Targeting gp100 and TRP-2 with a DNA vaccine: Incorporating T cell epitopes with a human IgG1 antibody induces potent T cell responses that are associated with favourable clinical outcome in a phase I/II trial

Abstract

A DNA vaccine, SCIB1, incorporating two CD8 and two CD4 epitopes from TRP-2/gp100 was evaluated in patients with metastatic melanoma. Each patient received SCIB1 via intramuscular injection with electroporation. The trial was designed to find the safest dose of SCIB1 which induced immune/clinical responses in patients with or without tumour. Fifteen patients with tumor received SCIB1 doses of 0.4-8 mg whilst 20 fully-resected patients received 2–8 mg doses. Twelve patients elected to continue immunization every 3 months for up to 39 months. SCIB1 induced dose-dependent T cell responses in 88% of patients with no serious adverse effects or dose limiting toxicities. The intensity of the T cell responses was significantly higher in patients receiving 4 mg doses without tumor when compared to those with tumor (p < 0.01). In contrast, patients with tumor showed a significantly higher response to the 8 mg dose than the 4 mg dose (p < 0.03) but there was no significant difference in the patients without tumor. One of 15 patients with measurable disease showed an objective tumor response and 7/15 showed stable disease. 5/20 fully-resected patients have experienced disease recurrence but all remained alive at the cut-off date with a median observation time of 37 months. A positive clinical outcome was associated with MHC-I and MHC-II expression on tumors prior to therapy (p = 0.027).We conclude that SCIB1 is well tolerated and stimulates potent T cell responses in melanoma patients. It deserves further evaluation as a single agent adjuvant therapy or in combination with checkpoint inhibitors in advanced disease.

In Vivo Assembly of Nanoparticles Achieved through Synergy of Structure‐Based Protein Engineering and Synthetic DNA Generates Enhanced Adaptive Immunity

“…Fewer immunizations of DLnanovaccine could induce the same, if not higher, titers of antibodies. Given recent advances in the EP technology has improved the potency and consistency of immune responses induced by DNA vaccines in patients,4,37–39,63,65 it will be important to determine whether DLnanovaccines can also help to reduce doses used in the clinic and lower the number of clinical visits required for vaccination. These advances may have important implications for outbreak control, and for global deployment including of vaccinations in more resource limited settings.…”

Vaccine Strategy in Melanoma

“…Neoepitope vaccination also resulted in a broadened repertoire of T cells 23 . A phase I clinical trial of DNA vaccine-encoding genes for immunogenic epitopes for gp100 and TRP2 demonstrated an immune response rate of 84%, comparable to other peptide vaccines using gp100 45,38 . Despite induction of an immune response, DNA vaccines evoke limited objective clinical responses 45 .…”

Current Strategies to Enhance Anti-Tumour Immunity

“…DNA vaccines have successfully combined a number of antigens. SCIB1 is a DNA vaccine that contains epitopes for glycoprotein 100 (gp100) and TRP-2 and has shown promising early results in patients [ 45 ]. SCIB1 induced dose-dependent T-cell responses in 88% of patients with no serious adverse effects or dose limiting toxicities.…”

“…The use of electroporation to successfully deliver a DNA vaccine encoding epitopes in the CDR regions of a human IgG1 antibody (SCIB1) in melanoma patients was well tolerated and showed minimal toxicity. SCIB1 vaccine targeting melanoma differentiation antigens gp100 and TRP-2 induced dose dependent T-cell responses in 88% of patients and is evidence of clinical responses [ 45 ]. The provision of T-cell help has been considered for some time a vital component for efficient induction of immune responses.…”