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

Madhav V. Dhodapkar, Mario Sznol, Biwei Zhao, Ding Wang, Richard D. Carvajal, Mary L. Keohan, Ellen Chuang, Rachel E. Sanborn, Jose Lutzky, John Powderly, Harriet Kluger, Sheela Tejwani, Jennifer Green, Venky Ramakrishna, Andrea Crocker, Laura Vitale, Michael Yellin, Thomas Davis, Tibor Keler

Research output: Contribution to journalArticlepeer-review

217 Scopus citations

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.

Original languageEnglish (US)
Article number232ra51
JournalScience Translational Medicine
Volume6
Issue number232
DOIs
StatePublished - Apr 16 2014
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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