A phase I, open label, dose escalation and cohort expansion study to evaluate the safety and immune response to autologous dendritic cells transduced with AdGMCA9 in patients with metastatic renal cell carcinoma

Ubiquitous membranous expression of carbonic anhydrase IX (CAIX) in renal cell carcinoma (RCC) makes it an attractive vaccine target. We developed a fusion gene construct, GM-CSF + CAIX, transduced by a replication deficient adenovirus into autologous dendritic cells (DC) that are injected in patients with metastatic RCC in this phase 1 study targeting CAIX overexpressed on RCC tumors.

A recombinant adenovirus encoding the GMCSF-CAIX fusion gene (AdGMCAIX) was manufactured per GMP in collaboration with the NCI Rapid Access to Intervention Development (RAID) program. The final product was produced using DCs cultured ex vivo from patients’ peripheral blood mononuclear cells (PBMC) and engineered with AdGMCAIX prior to intradermal injection. These injected transduced DCs were expected to stimulate an antigen specific immune response against CAIX expressing RCC. Three dose escalation cohorts (5, 15_, and 50 X 10⁶ cells/administration) were injected based on 3+3 design. DC-AdGMCAIX was given intradermally Q2 weeks X 3 doses. The primary aim is safety of the injections. Secondary aims are to evaluate immune responses & antitumor effects per RECIST 1.1. Eligibility criteria included patients with clear cell mRCC with ECOG 0-1, measurable disease, and adequate organ function.

Fifteen patients with clear cell mRCC were enrolled. Nine patients received all 3 planned vaccine doses. No SAE’s were seen. Grade 1/2 AEs include fatigue (3/1), leukopenia (1/1) and flu-like symptoms (0/1). Of the nine patients who received treatment, one expired of progressive disease, two patients were lost to follow-up and six patients are alive. Of the six patients, five have progressive disease and are currently receiving standard-of-care therapies, and one has completed treatment with stable disease at 6 mon follow up and is being evaluated for retreatment.

These early data show that autologous DC transduced by Ad-GMCAIX vector can be safely given to mRCC patients without any SAE’s noted at the doses tested. These data support further development of Ad-GMCAIX vaccine strategies either alone or in combination with approved therapies.