Aptamers against live targets: Is in vivo SELEX finally coming to the edge?

Targeted therapeutics underwent a revolution with the entry of monoclonal antibodies in the medical toolkit. Oligonucleotide aptamers form another family of target agents that have been lagging behind in reaching the clinical arena in spite of their potential clinical translation. Some of the reasons for this might be related to the challenge in identifying aptamers with optimal in vivo specificity, and the nature of their pharmacokinetics. Aptamers usually show exquisite specificity, but they are also molecules that display dynamic structures subject to changing environments. Temperature, ion atmosphere, pH, and other variables are factors that could determine the affinity and specificity of aptamers. Thus, it is important to tune the aptamer selection process to the conditions in which you want your final aptamer to function; ideally, for in vivo applications, aptamers should be selected in an in vivo-like system or, ultimately, in a whole in vivo organism. In this review we recapitulate the implementations in systematic evolution of ligands by exponential enrichment (SELEX) to obtain aptamers with the best in vivo activity

ICOS costimulation at the tumor site in combination with CTLA-4 blockade therapy elicits strong tumor immunity

Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) blockade therapy is able to induce long-lasting antitumor responses in a fraction of cancer patients. Nonetheless, there is still room for improvement in the quest for new therapeutic combinations. ICOS costimulation has been underscored as a possible target to include with CTLA-4 blocking treatment. Herein, we describe an ICOS agonistic aptamer that potentiates T cell activation and induces stronger antitumor responses when locally injected at the tumor site in combination with anti-CTLA-4 antibody in different tumor models. Furthermore, ICOS agonistic aptamer was engineered as a bi-specific tumor-targeting aptamer to reach any disseminated tumor lesions after systemic injection. Treatment with the bi-specific aptamer in combination with CTLA-4 blockade showed strong antitumor immunity, even in a melanoma tumor model where CTLA-4 treatment alone did not display any significant therapeutic benefit. Thus, this work provides strong support for the development of combinatorial therapies involving anti-CTLA-4 blockade and ICOS agonist tumor-targeting agents

Decoy-based, targeted inhibition of STAT3: A new step forward for B cell lymphoma immunotherapy

Increasing evidence has linked the aggressiveness of non-Hodgkin’s lymphoma, in particular activated B cell-like type diffuse large B cell lymphomas (ABC-DLBCL), to signaling by toll-like receptor 9 (TLR9)/ MyD88 and STAT3. In this issue of Molecular Therapy, Zhao et al.1 describe a dual function molecule comprising a clinically-relevant TLR9 agonist (CpG7909) fused to a STAT3 inhibitor in the form of a high-affinity decoy oligodeoxynucleotide (dODN). CpG-STAT3dODN blocked STAT3 DNA binding and activity, thus reducing expression of downstream target genes, such as MYC and BCL2L1, in human and mouse lymphoma cells. These effects led to the generation of lymphoma cell-specific CD8/ CD4-dependent T cell immunity that could protect mice from tumor rechallenge

Aptamer-iRNAs as therapeutics for cancer treatment

Aptamers are single-stranded oligonucleotides (ssDNA or ssRNA) that bind and recognize their targets with high affinity and specificity due to their complex tertiary structure. Aptamers are selected by a method called SELEX (Systematic Evolution of Ligands by EXponential enrichment). This method has allowed the selection of aptamers to different types of molecules. Since then, many aptamers have been described for the potential treatment of several diseases including cancer. It has been described over the last few years that aptamers represent a very useful tool as therapeutics, especially for cancer therapy. Aptamers, thanks to their intrinsic oligonucleotide nature, present inherent advantages over other molecules, such as cell-based products. Owing to their higher tissue penetrability, safer profile, and targeting capacity, aptamers are likely to become a novel platform for the delivery of many different types of therapeutic cargos. Here we focus the review on interfering RNAs (iRNAs) as aptamer-based targeting delivered agents. We have gathered the most reliable information on aptamers as targeting and carrier agents for the specific delivery of siRNAs, shRNA, microRNAs, and antisense oligonucleotides (ASOs) published in the last few years in the context of cancer therapy

ICOS costimulation at the tumor site in combination with CTLA-4 blockade therapy elicits strong tumor immunity

Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) blockade therapy is able to induce long-lasting antitumor responses in a fraction of cancer patients. Nonetheless, there is still room for improvement in the quest for new therapeutic combinations. ICOS costimulation has been underscored as a possible target to include with CTLA-4 blocking treatment. Herein, we describe an ICOS agonistic aptamer that potentiates T cell activation and induces stronger antitumor responses when locally injected at the tumor site in combination with anti-CTLA-4 antibody in different tumor models. Furthermore, ICOS agonistic aptamer was engineered as a bi-specific tumor-targeting aptamer to reach any disseminated tumor lesions after systemic injection. Treatment with the bi-specific aptamer in combination with CTLA-4 blockade showed strong antitumor immunity, even in a melanoma tumor model where CTLA-4 treatment alone did not display any significant therapeutic benefit. Thus, this work provides strong support for the development of combinatorial therapies involving anti-CTLA-4 blockade and ICOS agonist tumor-targeting agents