No abstract

Key Points• WT1 mRNA-electroporated DCs can prevent or delay relapse in 43% of patients with AML in remission after chemotherapy.• OS compares favorably with the new survival data from the Swedish Acute Leukemia Registry and correlates with molecular and WT1-specific CD8 1 T-cell responses.Relapse is a major problem in acute myeloid leukemia (AML) and adversely affects survival. In this phase 2 study, we investigated the effect of vaccination with dendritic cells (DCs) electroporated with Wilms' tumor 1 (WT1) messenger RNA (mRNA) as postremission treatment in 30 patients with AML at very high risk of relapse. There was a demonstrable antileukemic response in 13 patients. Nine patients achieved molecular remission as demonstrated by normalization of WT1 transcript levels, 5 of which were sustained after a median follow-up of 109.4 months. Disease stabilization was achieved in 4 other patients. Five-year overall survival (OS) was higher in responders than in nonresponders (53.8% vs 25.0%; P 5 .01). In patients receiving DCs in first complete remission (CR1), there was a vaccine-induced relapse reduction rate of 25%, and 5-year relapse-free survival was higher in responders than in nonresponders (50% vs 7.7%; P < .0001). In patients age £65 and >65 years who received DCs in CR1, 5-year OS was 69.2% and 30.8% respectively, as compared with 51.7% and 18% in the Swedish Acute Leukemia Registry. Long-term clinical response was correlated with increased circulating frequencies of polyepitope WT1-specific CD8 1 T cells. Long-term OS was correlated with interferon-g 1 and tumor necrosis factor-a 1 WT1-specific responses in delayed-type hypersensitivity-infiltrating CD8 1 T lymphocytes. In conclusion, vaccination of patients with AML with WT1 mRNA-electroporated DCs can be an effective strategy to prevent or delay relapse after standard chemotherapy, translating into improved OS rates, which are correlated with the induction of WT1-specific CD8 1 T-cell response. This trial was registered at www.clinicaltrials.gov as #NCT00965224. (Blood. 2017;130(15):1713-1721

Although cancer vaccination has yielded promising results in patients, the objective response rates are low. The right choice of adjuvant might improve the efficacy. Here, we review the biological rationale, as well as the preclinical and clinical results of polyinosinic:polycytidylic acid and its derivative poly-ICLC as cancer vaccine adjuvants. These synthetic immunological danger signals enhanced vaccine-induced anti-tumor immune responses and contributed to tumor elimination in animal tumor models and patients. Supported by these results, poly-ICLC-containing cancer vaccines are currently extensively studied in the ongoing trials, making it highly plausible that poly-ICLC will be part of the future approved cancer immunotherapies.

No abstract

No abstract

BackgroundAdoptive immunotherapy is gaining momentum to fight malignancies, whereby γδ T cells have received recent attention as an alternative cell source as to natural killer cells and αβ T cells. The advent of γδ T cells is largely due to their ability to recognize and target tumor cells using both innate characteristic and T cell receptor (TCR)-mediated mechanisms, their capacity to enhance the generation of antigen-specific T cell responses, and their potential to be used in an autologous or allogeneic setting.MethodsIn this study, we explored the beneficial effect of the immunostimulatory cytokine interleukin (IL)-15 on purified γδ T cells and its use as a stimulatory signal in the ex vivo expansion of γδ T cells for adoptive transfer. The expansion protocol was validated both with immune cells of healthy individuals and acute myeloid leukemia patients.ResultsWe report that the addition of IL-15 to γδ T cell cultures results in a more activated phenotype, a higher proliferative capacity, a more pronounced T helper 1 polarization, and an increased cytotoxic capacity of γδ T cells. Moreover γδ T cell expansion starting with peripheral blood mononuclear cells from healthy individuals and acute myeloid leukemia patients is boosted in the presence of IL-15, whereby the antitumor properties of the γδ T cells are strengthened as well.ConclusionsOur results support the rationale to explore the use of IL-15 in clinical adoptive therapy protocols exploiting γδ T cells.

Interferon-a (IFN-a), a type I IFN, is a well-known antitumoral agent. The investigation of its clinical properties in acute myeloid leukemia (AML) has been prompted by its pleiotropic antiproliferative and immune effects. So far, integration of IFN-a in the therapeutic arsenal against AML has been modest in view of the divergent results of clinical trials. Recent insights into the key pharmacokinetic determinants of the clinical efficacy of IFN along with advances in its pharmaceutical formulation, have sparked renewed interest in its use. This paper reviews the possible applicability of IFN-a in the treatment of AML and provides a rational basis to re-explore its efficacy in clinical trials.

After completing this course, the reader will be able to:1. Describe the current in vivo experimental and clinical dendritic cell (DC) vaccination studies encompassing the monitoring of natural killer (NK) cells.2. Discuss the evaluation of NK cell stimulating potency in the design of DC-based cancer vaccines in the preclinical phase and in clinical trials. Explain the added value of immune monitoring of NK cells in cancer vaccination trials.This article is available for continuing medical education credit at CME.TheOncologist.com. CME CME ABSTRACT NATURAL KILLER CELLS IN CANCERIn the early 1980s, the role of natural killer (NK) cells in defense against cancer was described in seminal reviews [1,2]. A myriad of reports rapidly followed, supporting the involvement and therapeutic potential of NK cells in cancer immunity [3,4]. A range of solid tumors [5][6][7][8][9][10][11][12] and hematological malignancies [13][14][15][16][17][18][19] were shown to be associated with significantly impaired NK cell functions. Importantly, NK cell abnormalities have been shown to be, at least in part, responsible for the failure of antitumor immunity. Deficiencies can reside in all NK cell populations, located in peripheral blood, in (lymphoid) organs, and in the tumor itself [16]. Functional impairment can originate from (a) primary NK cell dysfunction (e.g., imbalanced NK cell receptor expression, impaired cytolytic capacity, reduced cytokine secretion potency), (b) insufficient interaction with other immune cells (e.g., impaired killing of dendritic cells [DCs]) [14], (c) active immune suppression (e.g., regulatory T cell [Treg]-mediated suppression) [20,21], and (d) NK cell resistance mechanisms by tumor cells (e.g., shedding of decoy molecules for activating receptors) [22]. In this regard, multiple cancer studies point toward a prognostic value for NK cells. Table 1 summarizes valuable NK cell parameters used for prognosis of disease progression and patient survival as well as for prediction of therapy efficacy.In humans, NK cells are characterized by a CD56 ϩ CD3 Ϫ NKp46 ϩ phenotype. Based on their CD56 cell-surface density, they can be divided into two subsets with distinct phenotypic properties and key effector functions [23]. The majority (ϳ90%) of peripheral blood NK cells have a CD56 dim CD16 bright phenotype and were originally regarded as the more naturally cytotoxic subset, characterized by high cytotoxic granule and perforin expression and lower cytokine-secreting capacity. The smaller CD56 bright CD16dim/Ϫ NK cell fraction (ϳ10%) constitutively expresses a higher number of cytokine and chemokine receptors and a lower amount of cytotoxic granules, generally showing a poorer cytotoxic capacity but a superior ability to produce abundant immunoregulatory cytokines following activation, in particular the prototypic cytokine interferon (IFN)-␥. Remarkably, these seemingly subtype-specific effector functions appear to be not as restricted as previously thought. Several research groups recently demonstrated that CD56 d...