GM-CSF secreting leukemia cell vaccination for MDS/AML after allogeneic HSCT: a randomized, double-blinded, phase 2 trial

Abstract

Vaccination using irradiated, adenovirus transduced autologous myeloblasts to secrete GM-CSF (GVAX) early after allogeneic hematopoietic stem cell transplantation (HSCT) can induce potent immune responses. We conducted a randomized phase II trial of GVAX after HSCT for MDS-EB or relapsed/refractory AML. Myeloblasts were harvested before HSCT to generate the vaccine. Randomization to GVAX vs. placebo (1:1) was stratified by disease, transplant center, and conditioning. GVHD prophylaxis included tacrolimus and methotrexate. GVAX or placebo started between day +30-45 if there was engraftment and no GVHD. Vaccines were administered SC/ID weekly x 3, then q2 wks x 3. Tacrolimus taper began after vaccine completion. 123 patients enrolled, 92 proceeded to HSCT, and 57 (GVAX 30, Placebo 27) received at least 1 vaccination. No CTC grade ≥ 3 vaccine related adverse events were reported, but injection site reactions were more common after GVAX (10 vs. 1, p=0.006). With a median follow up of 39 months (range, 9-89), 18-month PFS, OS and relapse incidence were 53% vs 55% (p=0.79), 63% vs. 59% (p= 0.86), and 30% vs. 37% (p=0.51) for GVAX and placebo, respectively. NRM at 18 months was 17% vs. 7.7% (p=0.18), Grade II-IV aGVHD at 12 months 34% vs. 12% (p=0.13), and cGVHD at 3 years 49% vs. 57% for GVAX and placebo, respectively, p=0.26. Reconstitution of T, B, and NK cells were not decreased or enhanced by GVAX. There were no differences in serum MICA/B or other immune biomarkers between GVAX and placebo. GVAX does not improve survival after HSCT for MDS/AML. (Clinicaltrials.gov identifier: NCT01773395)

Maintenance therapy for AML after allogeneic HCT

“…Results from a phase 2 trial were recently published by the same group, which randomized 57 patients with AML/MDS to GVAX versus placebo after allo-HCT. GVAX was well tolerated with only injection site reactions noted as adverse events; however, no difference in overall survival or progression free survival were observed in GVAX recipients compared to placebo (54). Results from a phase 1 trial of a donor derived dendritic cell/AML fusion vaccine were also recently published (55).…”

Cancer vaccines: the next immunotherapy frontier

“…Despite numerous trials showing promising tumoral immune infiltration 93 , autologous tumor cells transfected to express GM-CSF (personalized GVAX) infused in patients after hematopoietic stem cell transplantation did not provide survival benefit in patients with AML 94 . Autologous tumor cells transfected to express GM-CSF and with anti-furin shRNA to prevent transforming growth factor (TGF)-β production (gemogenovatucel-T) demonstrated promising single-arm trial efficacy in Ewing's sarcoma 95 .…”

Dendritic Cells as a Therapeutic Strategy in Acute Myeloid Leukemia: Vaccines

“…As previously stated, IT applied to AML comprises checkpoint inhibitors (anti-PD-1, anti-PD-L1, anti-CTLA-4), T cells genetically redirected to leukemia cells (CAR-T therapies), antibodies against tumor antigens (GO, anti-CD33 antibodies), NK cell-based therapies, among others [ 78 , 79 , 80 , 81 , 82 , 83 ]. Additionally, other therapies, such as those based on anti-AML vaccines, are under clinical study [ 84 , 85 , 86 ].…”