Phase I Study Utilizing a Novel Antigen-Presenting Cell–Targeted Vaccine with Toll-like Receptor Stimulation to Induce Immunity to Self-antigens in Cancer Patients

Abstract

Purpose The use of tumor-derived proteins as cancer vaccines is complicated by tolerance to these self antigens. Tolerance may be broken by immunization with activated, autologous, ex vivo generated and antigen-loaded, antigen-presenting cells (APC); however, targeting tumor antigen directly to APC in vivo would be a less complicated strategy. We wished to test whether targeted delivery of an otherwise poorly immunogenic, soluble antigen to APC through their mannose receptors (MR) would induce clinically relevant immunity. Experimental Design Two phase I studies were performed with CDX-1307, a vaccine composed of human chorionic gonadotropin beta chain (hCG-β) fused to a MR-specific monoclonal antibody, administered either locally (intradermally) or systemically (intravenously) in patients with advanced epithelial malignancies. An initial dose-escalation of single agent CDX-1307 was followed by additional cohorts of CDX-1307 combined with GM-CSF and the Toll-like receptor (TLR)-3 agonist poly-ICLC and TLR7/8 agonist resiquimod to activate the APC. Results CDX-1307 induced consistent humoral and T cell responses to hCG-β when co-administered with TLR agonists. Greater immune responses and clinical benefit, including the longest duration of stable disease, were observed with immunization combined with local TLR agonists. Immune responses were induced equally efficiently in patients with elevated and non-elevated levels of serum hCG-β. Antibodies within the serum of vaccinated participants had tumor suppressive function in vitro. Toxicity consisted chiefly of mild injection site reactions. Conclusions APC targeting and activation induce adaptive immunity against poorly immunogenic self antigens which has implications for enhancing the efficacy of cancer immunotherapy.

Phase I Trial of Overlapping Long Peptides from a Tumor Self-Antigen and Poly-ICLC Shows Rapid Induction of Integrated Immune Response in Ovarian Cancer Patients

“…An increase in local injection site reactions was seen in Cohort 3 patients receiving both Montanide and Poly-ICLC and led to the discontinuation of vaccinations in this cohort. The skin reactions may have been related to the volume of diluent required for the administration of both adjuvants and seemed to be a local irritant phenomenon, as observed in other studies (23). Strong antibody responses against vaccine OLP, which excluded the most immunogenic N-terminal region for naturally induced antibodies, were induced in most patients after vaccination with OLP in Montanide, especially when combined with Poly-ICLC.…”

“…This innate immune activation is likely playing an important role in the nature and extent of the responses that we show here with OLP. Poly-ICLC increased the kinetics and number of antigenspecific effectors (23,30).…”

Cancer Vaccination, Will You Have To Pay The Toll?

“…In a completed phase I study of CDX-1307 (Celldex Therapeutics, Inc), a vaccine candidate composed of human chorionic gonadotropin β-chain fused to mannose receptor-specific antibody, administered with TLR3 and TLR7/8 agonists in patients with advanced breast, colorectal, pancreatic, ovarian, or bladder cancer, TLR stimulation enhanced antibody and T-cell specific responses [45]. This correlated with longer stable disease and clinical benefit as two patients with higher antibody titers and T-cell immunity had the best outcome.…”

Immunotherapy in Urologic Malignancies: The Evolution and Future of Pattern Recognition Receptors

“…The development of stabilized compounds, including polyICLC, has been used in phase II studies against gliomas (Butowski et al, 2009). A recent phase I trial against multiple malignancies including advanced bladder cancer utilized a novel vaccine approach combining a human chorionic gonadotropin- antigen fusion protein with adjuvants poly ICLC and the TLR7/8 agonist resiquimod (Morse et al, 2011). This orchestration of TLR-based adjuvant activation with tumor antigen stimulation is promising and utilizes the ability of TLRs for cross antigen presentation, allowing extracellular antigens to be processed and presented by class I MHC (Oh and Kedl, 2010).…”