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Chimeric antigen receptor-modified T (CAR-T) are genetically engineered cells to express tumor-specific antigens revolutionizing the treatment of hematologic malignancies. The hostile tumor microenvironment (TME) remains a challenge for CAR-T cell therapy in solid tumors. As a solution, combinational therapy with immune checkpoint inhibitors (ICIs) is shown to improve the safety and efficacy of CAR-T cell therapy. To avoid side effects related to the application of ICIs in combinational therapy, engineering CARs to express tumor-specific antigens may help improvement of clinical outcomes. Those CARs expressing single chain variable fragments (scFvs) or nanobodies against immune checkpoint stimulatory or inhibitory molecules, such as the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) signaling axis are being extensively studied in various clinical trials. In this review, we discuss the significance of anti-PD-(L)1 scFv-expressing CAR-T cells in the treatment of human cancers, describing current challenges and potential strategies to overcome such predicaments in the area of cancer immunotherapy. [Display omitted] • CAR-T can be a strategy for revolutionizing ICI efficacy. • Anti-PD-(L)1-expressing CAR-T shows equal or better efficacy vs. separate combinational therapy. • Anti-PD-(L)1-expressing CAR-T minimizes toxicities related to systemic ICI application. [ABSTRACT FROM AUTHOR]

Resistance to immune checkpoint inhibitors (ICIs) is a common predicament in cancer immunotherapy, which requires urgent interventions. V-domain immunoglobulin suppressor of T cell activation (VISTA) or programmed death-1 homolog (PD-1H) is a molecule belong to the CD28/B7 family that acts as an immune checkpoint and a negative immune regulator. VISTA shows high expression within tumor microenvironment (TME) and shapes the immune landscape of this milieu into an immunosuppressive entity through blunting the activity of anti-tumor cells and strengthening the power of pro-tumor cells. The increased expression profile is occurring essentially after inhibition of other checkpoints, which indicates that VISTA can constitute a novel and complementary target in cancer immunotherapy. Combination of anti-VISTA with appropriate ICIs potentiates tumor immunogenicity through increasing the effector activity of T cells, and results in more pronounced responses. VISTA also serves as a prognostic biomarker in differentiating early- from late-stage cancer. In this review, we aimed to discuss about VISTA and its regulation within TME and focusing on its prognostic and therapeutic values in cancer immunotherapy. [Display omitted] • VISTA is overexpressed particularly on myeloid progeny. • VISTA is upregulated secondary to the anti-PD-1/PD-L1 or anti-CTLA-4. • VISTA activity on T cells is independent on PD-1/PD-L1 or CTLA-4. • VISTA is an independent prognostic marker. • Dual VISTA/PD-L1 blockade represents promising clinical efficacy. [ABSTRACT FROM AUTHOR]

Radiotherapy is a common modality for more than half of cancer patients. Classically, radiation is known as a strategy to kill cancer cells via direct interaction with DNA or generation of free radicals. Nowadays, we know that modulation of immune system has a key role in the outcome of radiotherapy. Selecting an appropriate dose per fraction is important for stimulation of anti-tumor immunity. Unfortunately, cancer cells and other cells within tumor microenvironment (TME) promote some mechanisms implicated in the attenuation of anti-tumor immunity via exhaustion of CD8 + T lymphocytes and natural killer (NK) cells. Immunotherapy with immune checkpoint inhibitors (ICIs) has shown to be an interesting adjuvant for induction of more effective anti-tumor immunity. Clinical trial studies are ongoing for uncovering more knowledge about the efficacy of ICI combination with radiotherapy. Some newer pre-clinical studies show more effective therapeutic window for targeting PD-1 and some other targets in combination with hypofractionated radiotherapy. In this review, we explain cellular and molecular consequences in the TME following radiotherapy and promising immune targets to enhance anti-tumor immunity. [ABSTRACT FROM AUTHOR]

