic antibody.

Heat shock protein inducer.

STA-4783 is a novel agent that promotes natural killer cell activity and augments levels of heat shock protein 70.[28] It is active as a single agent and with a taxane in human xenografts in mice. In phase 1 studies, STA-4783 appeared to have little clinical activity in kidney cancer or melanoma. In a randomized phase 2 study[29] that included 84 patients, STA-4783 plus paclitaxel were administered weekly intravenously for 3 weeks on/1 week off until progression or dose-limiting toxicity. The primary study end point was PFS. An intent-to-treat analysis found that PFS was 112 days for the combination of STA-4783 plus paclitaxel vs 56 days for paclitaxel alone (P = .035). The RR was 15.1% in the combination group vs 3.6% for the paclitaxel group. Patients in the combination group had a 54% grade 3/4 adverse event rate, compared with 57% for the paclitaxel-alone group. STA-4783 is being studied further in a phase 3 randomized registration trial.

PD-1 antagonistic antibody.

PD-1, a member of the TNF super-family, is another inhibitory molecule present on T cells.[30] PD-1 is increased on activated T cells and can bind to the PDL-1 molecule present on macrophages and dendritic cells as well as many tumors. The PD-1/PDL-1 interaction appears to limit the immune response, acts as a down-modulatory influence on antigen-specific immunity, and may represent a means by which tumors actively suppress immunity.A human immunoglobulin G4 antibody has been prepared that binds to and abrogates the activity of PD-1. In vitro, it can significantly augment the proliferation and functional activity of activated T cells; it is active alone, with chemotherapy, or with CTLA-4 abrogating antibodies in different murine tumor models.[31] This antibody has been tested in a phase 1 trial and thus far has not resulted in any dose-limiting toxicities after single dosing.

CD40 agonistic antibody.

CD40 is a receptor expressed on a variety of immune cells, including B cells and antigen-presenting dendritic cells.[32] It is bound by CD40 ligand expressed on T cells and represents an important axis of stimulation for antigen-specific T cells. An agonistic CD40 antibody, CP-870893, has been tested in a phase 1 single-dosing study, predominantly in patients with melanoma, at doses ranging from 0.03 to 0.3 mg/kg.[33] The reported side effects consist of chills and fevers, with deep venous thrombus and headache being the dose-limiting toxicities. Among 29 patients in the trial, 4 of 15 (27%) with melanoma sustained a PR at day 43 after only 1 dose of CP-870893. All responders received the drug at a dose level of 0.2 mg/kg or above, suggesting a dose-response relationship. Multidose phase 2 trials are pending for this promising agent.