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

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

Modulating T Cell Responses by Targeting CD3

Simple Summary CD3 complex provides the first signal sensed by the TCR of the lymphocyte to trigger its activation. Thus, it becomes a very attractive receptor to determine the fate of the immune response in different contexts from tolerance induction to immune activation. We discuss CD3-TCR complex assembly and the current and emerging approaches to harvest CD3 activity for immunotherapy. Harnessing the immune system to fight cancer has become a reality with the clinical success of immune-checkpoint blockade (ICB) antibodies against PD(L)-1 and CTLA-4. However, not all cancer patients respond to ICB. Thus, there is a need to modulate the immune system through alternative strategies for improving clinical responses to ICB. The CD3-T cell receptor (TCR) is the canonical receptor complex on T cells. It provides the first signal that initiates T cell activation and determines the specificity of the immune response. The TCR confers the binding specificity whilst the CD3 subunits facilitate signal transduction necessary for T cell activation. While the mechanisms through which antigen sensing and signal transduction occur in the CD3-TCR complex are still under debate, recent revelations regarding the intricate 3D structure of the CD3-TCR complex might open the possibility of modulating its activity by designing targeted drugs and tools, including aptamers. In this review, we summarize the basis of CD3-TCR complex assembly and survey the clinical and preclinical therapeutic tools available to modulate CD3-TCR function for potentiating cancer immunotherapy

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