WT1-Peptide Vaccination Shows High Immunogenicity and Clinical Activity in Patients with Acute Myeloid Leukemia.

Abstract

BACKGROUND: The transcription factor Wilms tumor protein 1 (WT1) holds great promise for immunotherapy of leukemia. WT1 is strongly expressed in the majority of leukemic blasts, is essential for blast proliferation, and is spontaneously immunogenic.METHODS: In the present phase II trial, 12 HLA-A2+ patients with AML without curative treatment option, were vaccinated with WT1.126–134 peptide mixed with adjuvant KLH as T-helper protein and GM-CSF 4 times bi-weekly, then monthly.RESULTS: Patients characteristics, immune responses and clinical outcome are shown in table 1.Patient characteristics, immunologic response, and clinical outcomePatFAB/caryotypeprevious chemotherapydisease status at study onsetno. of vaccinationsclinical outcomeWT1Tetr+ T cells in PB after vaccinationWT1Tetr+ T cells in BM after vaccination1M4yes2.PR15CR 12 months0.49%0.87%2M2 11q23yes1.CR18cCR 30+ months0.43%0.91%3M2noPD4SD 3 months0.42%0.80%4M6yesPD4PDneg.neg.5M2yes1.PR6PD0.37%0.51%6M1yes2. PR9PD0.43%0.40%7M2yes2.PR9PD2.00%1.36%8M7yesPD4PDneg.neg.9M5byes2.CR12cCR 8+ months0.44%0.33%10sAML from MDSnoPD12SD 8 months0.23%0.13%11sAML from MPSnoPD12SD 9+ months0.22%0.53%12M4noPD8SD 3 months1.11%1.35%*PB, peripheral blood; BM, bone marrow; MDS, myelodysplastic syndrome; MPD, myeloproliferative disease.WT1-specific T cells could be detected in 3 patients before vaccination. An induction or enhancement of a T cell response against WT1 was observed in 10 of 12 patients after 2 – 6 vaccinations ranging from 0.22 to 2.00% (median 0.43%) in peripheral blood and from 0.33 to 1.36% (median 0.80%) in bone marrow as analysed by tetramer and cytokine staining. At study onset 6 patients had progressive AML (PD) with 40 – 90% marrow blasts, 4 patients partial remission (PR) following chemotherapy and two patients complete remission (CR) at high risk for relapse. Four of the 6 patients with progressive AML had disease stabilization for 3, 3, 8 and 9 months, which is ongoing in the latter patient. Disease stabilization was accompanied by a decrease/normalization of peripheral blasts in two patients and a >50% decrease in RBC transfusion requirements in a patient with AML evolved from MDS. One patient with PR at study onset had an early relapse and then achieved CR for 12 months (patient 1). Both patients vaccinated in CR are in continuous hematological CR (cCR) for 8+ and 30+ months (patient 2 and 9). The remaining 5 patients had PD after 4 – 9 vaccinations. Bone marrow WT1 RNA levels as molecular disease marker paralleled the clinical course as they decreased 1 – 2 logs in the 3 patients with CR or cCR after 6 vaccinations (Fig. 1A), stabilized or decreased in all 4 patients with SD (Fig. 1B), and increased 1 – 2 logs in 4 of the 5 patients with PD (Fig. 1B). No significant toxic effects were observed.CONCLUSION: WT1 peptide vaccination can efficiently induce a specific immune response and has clinical activity in the absence of significant toxicity. These results warrant further studies of WT1 vaccination in AML patients at high risk for relapse. [Display omitted]