Analysis of Immunological and Clinical Response Kinetics to WT1 Peptide Vaccine in Patients with AML and MDS: Need for Supplementation of IWG Response Criteria?.
Authors: Keilholz Ulrich , Letsch Anne , Busse Antonia , Asemissen Annemarie , Blau Igor W. , Hofmann Wolf K. , Uharek Lutz , Thiel Eckhard , Scheibenbogen Carmen 
Published: November 2019

Abstract
Background: Current habits in clinical trial design rightfully require patients to go off protocol in case of early disease progression to protect them from further exposure to ineffective treatments. This policy may not be adequate for leukemia vaccines as an effective clinical response would require an initial time interval to induce immunity, which can be expected to take several weeks.
Methods: We here correlated immunological and clinical response kinetics from patients treated with WT1 peptide-based vaccine within a clinical phase II study. Patients received intra/subcutaneous vaccinations of 62.5 mcg GM-CSF days 1–4 and on day 3 0.2 mg WT1.126–134 peptide and 1 mg keyhole limpet hemocyanin. Vaccination was biweekly x 4 followed by 4-weekly (cohort 1) or continuously biweekly (cohort 2). Early disease progression was allowed, if inclusion criteria were still met and chemotherapy not required. WT1-specific T cell responses were measured by tetramer and cytokine flow cytometry. Clinical response assessment followed IWG-MDS criteria, capturing stable disease and hematologic improvement. In patients responding following initial progression, the date for calculation of TTF remained the starting date of therapy, whereas response duration was calculated as usual from the date the response was first noted.
Results: Of 26 evaluable pts 18 had active disease at time of enrollment, additional 8 patients had high-risk CR. The percentage of patients with WT1 tetramer response continuously increased from 28% prior to vaccination to 60% at week 4, 76% at week 10, and 79% at week 18 (p<0.01) and to 100% in the 6 patients reaching week 42 of protocol treatment. WT1 peptide specific cytokine response increased from 19% pre-vaccine to 48% of patients at week 10 (p=0.05). According to strict IWG criteria, 9 SD (53%) were observed. However, if initial disease progression was accepted, one patient was re-classified as CR lasting 12 months after initial progression for 42 days and a total of 13 patients were classified as SD. Duration of early progression ranged from 35–70 days, median 42 days. There was no stabilization of disease observed in any patient with early progression beyond 10 weeks. Thus, kinetics of early disease progression and subsequent clinical efficacy of vaccination matched kinetics of induction of T cell responses.
Conclusions: The additional clinical efficacy of vaccination observed after initial disease progression in five of our patients including the long-lasting CR support the concept of continuing treatment through early disease progression with a vaccine causing minimal toxicity, if continuation does not disadvantage the patient. Acknowledgment of early disease progression with subsequent efficacy requires amendment of current rules for cancer vaccine clinical trials with respect to patient management as well as evaluation of outcome.