Toll‐like receptor 7/8‐matured RNA‐transduced dendritic cells as post‐remission therapy in acute myeloid leukaemia: results of a phase I trial

Abstract

Objectives Innovative post‐remission therapies are needed to eliminate residual AML cells. DC vaccination is a promising strategy to induce anti‐leukaemic immune responses. Methods We conducted a first‐in‐human phase I study using TLR7/8‐matured DCs transfected with RNA encoding the two AML‐associated antigens WT1 and PRAME as well as CMVpp65. AML patients in CR at high risk of relapse were vaccinated 10× over 26 weeks. Results Despite heavy pretreatment, DCs of sufficient number and quality were generated from a single leukapheresis in 11/12 cases, and 10 patients were vaccinated. Administration was safe and resulted in local inflammatory responses with dense T‐cell infiltration. In peripheral blood, increased antigen‐specific CD8+ T cells were seen for WT1 (2/10), PRAME (4/10) and CMVpp65 (9/10). For CMVpp65, increased CD4+ T cells were detected in 4/7 patients, and an antibody response was induced in 3/7 initially seronegative patients. Median OS was not reached after 1057 days; median RFS was 1084 days. A positive correlation was observed between clinical benefit and younger age as well as mounting of antigen‐specific immune responses. Conclusions Administration of TLR7/8‐matured DCs to AML patients in CR at high risk of relapse was feasible and safe and resulted in induction of antigen‐specific immune responses. Clinical benefit appeared to occur more likely in patients <65 and in patients mounting an immune response. Our observations need to be validated in a larger patient cohort. We hypothesise that TLR7/8 DC vaccination strategies should be combined with hypomethylating agents or checkpoint inhibition to augment immune responses. Trial registration The study was registered at https://clinicaltrials.gov on 17 October 2012 (NCT01734304) and at https://www.clinicaltrialsregister.eu (EudraCT‐Number 2010‐022446‐24) on 10 October 2013.

Induced dendritic cells co-expressing GM-CSF/IFN-α/tWT1 priming T and B cells and automated manufacturing to boost GvL

“…OS was correlated with molecular and WT1-specific CD8 + CTL responses. Recently, Subklewe and colleagues 27 evaluated autologous DCs transfected with mRNAs (encoding the LAAs WT1 and preferentially expressed antigen in melanoma [PRAME] combined with HCMV-pp65 antigen) and matured with Toll-like receptor agonists. A first-in-human phase I study showed that DC administration to AML patients during remission and at high risk of relapse was feasible and safe and stimulated antigenic T cell responses.…”

“…As discussed above, the manufacturing of DCs modified with mRNAs encoding WT1 for phase I and II clinical trials was feasible, and promising immunological and therapeutic effects against AML were observed. 27 , 39 Nevertheless, the manufacturing of these ex vivo -cultivated DC vaccines is complex and requires several steps and different types of GMP-grade reagents for antigen loading and maturation. We previously demonstrated feasibility of a 2-day protocol for GL manufacturing of iDCpp65 after CD14 + monocyte selection on CliniMACS and subsequent LV transduction in bags.…”

mRNA vaccines manufacturing: Challenges and bottlenecks

“…Since then, mRNA-based DC vaccines have shown their potential in cancer applications in over 70 completed clinical trials. Recently, a phase I study where RNA transduced DCs were evaluated as a post-remission therapy in acute myeloid leukaemia (AML) was published [61] . This treatment induced an immune response with a positive relation between higher survival rate of patients with ≤ 65 years.…”

T-cell-based immunotherapy of acute myeloid leukemia: current concepts and future developments

“…However, these antigens may be found on nonhematopoietic tissues, resulting in on-target off-tumor toxicities. WT1 and PRAME are being evaluated in earlyphase clinical trials in patients with AML [11][12][13]. Strategies to identify additional antigens that are exclusively expressed on AML cells (including LSCs) includes comparing transcriptome and surfaceome data of AML cell lines, primary AML cells and healthy hematopoietic cells.…”