Autologous CLL cell vaccination early after transplant induces leukemia-specific T cells
Ute E. Burkhardt, … , Edwin P. Alyea, Catherine J. Wu
Ute E. Burkhardt, … , Edwin P. Alyea, Catherine J. Wu
Published August 5, 2013
Citation Information: J Clin Invest. 2013;123(9):3756-3765. https://doi.org/10.1172/JCI69098.
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Clinical Research and Public Health

Autologous CLL cell vaccination early after transplant induces leukemia-specific T cells

Abstract

Background. Patients with advanced hematologic malignancies remain at risk for relapse following reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (allo-HSCT). We conducted a prospective clinical trial to test whether vaccination with whole leukemia cells early after transplantation facilitates the expansion of leukemia-reactive T cells and thereby enhances antitumor immunity.

Methods. We enrolled 22 patients with advanced chronic lymphocytic leukemia (CLL), 18 of whom received up to 6 vaccines initiated between days 30 and 45 after transplantation. Each vaccine consisted of irradiated autologous tumor cells admixed with GM-CSF–secreting bystander cells. Serial patient PBMC samples following transplantation were collected, and the impact of vaccination on T cell activity was evaluated.

Results. At a median follow-up of 2.9 (range, 1–4) years, the estimated 2-year progression-free and overall survival rates of vaccinated subjects were 82% (95% CI, 54%–94%) and 88% (95% CI, 59%–97%), respectively. Although vaccination only had a modest impact on recovering T cell numbers, CD8+ T cells from vaccinated patients consistently reacted against autologous tumor, but not alloantigen-bearing recipient cells with increased secretion of the effector cytokine IFN-γ, unlike T cells from nonvaccinated CLL patients undergoing allo-HSCT. Further analysis confirmed that 17% (range, 13%–33%) of CD8+ T cell clones isolated from 4 vaccinated patients by limiting dilution of bulk tumor-reactive T cells solely reacted against CLL-associated antigens.

Conclusion. Our studies suggest that autologous tumor cell vaccination is an effective strategy to advance long-term leukemia control following allo-HSCT.

Trial registration. Clinicaltrials.gov NCT00442130.

Funding. NCI (5R21CA115043-2), NHLBI (5R01HL103532-03), and Leukemia and Lymphoma Society Translational Research Program.

Authors

Ute E. Burkhardt, Ursula Hainz, Kristen Stevenson, Natalie R. Goldstein, Mildred Pasek, Masayasu Naito, Di Wu, Vincent T. Ho, Anselmo Alonso, Naa Norkor Hammond, Jessica Wong, Quinlan L. Sievers, Ana Brusic, Sean M. McDonough, Wanyong Zeng, Ann Perrin, Jennifer R. Brown, Christine M. Canning, John Koreth, Corey Cutler, Philippe Armand, Donna Neuberg, Jeng-Shin Lee, Joseph H. Antin, Richard C. Mulligan, Tetsuro Sasada, Jerome Ritz, Robert J. Soiffer, Glenn Dranoff, Edwin P. Alyea, Catherine J. Wu

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Figure 3

CLL-specific CD8+ T cell immunity evolving in CLL patients treated with autologous tumor cells early after allo-HSCT.

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CLL-specific CD8+ T cell immunity evolving in CLL patients treated with ...
(A) Schema of the target cell panel used to distinguish antigen specificities of responding T cells. (B) Representative ELISpot experiment examining serial pre- and post-HSCT CD8+ T cell samples obtained from a VAX5–6 patient (Patient 9) for reactivity against autologous tumor cells or alloantigen-bearing recipient cells (PHA T cell blasts and fibroblasts). (C) Depiction of the mean ± SEM tumor- or alloantigen-specific IFN-γ spot production of CD8+ T cells isolated from VAX5–6 (n = 8), VAX1–3/GvHD (n = 4), or control patients (with RIC allo-HSCT for advanced CLL, but without vaccine or GvHD within the first 100 days after transplantation; n = 5). Individual values are indicated by symbols. Bars denote the period of vaccine administration. *P < 0.05, tumor versus fibroblast CD8+ T cell reactivity; 2-sided Wilcoxon matched-pairs, signed-rank test. SFC, spot-forming cells.