Granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting cellular immunotherapy in combination with autologous stem cell transplantation (ASCT) as postremission therapy for acute myeloid leukemia (AML)

Abstract

Preclinical models have demonstrated the efficacy of granulocyte-macrophage colony-stimulating factor-secreting cancer immunotherapies (GVAX platform) accompanied by immunotherapy-primed lymphocytes after autologous stem cell transplantation in hematologic malignancies. We conducted a phase 2 study of this combination in adult patients with acute myeloid leukemia. Immunotherapy consisted of autologous leukemia cells admixed with granulocyte-macrophage colony-stimulating factor-secreting K562 cells. "Primed" lymphocytes were collected after a single pretransplantation dose of immunotherapy and reinfused with the stem cell graft. Fifty-four subjects were enrolled; 46 (85%) achieved a complete remission, and 28 (52%) received the pretransplantation immunotherapy. For all patients who achieved complete remission, the 3-year relapse-free survival (RFS) rate was 47.4% and overall survival was 57.4%. For the 28 immunotherapy-treated patients, the RFS and overall survival rates were 61.8% and 73.4%, respectively. Posttreatment induction of delayed-type hypersensitivity reactions to autologous leukemia cells was associated with longer 3-year RFS rate (100% vs 48%). Minimal residual disease was monitored by quantitative analysis of Wilms tumor-1 (WT1), a leukemia-associated gene. A decrease in WT1 transcripts in blood was noted in 69% of patients after the first immunotherapy dose and was also associated with longer 3-year RFS (61% vs 0%). In conclusion, immunotherapy in combination with primed lymphocytes and autologous stem cell transplantation shows encouraging signals of potential activity in acute myeloid leukemia (ClinicalTrials.gov: NCT00116467).

Figures

Figure 1

Study design. Design included leukemia harvest at diagnosis of AML, induction chemotherapy with high-dose cytarabine (Ara-C) and daunorubicin (Dauno), consolidation chemotherapy with high-dose Ara-C and etoposide (VP16), followed by stem cell mobilization with GCSF, peripheral blood stem cell (PBSC) collection, single pretransplantation dose of immunotherapy, followed by collection of primed lymphocytes by lymphapheresis, pretransplantation myeloablative preparative regimen with Busulfan (Bu) and cyclophosphamide (Cy), PBSC and primed lymphocyte infusion, and posttransplantation immunotherapy treatments administered every 3 weeks for 8 doses, beginning at least 6 weeks after transplantation.

Figure 2

In vitro T-cell immune response to autologous tumor. Results of Elispot assay in 2 representative patients. Blood samples were analyzed at various study time points for T-cell response to autologous leukemia cells and assessed for interferon-γ and granzyme-B production by Elispot. Patient 028-404 showed induction of T-cell response by both interferon-γ (A) and granzyme-B (B) after pre- and posttransplantation immunotherapy. A typical pattern is seen with waning of the pretransplantation response soon after transplantation, followed by recovery with posttransplantation treatments. Patient 028-405 showed induction of T-cell response by both interferon-γ (C) and granzyme-B (D) after posttransplantation immunotherapy only. This response coincided with induction of a tumor DTH skin test response at posttransplantation treatment 8. Analysis time points included: pretransplantation immunotherapy baseline (day 0) and day 14 after the first immunotherapy dose (day 14), before posttransplantation immunotherapy 1 (∼6 weeks after transplantation) and at posttransplantation immunotherapy 4 and 8, and follow-up at month 9 and 12.

Figure 3

Detectable WT1 transcript levels in blood and bone marrow. Percentage of patients with detectable WT1 transcript levels in peripheral blood (PB) and bone marrow (BM) at enrollment, CR, pretransplantation immunotherapy day 0 and day 14, posttransplantation immunotherapy 1 (Vax 1) and 4 (Vax 4), and follow-up (post Vax 4). Boxes signify chemotherapy treatments including induction, consolidation (Consol), and ASCT. Arrows signify immunotherapy administration. Numbers along the bottom of the chart signify the number of patients with data at each time point.

Figure 4

WT1 transcript levels in patients with continuous CR versus relapse. Median log10 change from baseline in WT1 transcript levels for patients who achieved a CR and remained in continuous CR (CCR) throughout the study () versus those who relapsed (–). Time points include: enrollment (enroll), CR, pretransplantation immunotherapy day 0 and day 14, posttransplantation immunotherapy 1 (Vax 1) and 4 (Vax 4), and last study measurement (Off-Study). Boxes signify chemotherapy treatments including induction, consolidation (Consol), and ASCT. Arrows signify immunotherapy administration.

Figure 5

Relapse-free survival in subsets. (A) Reduction in WT1 after pretransplantation dose of immunotherapy. (B) Achievement of undetectable WT1 status at any time during the trial. (C) Achievement of undetectable WT1 status before ASCT. (D) Induction of autologous tumor DTH response (yes, ; no, –).