Improvement of current immunotherapies with engineered oncolytic viruses that target cancer stem cells.

The heterogeneity of the solid tumor microenvironment (TME) impairs the therapeutic efficacy of standard therapies and also reduces the infiltration of antitumor immune cells, all of which lead to tumor progression and invasion. In addition, self-renewing cancer stem cells (CSCs) support tumor dormancy, drug resistance, and recurrence, all of which might pose challenges to the eradication of malignant tumor masses with current therapies. Natural forms of oncolytic viruses (OVs) or engineered OVs are known for their potential to directly target and kill tumor cells or indirectly eradicate tumor cells by involving antitumor immune responses, including enhancement of infiltrating antitumor immune cells, induction of immunogenic cell death, and reprogramming of cold TME to an immune-sensitive hot state. More importantly, OVs can target stemness factors that promote tumor progression, which subsequently enhances the efficacy of immunotherapies targeting solid tumors, particularly the CSC subpopulation. Herein, we describe the role of CSCs in tumor heterogeneity and resistance and then highlight the potential and remaining challenges of immunotherapies targeting CSCs. We then review the potential of OVs to improve tumor immunogenicity and target CSCs and finally summarize the challenges within the therapeutic application of OVs in preclinical and clinical trials.

Engineering and design of promising T-cell-based multi-epitope vaccine candidates against leishmaniasis.

Cutaneous leishmaniasis (CL) is a very common parasitic infection in subtropical areas worldwide. Throughout decades, there have been challenges in vaccine design and vaccination against CL. The present study introduced novel T-cell-based vaccine candidates containing IFN-γ Inducing epitopic fragments from Leishmania major (L. major) glycoprotein 46 (gp46), cathepsin L-like and B-like proteases, histone H2A, glucose-regulated protein 78 (grp78) and stress-inducible protein 1 (STI-1). For this aim, top-ranked human leukocyte antigen (HLA)-specific, IFN-γ Inducing, antigenic, CD4+ and CD8+ binders were highlighted. Four vaccine candidates were generated using different spacers (AAY, GPGPG, GDGDG) and adjuvants (RS-09 peptide, human IFN-γ, a combination of both, Mycobacterium tuberculosis Resuscitation promoting factor E (RpfE)). Based on the immune simulation profile, those with RS-09 peptide (Leish-App) and RpfE (Leish-Rpf) elicited robust immune responses and their tertiary structure were further refined. Also, molecular docking of the selected vaccine models with the human toll-like receptor 4 showed proper interactions, particularly for Leish-App, for which molecular dynamics simulations showed a stable connection with TLR-4. Upon codon optimization, both models were finally ligated into the pET28a( +) vector. In conclusion, two potent multi-epitope vaccine candidates were designed against CL and evaluated using comprehensive in silico methods, while further wet experiments are, also, recommended.