Induction of antigen-specific immunity with a vaccine targeting NY-ESO-1 to the dendritic cell receptor DEC-205

Abstract

Immune-based therapies for cancer are generating substantial interest because of the success of immune checkpoint inhibitors. This study aimed to enhance anticancer immunity by exploiting the capacity of dendritic cells (DCs) to initiate T cell immunity by efficient uptake and presentation of endocytosed material. Delivery of tumor-associated antigens to DCs using receptor-specific monoclonal antibodies (mAbs) in the presence of DC-activating agents elicits robust antigen-specific immune responses in preclinical models. DEC-205 (CD205), a molecule expressed on DCs, has been extensively studied for its role in antigen processing and presentation. CDX-1401 is a vaccine composed of a human mAb specific for DEC-205 fused to the full-length tumor antigen NY-ESO-1. This phase 1 trial assessed the safety, immunogenicity, and clinical activity of escalating doses of CDX-1401 with the Toll-like receptor (TLR) agonists resiquimod (TLR7/8) and Hiltonol (poly-ICLC, TLR3) in 45 patients with advanced malignancies refractory to available therapies. Treatment induced humoral and cellular immunity to NY-ESO-1 in patients with confirmed NY-ESO-1-expressing tumors across various dose levels and adjuvant combinations. No dose-limiting or grade 3 toxicities were reported. Thirteen patients experienced stabilization of disease, with a median duration of 6.7 months (range, 2.4+ to 13.4 months). Two patients had tumor regression (~20% shrinkage in target lesions). Six of eight patients who received immune-checkpoint inhibitors within 3 months after CDX-1401 administration had objective tumor regression. This first-in-human study of a protein vaccine targeting DCs demonstrates its feasibility, safety, and biological activity and provides rationale for combination immunotherapy strategies including immune checkpoint blockade.

Trial registration: ClinicalTrials.gov NCT00948961.

Conflict of interest statement

Competing interests: B.Z., J.G., V.R., A.C., L.V., M.Y., T.D., and T.K. have equity interest in and are employees of Celldex Therapeutics Inc., which develops CDX-1401. The other authors have no competing interests.

Figures

Fig. 1.. Patient allocation to treatment cohorts. i.c., intracutaneous; sc, subcutaneous.

As shown in Table 2, nearly half of the enrolled patients had melanoma. Additional cancer types included ovarian, sarcoma, non–small cell lung, and colorectal cancers. Distant metastases were noted in 87% of the treated patients, consistent with the presence of advanced disease, as required for enrollment. Expression of the NY-ESO-1 antigen in tumor specimen was confirmed by IHC or PCR in 27 of 42 (64%) of the treated patients with available tissue. In cohorts 1 to 4, 12 of 30 (40%) had confirmed tumor NY-ESO-1 expression, whereas revised entry criteria required that all patients in cohorts 5 and 6 had confirmed tumor NY-ESO-1 expression.

Fig. 2.. Induction of anti–NY-ESO-1 IgG titers in patients vaccinated with CDX-1401.

Pre- and posttreatment sera were tested for anti–NYESO-1 IgG responses by enzyme-linked immunosorbent assay (ELISA) using full-length recombinant NY-ESO-1. The titer was established by determining the endpoint dilution with the peak response shown by color map as indicated in the legend. Patients with archival tumor that demonstrated NY-ESO-1 expression by IHC or PCR are indicated with green shading. Patients who experienced stable disease are indicated by asterisk.

Fig. 3.. Induction of NY-ESO-1–specific T cell responses in patients vaccinated with CDX-1401.

Cell-mediated immune responses as evaluated by IFN-g ELISpot assay. PBMCs were re-stimulated in vitrowithNYESO-1 peptide pool for 7 days with low-dose interleukin-2 (IL-2) and tested in an IFN-g ELISpot assay. Effector lymphocytes were incubated with T-depleted APCs (5:1) loaded with an NY-ESO-1 peptide pool or a control peptide pool and plated in anti–IFN-γ–coated ELISpot plates and incubated overnight at 37°C. HLA class I– and class II–binding CEF peptide pools served as positive controls. (A) Colormap of IFN-γ–producing NYESO- 1–specific T cells (spot counts) detected in a pre- and a selected post-vaccinated sample. (B) Selected patients, NY-ESO-1– (top) and NY-ESO-1+ (bottom), with sustained NY-ESO-1 specific IFN-γ response through multiple cycles of treatment.

Fig. 4.. Detection of NY-ESO-1–specific IFN-γ production by circulating T cell subsets assessed by intracellular cytokine staining assay.

Patient PBMC samples were treated as described in Fig. 3. After stimulation with NY-ESO-1 or control peptide pools, cells were stained for surface markers and then permeabilized for detection of IFN-g and TNF-α before analysis by flow cytometry. (A) PBMCs from patient 01-0101 at cycle 3 day 70 were analyzed for IFN-γ and TNF-α. (B) PBMCs from patient 02-0206 from cycle 2 day 70 and cycle 3 day 42 were analyzed for IFN-γ.