Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) are inhibitory checkpoints that are commonly seen on activated T cells and have been offered as promising targets for the treatment of cancers. Immune checkpoint inhibitors (ICIs)targeting PD-1, including pembrolizumab and nivolumab, and those targeting its ligand PD-L1, including avelumab, atezolizumab, and durvalumab, and two drugs targeting CTLA-4, including ipilimumab and tremelimumab have been approved for the treatment of several cancers and many others are under investigating in advanced trial phases. ICIs increased antitumor T cells’ responses and showed a key role in reducing the acquired immune system tolerance which is overexpressed by cancer and tumor microenvironment. However, 50% of patients could not benefit from ICIs monotherapy. To overcome this, a combination of ipilimumab and nivolumab is frequently investigated as an approach to improve oncological outcomes. Despite promising results for the combination of ipilimumab and nivolumab, safety concerns slowed down the development of such strategies. Herein, we review data concerning the clinical activity and the adverse events of ipilimumab and nivolumab combination therapy, assessing ongoing clinical trials to identify clinical outlines that may support combination therapy as an effective treatment. To the best of our knowledge, this paper is one of the first studies to evaluate the efficacy and safety of ipilimumab and nivolumab combination therapy in several cancers.

Although the ever-increasing number of cancer patients pose substantial challenges worldwide, finding a treatment with the highest response rate and the lowest number of side effects is still undergoing research. Compared to chemotherapy, the relatively low side effects of cancer immunotherapy have provided ample opportunity for immunotherapy to become a promising approach for patients with malignancy. However, the clinical translation of immune-based therapies requires robust anti-tumoral immune responses. Immune checkpoints have substantial roles in the induction of an immunosuppressive tumor microenvironment and tolerance against tumor antigens. Identifying and targeting these inhibitory axes, which can be established between tumor cells and tumor-infiltrating lymphocytes, can facilitate the development of anti-tumoral immune responses. Bispecific T-cell engagers, which can attract lymphocytes to the tumor microenvironment, have also paved the road for immunological-based tumor elimination. The development of CAR-T cells and their gene editing have brought ample opportunity to recognize tumor antigens, independent from immune checkpoints and the major histocompatibility complex (MHC). Indeed, there have been remarkable advances in developing various CAR-T cells to target tumoral cells. Knockout of immune checkpoints via gene editing in CAR-T cells might be designated for a breakthrough for patients with malignancy. In the midst of this fast progress in cancer immunotherapies, there is a need to provide up-to-date information regarding immune checkpoints, bispecific T-cell engagers, and CAR-T cells. Therefore, this review aims to provide recent findings of immune checkpoints, bispecific T-cell engagers, and CAR-T cells in cancer immunotherapy and discuss the pertained clinical trials.

Immune checkpoints (ICs) have pivotal roles in regulating immune responses. The inhibitory ICs in the tumor microenvironment (TME) have been implicated in the immune evasion of tumoral cells. Therefore, identifying and targeting these inhibitory ICs might be critical for eliminating tumoral cells. V-domain immunoglobulin suppressor of T cell activation (VISTA) is a novel inhibitory IC that is expressed on myeloid cells, lymphoid cells, and tumoral cells; therefore, VISTA can substantially regulate innate and adaptive anti-tumoral immune responses. Besides, growing evidence indicates that VISTA blockade can enhance the sensitivity of tumoral cells to conventional IC-based immunotherapy, e.g., cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors. In this regard, the current study aimed to review the current evidence about the structure and expression pattern of VISTA, its role in TME, the clinicopathological significance of VISTA, and its prognostic values in various cancers. Besides, this review intended to collect the lessons from the recent pre-clinical and clinical studies and propose a strategy to overcome tumor immune-resistance states.

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BackgroundCancer stem cells have been implicated in tumor relapse, tumor invasion, and cancer therapy resistance in high-grade gliomas; thus, characterizing cancer stem cell-related markers can help determine the prognosis of affected patients. Preclinical studies have reported that CD133 is implicated in tumor recurrence and cancer therapy resistance in high-grade gliomas; however, clinical studies have reported inconclusive results regarding its prognostic value in patients with high-grade gliomas.MethodsWe systematically searched the PubMed, Scopus, Web of Science, and Embase databases to obtain peer-reviewed studies published before March 10, 2021. Then, we conducted the current systematic review and meta-analysis based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statements. By applying the random-effect model, the effect size of studies investigating the progression-free survival (PFS), time to local recurrence (TTL), and time to distant recurrence (TTD) were calculated using RevMan version 5.4. The heterogeneity between the included studies was studied by the I2 index and Cochran’s Q test. Egger test was performed on funnel plots to investigate the potential asymmetry and publication bias among the included studies using CMA version 2.ResultsWith the 10% cut-off, CD133 protein overexpression is associated with the inferior PFS of patients with high-grade gliomas. Increased CD133 protein expression is associated with sooner distant tumor recurrence on MRI in glioblastoma patients and patients with high-grade gliomas and improved TTL on MRI in glioblastoma patients.ConclusionBased on the current evidence from 1086 patients with high-grade gliomas, CD133 overexpression is a valuable marker to predict tumor relapse and tumor recurrence patterns in patients with high-grade gliomas.