Failure to define window of time for autologous tumor vaccination in patients with newly diagnosed or relapsed acute lymphoblastic leukemia.
OBJECTIVE
We and others have shown that B cell precursor acute lymphoblastic leukemia cells (ALL) stimulated with CD40 ligand become efficient antigen-presenting cells (APC) capable of expanding autologous, tumor-specific T cells from patients. Translation of these preclinical findings to a novel treatment strategy required four separate issues to be determined: (1) if a CD40-ALL vaccine could be generated for clinical use; (2) whether clinical translation could be achieved; (3) whether the vaccination was safe; and (4) whether a window of time could be identified that would optimize the efficacy of vaccination.


METHODS
Nine patients with relapsed/refractory ALL were enrolled in a phase I trial of vaccination with autologous CD40-ALL. Immunologic reconstitution was measured in a separate cohort of 23 patients with newly diagnosed ALL.


RESULTS
We successfully prepared autologous vaccines for all nine patients in the phase I trial. CD40-ALL were potent APC, capable of stimulating allogeneic and peptide-specific T cells in vitro. Two patients were vaccinated without adverse events. Five patients died or progressed before vaccination, suggesting that rapid disease progression limits vaccination in patients with relapse disease, thus limiting clinical translation. We therefore sought to identify a window of time for vaccination during which this approach might be feasible. To achieve this end, we evaluated immunological reconstitution in newly diagnosed patients with ALL patients. Despite recovery of myelopoiesis, most patients had profound defects in T, B, and natural killer (NK) cell numbers that failed to recover at any point during therapy.


CONCLUSIONS
Autologous tumor vaccination at a time of ALL relapse is not feasible. Alternative strategies for immunotherapy of ALL may require ex vivo generation of antigen specific T cells and adoptive therapy.
Haining
W Nicholas
WN
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. nicholas_haining@dfci.harvard.edu
Cardoso
Angelo A
AA
Keczkemethy
Heather L
HL
Fleming
Mark
M
Neuberg
Donna
D
DeAngelo
Daniel J
DJ
Stone
Richard M
RM
Galinsky
Ilene
I
Silverman
Lewis B
LB
Sallan
Stephen E
SE
Nadler
Lee M
LM
Guinan
Eva C
EC
D000293:Adolescent; D000328:Adult; D000938:Antigen-Presenting Cells / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive; D008297:Male; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000276:immunology / Q000628:therapy*; D055502:Secondary Prevention; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D013997:Time Factors
D019013:CD40 Antigens; D019496:Cancer Vaccines