Pilot trial of K562/GM-CSF whole-cell vaccination in MDS patients

Abstract

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell malignancies. Currently, approved drugs are given with non-curative intent as the only known cure is allogeneic bone marrow transplantation, which relies on the donor's immune system driving an allogeneic effect. Previous efforts to harness the endogenous immune system have been less successful. We present the results of a pilot study of K562/GM-CSF (GVAX) whole-cell vaccination in MDS patients. The primary objective of safety was met as there were no serious adverse events. One patient had a decrease in transfusion requirements and another demonstrated hematologic improvement suggesting a signal for clinical activity. In vitro correlative studies indicated biological effects on immune cells following vaccination. Although only a pilot study, results are encouraging that an immunotherapeutic approach with a whole-cell vaccine may be feasible in MDS patients.

Keywords: Cancer vaccine; immunotherapy; myelodysplastic syndrome; phase 1 clinical trial.

Conflict of interest statement

Disclosure of interest

The authors report no conflicts of interest.

Figures

Figure 1.. Antigen-specific T cell responses are demonstrated in patients with varying levels of clinical activity.

A) PBMCs were isolated from patients at indicated timepoints and used as effector cells in a JAM assay to measure specific lysis as outlined in Methods. GVAX vaccine cells were radiolabeled and used as targets in the assay. B) PBMC were stimulated with GVAX vaccine cells for 3 days before addition of 3H thymidine to the culture. Incorporation of radioactivity was measured and stimulation index was calculated as fold increase over stimulation with media alone. Error bars represent standard deviation of triplicates.

Figure 2.. PBMC from responder have increased production of inflammatory cytokines, and less production of Th cytokines.

PBMC were co-cultured with GVAX cells and secreted cytokines were measured in the supernatants. Background production of cytokines from media stimulation has been subtracted. Data for selected cytokines are presented, and complete data for all cytokines measured are presented in Table 2.

Figure 3.. TCR diversity is increased following primary K562 vaccination.

A) CD4 and CD8 T cells were isolated from patient B PBMCs at indicated timepoints and deep sequencing of TCR Vβ CDR3 regions was performed as described in methods. Each colored oval represents the results from the indicated timepoint, and the numbers inside indicate the number of unique TCR sequences. Numbers on the periphery contained only in one oval represent the number of sequences that were unique to that particular timepoint, and numbers in intersections of ovals indicate the number of sequences that were found in both timepoints. CD4 data are presented on the left, and CD8 on the right. B) The fraction of the total TCR repertoire occupied by the top 20 most frequent clones is indicated as colored bars. A larger colored bar therefore indicates a more clonal T cell response, and conversely a larger grey bar indicates a greater amount of diversity. CD4 data are presented at the top, and CD8 data are presented at the bottom. As a control, one healthy, age-matched donor was sequenced and is presented at the far right.