Incapacitated immune system is a characteristic hallmark of solid tumors. Immune system within a tumor undergoes an imbalance in cellular dispersion and functionality. Effector cells are precluded from the invasive margin of tumor; instead, immune suppressor cells are present at high fractions. Conditions in the tumor microenvironment (TME) like altered metabolism, chronic hypoxia and chronic inflammation are the known predisposing factors, implicated in the immune malfunctioning. Deficiency of innate immune sensing mediated by checkpoint receptors including programmed death-1 receptor (PD-1), CTL-associated antigen-4 (CTLA-4) hijacked by tumor cells takes a major part of the blame, requiring a need for appropriate strategies in order to bring back the balance in the immune system. Immune checkpoint inhibitor (ICI) therapy has been in the eye of the current research rendering promising results. The story is not, however, that easy in which it is not so effective for Cold tumors, it may cause severe adverse effects, and that patients may acquire resistance to such therapy; this requires for updating the current knowledge about the immune ecosystem, using tumor type dependent dose calculation and exploiting proper adjuvants in order for evolving desired responses. Unlabelled Image [ABSTRACT FROM AUTHOR]

Immunotherapy has revolutionized treatment of cancer during the last decades. Oncolytic virotherapy has also emerged as a strategy to fight against cancer cells both via lysis of malignant cells and activating immune responses. Accepted as a logical strategy, combination of monoclonal antibodies particularly against the programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) is introduced to improve clinical responses to immune checkpoint inhibitors (ICIs). Accordingly, Talimogene laherparepvec (T-VEC) has received approval for clinical use, while a number of oncolytic Adenoviruses (Ads) are being investigated in clinical trials of malignancies. Combination of oncolytic Ads with PD-1/PD-L1 inhibitors have shown potentials in promoting responses to ICIs, changing the tumor microenvironment, inducing long-term protection against tumor, and promoting survival among mice models of malignancies. Regarding the increasing importance of oncolytic Ads in combination therapy of cancers, in this review we decide to outline recent studies in this field. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment in the last decade. Among various checkpoints identified so far, interaction between programmed death-1 (PD-1) with programmed death ligand 1 (PD-L1) and their targeting using human monoclonal antibodies has attracted the most attention and is considered as the most prominent treatment with the best clinical outcomes. Accumulating evidence is the witness for the impact of gut microbiota on clinical responses and ICI efficacy. Specific bacterial species are identified in fecal specimens of cancer patients responding to the anti-PD-(L)1 immunotherapy, while non-responders demonstrate high abundance of other bacterial sources. Thus, the composition of gut microbiota may suggest potential biomarker in identification of patients with the best responses to immunotherapy. Notably, fecal microbial transplantation (FMT) from responders to non-responders has shown hopeful results in improving clinical outcomes and overcoming resistance to ICIs. Additionally, some bacterial components, such as the use of antibiotics and probiotic supplements have been shown to affect the efficacy of ICIs treatment. However, employment of these findings requires further investigations and precise understanding of the impact of gut microbiota on the host's immune responses. In the current review, we aim to discuss the roles of PD-1/PD-L1 checkpoint pathway, their therapeutic significance, and the impact of gut microbiota/products on the PD-1/PD-L1 immunotherapy outcomes. The impact of gut microbiota on ICI responses. Specific bacterial species are identified in fecal specimens of cancer patients responding to the anti-PD-(L)1 immunotherapy, while non-responders demonstrate high abundance of other bacterial sources. Thus, the composition of gut microbiota may suggest potential biomarker in identification of patients with the best responses to immunotherapy. [Display omitted] • PD-1/PD-L1 axis plays crucial roles in regulation of immune responses. • Tumor cells exploit the PD-1/PD-L1 axis to escape from immunosurveillance. • Gut microbiota affects the efficacy and responses to ICIs in cancer patients. • FMT can improve anti-cancer responses in ICI-treated patients. [ABSTRACT FROM AUTHOR]