Stimulatory Effects Observed With Vaccine in Early-Stage CRC

Karen E. Knudsen, PhD

Karen E. Knudsen, PhD

Investigators on a first-in-human phase I trial (NCT01972737) found that antibody and T-cell responses were detected in a vaccine targeting GUCY2C, a commonly overexpressed protein in patients with early-stage colorectal cancer (CRC).^1,2

Responses from cytotoxic CD8+ T cells, but not autoimmune CD4+ T cells, had been observed with GUCY2C in prior mouse studies exhibiting that self-tolerance to the protein is split. This mechanism of split tolerance to GUCY2C is key to the vaccine's antitumor immunity without added autoimmune toxicity. 

“There is an urgent need to understand what fuels colorectal cancer growth, and to harness that knowledge for developing novel therapies,” Karen E. Knudsen, PhD, executive vice president of Oncology Services, director, Sidney Kimmel Cancer Center at Jefferson Health, said in a press release. “This pivotal study provides some of the first evidence that it may be possible to safely direct a patient’s own immune system to seek and destroy this cancer type.”

The vaccine, Ad5-GUCY2C-PADRE, is comprised of an E1/E3-deleted recombinant human type 5 adenovirus. The adenovirus expresses the human GUCY2C extracellular domain (ECD; GUCY2C1—429) and is bound on its C-terminus to the universal CD4+ T-helper cell epitope PADRE.

In the trial, which was conducted by Jefferson Health researchers, 10 patients with stage I (n = 1) or II (n = 9) CRC within 3 years of surgery, who showed no clinical or laboratory evidence of local or systemic recurrence, received a single intramuscular injection of 1011 viral particles of Ad5-GUCY2C-PADRE. Efficacy and safety served as coprimary endpoints of the study.

Patients had a median age of 65 years (range, 49-76). The majority of patients were Caucasian (n = 8), and an even number of female and male patients were enrolled (n = 5 each). Those who received prior chemotherapy, radiation therapy, and immunotherapy were excluded from enrollment.

Treatment-related acute toxicity was assessed in the clinic every 10 minutes for 30 minutes following injection. Further safety assessments were conducted in clinic for 30 minutes and via phone on days 3 and 8, after which patients returned for in-clinic assessments and blood collection on days 30, 90, and 180.

Grade 1/2 adverse events (AEs) were reported at the injection site, and no grade 3/4 AEs were reported during the 6-month follow-up period. The most common AEs included chills/rigor (n = 2) and tenderness/swelling at the injection site (n = 2). Moreover, the blood tests performed on days 30, 90, and 180 revealed no vaccine-related AEs.

“We are preparing for a phase II study that will begin recruiting patients this fall,” lead author Adam Snook, PhD, assistant professor in the Department of Pharmacology and Experimental Therapeutics at Thomas Jefferson University, said in the press release. “We used lessons learned in the first study to modify the vaccine to hopefully make it even more effective.”

Of note, GUCY2C is present in approximately 60% of patients with pancreatic, gastric, and esophageal cancers, and the vaccine could potentially benefit patients beyond those with CRC in subsequent studies.

“The goal of the study to begin this fall is to show that version 2.0 of the vaccine is even better and that it may benefit a much bigger group of the overall cancer patient population,” Snook said in the press release.

References:

1. Snook A, Baybutt T, Xiang B, et al. Split tolerance permits safe AD5-GUCY2C-PADRE vaccine-induced T-cell responses in colon cancer patients.J Immunother Can. 2019;7(104). doi: 10.1186/s40425-019-0576-2.
2. Novel Vaccine for Colorectal Cancer Shows Positive Phase I Results. Jefferson Health. Published April 29, 2019. https://bit.ly/2PLjDvo. Accessed April 30, 2019.