First in man study: Bcl-Xl_42-CAF ® 09b vaccines in patients with locally advanced prostate cancer.

Background: The B-cell lymphoma-extra-large (Bcl-XL) protein plays an important role in cancer cells' resistance to apoptosis. Pre-clinical studies have shown that vaccination with Bcl-XL-derived peptides can induce tumor-specific T cell responses that may lead to the elimination of cancer cells. Furthermore, pre-clinical studies of the novel adjuvant CAF ^® 09b have shown that intraperitoneal (IP) injections of this adjuvant can improve the activation of the immune system. In this study, patients with hormone-sensitive prostate cancer (PC) received a vaccine consisting of Bcl-XL-peptide with CAF ^® 09b as an adjuvant. The primary aim was to evaluate the tolerability and safety of IP and intramuscular (IM) administration, determine the optimal route of administration, and characterize vaccine immunogenicity.
Patients and Methods: Twenty patients were included. A total of six vaccinations were scheduled: in Group A (IM to IP injections), ten patients received three vaccines IM biweekly; after a three-week pause, patients then received three vaccines IP biweekly. In Group B (IP to IM injections), ten patients received IP vaccines first, followed by IM under a similar vaccination schedule. Safety was assessed by logging and evaluating adverse events (AE) according to Common Terminology Criteria for Adverse Events (CTCAE v. 4.0). Vaccines-induced immune responses were analyzed by Enzyme-Linked Immunospot and flow cytometry.
Results: No serious AEs were reported. Although an increase in T cell response against the Bcl-XL-peptide was found in all patients, a larger proportion of patients in group B demonstrated earlier and stronger immune responses to the vaccine compared to patients in group A. Further, we demonstrated vaccine-induced immunity towards patient-specific CD4, and CD8 T cell epitopes embedded in Bcl-XL-peptide and an increase in CD4 and CD8 T cell activation markers CD107a and CD137 following vaccination. At a median follow-up of 21 months, no patients had experienced clinically significant disease progression.
Conclusion: The Bcl-XL-peptide-CAF ^® 09b vaccination was feasible and safe in patients with l hormone-sensitive PC. In addition, the vaccine was immunogenic and able to elicit CD4 and CD8 T cell responses with initial IP administration eliciting early and high levels of vaccine-specific responses in a higher number og patients.
Clinical Trial Registration: https://clinicaltrials.gov, identifier NCT03412786.
Competing Interests: MD has the past two years received proprietary data access from Bristol-Myers Squibb and Genentech, is advisor of Achilles Therapeutics, and has received honoraria for lectures from Roche and Novartis. IS has received for consultancies honoraria as well as lectures from Roche, MSD, Novartis, Pierre Fabre, and Bristol-Myers Squibb; and financial support to attend conferences from Bristol-Myers Squibb, MSD, and Novartis. GW, LA, and DC are co-inventors on patents covering CAF®09b. All the rights have been assigned to Statens Serum Institut SSI, a Danish not-for-profit governmental institute.Within the last two years, PK has received honoraria for lectures from Jannsen Cilag and financial support to attend conferences from Pfizer. Author EM was employed by company IO Biotech Aps, Copenhagen, Denmark. Author MK was employed by company EVAXION BIOTECH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer SEBM declared a past co-authorship with the author DC to the handling editor.
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