Oncolytic adenoviruses coated with MHC-I tumor epitopes increase the antitumor immunity and efficacy against melanoma

Abstract

The stimulation of the immune system using oncolytic adenoviruses (OAds) has attracted significant interest and several studies suggested that OAds immunogenicity might be important for their efficacy. Therefore, we developed a versatile and rapid system to adsorb tumor-specific major histocompatibility complex class I (MHC-I) peptides onto the viral surface to drive the immune response toward the tumor epitopes. By studying the model epitope SIINFEKL, we demonstrated that the peptide-coated OAd (PeptiCRAd) retains its infectivity and the cross presentation of the modified-exogenous epitope on MHC-I is not hindered. We then showed that the SIINFEKL-targeting PeptiCRAd achieves a superior antitumor efficacy and increases the percentage of antitumor CD8+ T cells and mature epitope-specific dendritic cells in vivo. PeptiCRAds loaded with clinically relevant tumor epitopes derived from tyrosinase-related protein 2 (TRP-2) and human gp100 could reduce the growth of primary-treated tumors and secondary-untreated melanomas, promoting the expansion of antigen-specific T-cell populations. Finally, we tested PeptiCRAd in humanized mice bearing human melanomas. In this model, a PeptiCRAd targeting the human melanoma-associated antigen A1 (MAGE-A1) and expressing granulocyte and macrophage colony-stimulating factor (GM-CSF) was able to eradicate established tumors and increased the human MAGE-A1-specific CD8+ T cell population. Herein, we show that the immunogenicity of OAds plays a key role in their efficacy and it can be exploited to direct the immune response system toward exogenous tumor epitopes. This versatile and rapid system overcomes the immunodominance of the virus and elicits a tumor-specific immune response, making PeptiCRAd a promising approach for clinical testing.

Innate immunity to adenovirus: lessons from mice

“…Although shielding of HAdv with PEG effectively prevents virus neutralization by preexisting neutralizing antibodies, allowing for repeated gene delivery in a gene transfer or vaccination setting [132,133], the utility of this approach in other applications has limitations. Specifically, although shielding oncolytic HAdv with PEG or protein conjugates significantly increases the efficacy of oncolytic HAdvbased vectors in mouse models [130,132], after the initial round of replication, the progeny of oncolytic virus produced in tumor sites would not be covered with PEG or protein shields, thus exposing the virus to receptors and cells of the innate immune system. Moreover, certain cytokines, most notably IL-6 and IL-12, still remain elevated after systemic delivery [134] or direct blood cell exposure to PEGylated HAdv vectors [48], demonstrating that any single-pronged approach to avoiding virus recognition by the innate immune system is unlikely to prevent or alleviate all factors and mechanisms responsible for triggering multifaceted host innate immune and inflammatory responses to HAdv.…”

Oncolytic Adenovirus Loaded with L-carnosine as Novel Strategy to Enhance the Antitumor Activity

“…It was already reported that the complex presented good stability and no significant decrease of zeta potential was observed 15, 30, and 45 minutes after incubation in the same conditions (MilliQ water ph 7.4). Moreover, no aggregation was seen at these time points (14). First, the electric surface charge (zeta potential) of the complex was analyzed to see whether the addition of the Carnosine6K was influencing the charge and the size of the adenovirus-carnosine complex (Fig.…”

Short Overview of Clinical Trials With Current Immunotherapeutic Tools for Cancer Treatment

“…PeptiCRAd, нагруженные эпитопами опухолевых антигенов -TRP2 и gp100 -умень-шают рост как инъецированной опухоли, так и вторичных необработанных меланом. В мыши-ной ксенографтной модели меланомы человека PeptiCRAd, несущий эпитопы MAGE-A1 и экс-прессирующий GM-CSF, увеличил долю CD8 + Т-лимфоцитов, специфичных к MAGE-A1, и вызывал регрессию опухолей [13]. Для обе-спечения адресной доставки, например в слу-чае, когда инъекция внутрь опухоли затруднена, можно использовать для доставки онколитиче-ских вирусов инфицированные клетки, напри-мер мезенхимные стволовые клетки, обладаю-щие опухолетропностью, как это было показано для вируса Delta24-RGD.…”