An RNA toolbox for cancer immunotherapy

Pastor, Fernando; Berraondo, Pedro; Etxeberría, Iñaki; Frederick, Josh P.; Şahin, Uğur; Gilboa, Eli; Melero, Ignacio

doi:10.1038/nrd.2018.132

Cited by 179 publications

(166 citation statements)

References 172 publications

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“…However, the use of mRNA as a therapeutic drug or in cancer vaccination is not the focus of this review and has been extensively reviewed elsewhere. 52,[150][151][152] In contrast with cancer, where the lack of conventional vaccines makes it difficult to weigh the effectiveness of RNA as a platform, infectious diseases offer a portfolio of traditional vaccines to benchmark. To this end, considerable preclinical research (Tables 2 and 3) and early clinical trials (Table 4) on infectious diseases have been conducted.…”

Section: Self-amplifying Mrna Vaccinesmentioning

confidence: 99%

mRNA as a Transformative Technology for Vaccine Development to Control Infectious Diseases

et al. 2019

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Section: Self-amplifying Mrna Vaccinesmentioning

confidence: 99%

mRNA as a Transformative Technology for Vaccine Development to Control Infectious Diseases

et al. 2019

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“…A phase I trial testing the IL-15 super-agonist complex ALT-803 in patients relapsing after allo-HCT showed a very promising response rate (19% of evaluable patients), correlated to the expansion of both NK and T cells (187). Recently, novel approaches to transfer high concentration of cytokines to the tumor site and reduce their systemic effects are emerging, including gene therapy "Trojan Horse" strategies (188) and the use of lipid nanoparticles to convey to the tumor site mRNAs encoding cytokines (189).…”

Section: Cytokine Therapiesmentioning

confidence: 99%

Mechanisms of Leukemia Immune Evasion and Their Role in Relapse After Haploidentical Hematopoietic Cell Transplantation

et al. 2020

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Over the last decade, the development of multiple strategies to allow the safe transfer from the donor to the patient of high numbers of partially HLA-incompatible T cells has dramatically reduced the toxicities of haploidentical hematopoietic cell transplantation (haplo-HCT), but this was not accompanied by a similar positive impact on the incidence of post-transplantation relapse. In the present review, we will elaborate on how the unique interplay between HLA-mismatched immune system and malignancy that characterizes haplo-HCT may impact relapse biology, shaping the selection of disease variants that are resistant to the "graft-vs.-leukemia" effect. In particular, we will present current knowledge on genomic loss of HLA, a relapse modality first described in haplo-HCT and accounting for a significant proportion of relapses in this setting, and discuss other more recently identified mechanisms of post-transplantation immune evasion and relapse, including the transcriptional downregulation of HLA class II molecules and the enforcement of inhibitory checkpoints between T cells and leukemia. Ultimately, we will review the available treatment options for patients who relapse after haplo-HCT and discuss on how a deeper insight into relapse immunobiology might inform the rational and personalized selection of therapies to improve the largely unsatisfactory clinical outcome of relapsing patients.

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“…www.nature.com/scientificreports www.nature.com/scientificreports/ RNA-interference (RNAi) is a highly specific post-transcriptional gene silencing mechanism induced by short interfering RNAs (siRNAs) 17,18 . In the cytoplasm, the siRNA molecule is loaded into the RNA-induced silencing complex (RISC), followed by Argonaute 2-mediated cleavage of the passenger (sense) strand and subsequent target mRNA cleavage 19 .…”

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confidence: 99%

Targeting Plk1 with siRNNs in primary cells from pediatric B-cell acute lymphoblastic leukemia patients

Goroshchuk

Vidarsdóttir

Björklund

et al. 2020

Sci Rep

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B-cell acute lymphoblastic leukemia (B-ALL) accounts for nearly one fifth of all childhood cancers and current challenges in BALL treatment include resistance, relapse and late-onset side effects due to the chemotherapy. To overcome these hurdles, novel therapies need to be investigated. One promising target is Polo-like kinase 1 (Plk1), a key regulator of the cell cycle. In this study, the Plk family expression is investigated in primary peripheral blood and bone marrow mononuclear cells from ten pediatric BALL patients. For the first time, short interfering RiboNucleic Neutrals (siRNNs) that enter cells without a transfection reagent are used to target Plk1 mRNA in primary cells from pediatric BALL patients. Our results show that the expression of Plk1 and Plk4 is significantly higher in pediatric BALL patients compared to healthy donors. Moreover, treatment of primary peripheral blood and bone marrow mononuclear cells from pediatric BALL patients, cultured ex vivo, with Plk1-targeting siRNNs results in cleavage of Plk1 mRNA. Importantly, the Plk1 knockdown is specific and does not affect other Plk members in contrast to many small molecule Plk1 inhibitors. Thus, Plk1 is a potential therapeutic target in pediatric BALL and selective targeting of Plk1 can be achieved by the use of siRNNs. B-cell acute lymphoblastic leukemia (B-ALL) is one of the most common hematological malignancies among children and corresponds to approximately 85% of all pediatric ALL cases 1. Although more than 80% of pediatric BALL patients reach complete remission after the primary induction therapy, there are still many patients who suffer from resistance and relapse. An aggressive form of the disease causes relapse in 10-15% of treated children and 2% are refractory to the induction therapy 2. The event-free survival of patients with first relapse remains poor and many pediatric patients suffer from therapy-related side effects several years after treatment. Thus, novel therapies need to be investigated to improve outcome and to reduce toxic side effects in patients with pediatric BALL. The Polo-like kinase family (Plk) consists of five serine/threonine kinases. Four members of the family, Plk1-4, are directly involved in cell cycle regulation in both normal and tumor cells, whereas the fifth member, Plk5, has a truncated, inactive kinase domain and is primarily expressed in brain tissue 3. Several structural features are shared within the Plk family including a kinase domain with an ATP-binding pocket and a polo-box domain 4. Inhibitors targeting either of the domains have been investigated in many preclinical studies 5. The most well-studied member, Polo-like kinase 1 (Plk1), has a number of distinct roles in cell cycle regulation such as G2/M transition, mitotic spindle assembly and cytokinesis that all promote cell cycle progression 6-8. Due to these functions, Plk1 expression is high in actively dividing tissues and often overexpressed both in solid tumor and hematologic malignancies 9-12. Similarly to Plk1, Plk4 was recently found...

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An RNA toolbox for cancer immunotherapy

Cited by 179 publications

References 172 publications

mRNA as a Transformative Technology for Vaccine Development to Control Infectious Diseases

mRNA as a Transformative Technology for Vaccine Development to Control Infectious Diseases

Mechanisms of Leukemia Immune Evasion and Their Role in Relapse After Haploidentical Hematopoietic Cell Transplantation

Targeting Plk1 with siRNNs in primary cells from pediatric B-cell acute lymphoblastic leukemia patients

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