TY - JOUR
T1 - First in man study
T2 - Bcl-Xl_42-CAF®09b vaccines in patients with locally advanced prostate cancer
AU - Mørk, Sofie Kirial
AU - Kongsted, Per
AU - Westergaard, Marie Christine Wulff
AU - Albieri, Benedetta
AU - Granhøj, Joachim Stoltenborg
AU - Donia, Marco
AU - Martinenaite, Evelina
AU - Holmström, Morten Orebo
AU - Madsen, Kasper
AU - Kverneland, Anders H
AU - Kjeldsen, Julie Westerlin
AU - Holmstroem, Rikke Boedker
AU - Lorentzen, Cathrine Lund
AU - Nørgaard, Nis
AU - Andreasen, Lars Vibe
AU - Wood, Grith Krøyer
AU - Christensen, Dennis
AU - Klausen, Michael Schantz
AU - Hadrup, Sine Reker
AU - Thor Straten, Per
AU - Andersen, Mads Hald
AU - Svane, Inge Marie
N1 - Copyright © 2023 Mørk, Kongsted, Westergaard, Albieri, Granhøj, Donia, Martinenaite, Holmström, Madsen, Kverneland, Kjeldsen, Holmstroem, Lorentzen, Nørgaard, Andreasen, Wood, Christensen, Klausen, Hadrup, thor Straten, Andersen and Svane.
PY - 2023/3/14
Y1 - 2023/3/14
N2 - 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.
AB - 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.
KW - Male
KW - Humans
KW - CD8-Positive T-Lymphocytes
KW - Vaccines
KW - Vaccination
KW - Prostatic Neoplasms/therapy
KW - Hormones
UR - http://www.scopus.com/inward/record.url?scp=85151071334&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2023.1122977
DO - 10.3389/fimmu.2023.1122977
M3 - Journal article
C2 - 36999039
SN - 1664-3224
VL - 14
JO - Frontiers in Immunology
JF - Frontiers in Immunology
M1 - 1122977
ER -