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Clinical Trial
. 2013 Sep;123(9):3756-65.
doi: 10.1172/JCI69098. Epub 2013 Aug 5.

Autologous CLL Cell Vaccination Early After Transplant Induces Leukemia-Specific T Cells

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Free PMC article
Clinical Trial

Autologous CLL Cell Vaccination Early After Transplant Induces Leukemia-Specific T Cells

Ute E Burkhardt et al. J Clin Invest. .
Free PMC article

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.

Figures

Figure 1
Figure 1. Clinical protocol schema.
The study protocol was divided into two phases: (a) collection of autologous CLL cells from peripheral blood (PB), bone marrow (BM), or lymph node (LN), after which subjects underwent salvage chemotherapy; and (b) treatment, which included RIC, subsequent PBSC infusion, and posttransplant vaccination (up to 6 vaccine doses consisting of irradiated autologous tumor cells together with irradiated GM-CSF– secreting bystander cells) between posttransplant days 30 and 100, while maintaining stable GvHD prophylaxis.
Figure 2
Figure 2. Number of participants and reasons for exclusion of study subjects from the treatment phase of the clinical trial.
Figure 3
Figure 3. CLL-specific CD8+ T cell immunity evolving in CLL patients treated with autologous tumor cells early after allo-HSCT.
(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.
Figure 4
Figure 4. Polyfunctional tumor-reactive CD8+ T cell responses are induced following early posttransplant CLL/GM-K562 cell vaccination.
Functional capacity of CD8+ T cells isolated at serial pre- and post-HSCT time points from (A) VAX5–6 (n = 6), (B) VAX1–3/GvHD (n = 4) study subjects, or (C) control patients (with RIC allo-HSCT for advanced CLL, but without vaccine or GvHD within the first 100 days after transplantation; n = 5) in response to autologous tumor cells was analyzed by simultaneous assessment of secreted GM-CSF, TNF-α, IL-2, and IL-10. Bars represent the median concentration of the corresponding cytokine in pg/ml. Individual values are depicted as black circles. *P < 0.05 (VAX5–6 vs. control group and VAX5–6 vs. VAX1–3/GvHD group CD8+ T cell reactivity; 2-sided Wilcoxon rank-sum test).
Figure 5
Figure 5. Reactivity patterns of T cell clones obtained from CLL/GM-K562–vaccinated patients.
T cell clones obtained by limiting dilution from posttransplant tumor-reactive T cell pools show different patterns of reactivity on IFN-γ ELISpot assays, namely, (a) sole reactivity against CLL-associated antigens; (b) reactivity against hematopoietically restricted alloantigens; (c) reactivity against broadly expressed alloantigens; or (d) absent reactivity against the tested target cells.

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