Vaccination with LAG-3Ig (IMP321) and Peptides Induces Specific CD4 and CD8 T-Cell Responses in Metastatic Melanoma Patients—Report of a Phase I/IIa Clinical Trial

Abstract

Purpose: Cancer vaccines aim to generate and maintain antitumor immune responses. We designed a phase I/IIa clinical trial to test a vaccine formulation composed of Montanide ISA-51 (Incomplete Freund's Adjuvant), LAG-3Ig (IMP321, a non-Toll like Receptor agonist with adjuvant properties), and five synthetic peptides derived from tumor-associated antigens (four short 9/10-mers targeting CD8 T-cells, and one longer 15-mer targeting CD4 T-cells). Primary endpoints were safety and T-cell responses.Experimental Design: Sixteen metastatic melanoma patients received serial vaccinations. Up to nine injections were subcutaneously administered in three cycles, each with three vaccinations every 3 weeks, with 6 to 14 weeks interval between cycles. Blood samples were collected at baseline, 1-week after the third, sixth and ninth vaccination, and 6 months after the last vaccination.Circulating T-cells were monitored by tetramer staining directly ex vivo, and by combinatorial tetramer and cytokine staining on in vitro stimulated cells.Results: Side effects were mild to moderate, comparable to vaccines with Montanide alone. Specific CD8 T-cell responses to at least one peptide formulated in the vaccine preparation were found in 13 of 16 patients. However, two of the four short peptides of the vaccine formulation did not elicit CD8 T-cell responses. Specific CD4 T-cell responses were found in all 16 patients.Conclusions: We conclude that vaccination with IMP321 is a promising and safe strategy for inducing sustained immune responses, encouraging further development for cancer vaccines as components of combination therapies.

Coinhibitory Pathways in Immunotherapy for Cancer

“…The anti-LAG3 antibody BMS986016 has entered a phase 1 cancer clinical trial and includes a nivolumab (anti-PD-1) combination arm (NCT01968109). A LAG3-Fc fusion protein, IMP321 (Immutep), also is in clinical development and has been shown to increase tumor-reactive T cell responses in a phase I clinical trial (137).…”

Cancer immunotherapy: moving forward with peptide T cell vaccines

“…Unfortunately, numerous clinical studies using peptide vaccines have resulted in suboptimal therapeutic benefit in most patients [29–31]. We attribute this failure to two major causes: 1) suboptimal immunogenicity, and 2) the presence of an immunosuppressive tumor microenvironment.…”

Heterogeneity assessment of functional T cell avidity

“…In addition, several factors that are independent of TCR affinity regulate functional avidity of T cells, such as TCR clustering, involvement of the co-receptor CD8, adhesion molecules, and co-activating and co-inhibitory receptors/ligands25 or recognition efficiency32627. The mean functional avidity is assessed by cellular assays such as the 51 Chromium release cytotoxicity assay2829 or the IFN-γ Elispot assay30, using titrated amounts of peptide.…”