BACKGROUND: We previously showed that vaccination with one dose of PR1 and WT1 peptides induces transient anti-leukemia immunity. We hypothesized that maintenance of a sustained anti-leukemia response may require frequent boost injections. DESIGN AND METHODS: Eight patients with myeloid malignancies were enrolled in this phase II study, and 6 completed 6 injections of PR1 and WT1 peptides in Montanide-adjuvant with GM-CSF, every two weeks. RESULTS: Both high- and low-avidity PR1 or WT1-specific CD8(+) T cells were detected in all evaluable patients after the first vaccine dose. Repeated vaccination led to selective deletion of high avidity PR1- and WT1-specific CD8(+) T cells and was not associated with significant reduction in WT1-expression. Additional boosting failed to increase vaccine-induced CD8(+) T-cell frequencies further and in all patients the response was lost before the 6(th) dose. PR1- or WT1-specific CD8(+) T cells were not detected in bone marrow samples, excluding their preferential localization to this site. Following a booster injection three months after the 6(th) vaccine dose, no high-avidity PR1 or WT1-specific CD8(+) T cells could be detected, whereas low-avidity T cells were readily expanded. CONCLUSIONS: These data support the immunogenicity of PR1 and WT1 peptide vaccines. However, repeated delivery of peptides with Montanide-adjuvant and GM-CSF leads to rapid loss of high-avidity peptide-specific CD8(+) T cells. These results may offer an explanation for the lack of correlation between immune and clinical responses observed in a number of clinical trials of peptide vaccination. New approaches are needed to induce long-term high-avidity memory responses against leukemia antigens.
BACKGROUND: We previously showed that vaccination with one dose of PR1 and WT1 peptides induces transient anti-leukemia immunity. We hypothesized that maintenance of a sustained anti-leukemia response may require frequent boost injections. DESIGN AND METHODS: Eight patients with myeloid malignancies were enrolled in this phase II study, and 6 completed 6 injections of PR1 and WT1 peptides in Montanide-adjuvant with GM-CSF, every two weeks. RESULTS: Both high- and low-avidity PR1 or WT1-specific CD8(+) T cells were detected in all evaluable patients after the first vaccine dose. Repeated vaccination led to selective deletion of high avidity PR1- and WT1-specific CD8(+) T cells and was not associated with significant reduction in WT1-expression. Additional boosting failed to increase vaccine-induced CD8(+) T-cell frequencies further and in all patients the response was lost before the 6(th) dose. PR1- or WT1-specific CD8(+) T cells were not detected in bone marrow samples, excluding their preferential localization to this site. Following a booster injection three months after the 6(th) vaccine dose, no high-avidity PR1 or WT1-specific CD8(+) T cells could be detected, whereas low-avidity T cells were readily expanded. CONCLUSIONS: These data support the immunogenicity of PR1 and WT1 peptide vaccines. However, repeated delivery of peptides with Montanide-adjuvant and GM-CSF leads to rapid loss of high-avidity peptide-specific CD8(+) T cells. These results may offer an explanation for the lack of correlation between immune and clinical responses observed in a number of clinical trials of peptide vaccination. New approaches are needed to induce long-term high-avidity memory responses against leukemia antigens.
Authors: Noelia Casares; Laura Arribillaga; Pablo Sarobe; Javier Dotor; Ascensión Lopez-Diaz de Cerio; Ignacio Melero; Jesús Prieto; Francisco Borrás-Cuesta; Juan J Lasarte Journal: J Immunol Date: 2003-12-01 Impact factor: 5.422
Authors: Jeffrey J Molldrem; Peter P Lee; Shreya Kant; Eric Wieder; Weidong Jiang; Sijie Lu; Changqing Wang; Mark M Davis Journal: J Clin Invest Date: 2003-03 Impact factor: 14.808
Authors: E Beillard; N Pallisgaard; V H J van der Velden; W Bi; R Dee; E van der Schoot; E Delabesse; E Macintyre; E Gottardi; G Saglio; F Watzinger; T Lion; J J M van Dongen; P Hokland; J Gabert Journal: Leukemia Date: 2003-12 Impact factor: 11.528
Authors: Katayoun Rezvani; Matthias Grube; Jason M Brenchley; Giuseppe Sconocchia; Hiroshi Fujiwara; David A Price; Emma Gostick; Ko Yamada; Jan Melenhorst; Richard Childs; Nancy Hensel; Daniel C Douek; A John Barrett Journal: Blood Date: 2003-06-26 Impact factor: 22.113
Authors: Katayoun Rezvani; Joshua D Brody; Holbrook E Kohrt; Aaron C Logan; Ranjana Advani; Debra Katherine Czerwinski; Wen-Kai Weng; Robert S Negrin; Victoria Carlton; Malek Faham; Ronald Levy; John Barrett Journal: Biol Blood Marrow Transplant Date: 2012-10-03 Impact factor: 5.742