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In recent decades, the advent of immune-based therapies, most notably Chimeric antigen receptor (CAR)-T cell therapy has revolutionized cancer treatment. The promising results of numerous studies indicate that CAR-T cell therapy has had a remarkable ability and successful performance in treating blood cancers. However, the heterogeneity and immunosuppressive tumor microenvironment (TME) of solid tumors have challenged the effectiveness of these anti-tumor fighters by creating various barriers. Despite the promising results of this therapeutic approach, including tumor degradation and patient improvement, there are some concerns about the efficacy and safety of the widespread use of this treatment in the clinic. Complex and suppressing tumor microenvironment, tumor antigen heterogeneity, the difficulty of cell trafficking, CAR-T cell exhaustion, and reduced cytotoxicity in the tumor site limit the applicability of CAR-T cell therapy and highlights the requiring to improve the performance of this treatment. With this in mind, in the last decade, many efforts have been made to use other treatments for cancer in combination with tuberculosis to increase the effectiveness of CAR-T cell therapy, especially in solid tumors. The combination therapy results have promising consequences for tumor regression and better cancer control compared to single therapies. Therefore, this study aimed to comprehensively discuss different cancer treatment methods in combination with CAR-T cell therapy and their therapeutic outcomes, which can be a helpful perspective for improving cancer treatment in the near future. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy has enormous potential in inducing long-term remission in cancer patients, and chimeric antigen receptor (CAR)-engineered T cells have been largely successful in treating hematological malignancies in the clinic. CAR-T therapy has not been as effective in treating solid tumors, in part due to the immunosuppressive tumor microenvironment. Additionally, CAR-T therapy can cause dangerous side effects, including off-tumor toxicity, cytokine release syndrome, and neurotoxicity. Animal models of CAR-T therapy often fail to predict such adverse events and frequently overestimate the efficacy of the treatment. Nearly all preclinical CAR-T studies have been performed in mice, including syngeneic, xenograft, transgenic, and humanized mouse models. Recently, a few studies have used primate models to mimic clinical side effects better. To date, no single model perfectly recapitulates the human immune system and tumor microenvironment, and some models have revealed CAR-T limitations that were contradicted or missed entirely in other models. Careful model selection based on the primary goals of the study is a crucial step in evaluating CAR-T treatment. Advancements are being made in preclinical models, with the ultimate objective of providing safer, more effective CAR-T therapy to patients. [ABSTRACT FROM AUTHOR]

Adoptive transfer of T cells is a promising cancer therapy and expression of chimeric antigen receptors can enhance tumour recognition and T-cell effector functions. The programmed death protein 1 ( PD1) receptor is a prospective target for a chimeric antigen receptor because PD1 ligands are expressed on many cancer types, including lymphoma. Therefore, we developed a murine chimeric PD1 receptor (ch PD1) consisting of the PD1 extracellular domain fused to the cytoplasmic domain of CD3ζ. Additionally, chimeric antigen receptor therapies use various co-stimulatory domains to enhance efficacy. Hence, the inclusion of a Dap10 or CD28 co-stimulatory domain in the ch PD1 receptor was compared to determine which domain induced optimal anti-tumour immunity in a mouse model of lymphoma. The ch PD1 T cells secreted pro-inflammatory cytokines and lysed RMA lymphoma cells. Adoptive transfer of ch PD1 T cells significantly reduced established tumours and led to tumour-free survival in lymphoma-bearing mice. When comparing ch PD1 receptors containing a Dap10 or CD28 domain, both receptors induced secretion of pro-inflammatory cytokines; however, ch PD1- CD28 T cells also secreted anti-inflammatory cytokines whereas ch PD1-Dap10 T cells did not. Additionally, ch PD1-Dap10 induced a central memory T-cell phenotype compared with ch PD1- CD28, which induced an effector memory phenotype. The ch PD1-Dap10 T cells also had enhanced in vivo persistence and anti-tumour efficacy compared with ch PD1- CD28 T cells. Therefore, adoptive transfer of ch PD1 T cells could be a novel therapy for lymphoma and inclusion of the Dap10 co-stimulatory domain in chimeric antigen receptors may induce a preferential cytokine profile and T-cell differentiation phenotype for anti-tumour therapies. [ABSTRACT FROM AUTHOR]

The therapeutic potential of adoptive cell therapy (ACT) in cancer patients was first acknowledged 3 decades ago, but it was an esoteric approach at the time. In recent years, technological advancements have transformed ACT into a viable therapeutic option that can be curative in some patients. In fact, current ACT response rates are 80% to 90% for hematological malignancies and 30% for metastatic melanoma refractory to multiple lines of therapy. Although these results are encouraging, there is still much to be done to fulfill ACT's potential, specifically with regard to improving clinical efficacy, expanding clinical indications, reducing toxicity, and increasing production and cost-effectiveness. This review addresses the current major obstacles to ACT and presents potential solutions. Cancer 2017;123:2154-62. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR)-engineered T cells (CAR-T cells) have yielded unprecedented efficacy in B cell malignancies, most remarkably in anti-CD19 CAR-T cells for B cell acute lymphoblastic leukemia (B-ALL) with up to a 90% complete remission rate. However, tumor antigen escape has emerged as a main challenge for the long-term disease control of this promising immunotherapy in B cell malignancies. In addition, this success has encountered significant hurdles in translation to solid tumors, and the safety of the on-target/off-tumor recognition of normal tissues is one of the main reasons. In this mini-review, we characterize some of the mechanisms for antigen loss relapse and new strategies to address this issue. In addition, we discuss some novel CAR designs that are being considered to enhance the safety of CAR-T cell therapy in solid tumors. [ABSTRACT FROM AUTHOR]

Adoptive cell therapy with chimeric antigen receptor (CAR)‐engineered T cells produced lasting remissions in the treatment of advanced, so far refractory B‐cell malignancies; however, the elimination of solid tumors remains so far elusive. The low efficacy of CAR T cells is thought to be due to the immune‐repressive milieu within the tumor lesion, predominantly mediated by transforming growth factor‐β (TGF‐β) that represses effector T‐cell activities and drives differentiation towards regulatory T cells (Tregs). Seeking to boost antitumor immunity, TGF‐β is currently targeted by different means in pre‐clinical studies. While a recent clinical trial showed the utility of shielding CAR T cells from TGF‐β repression, further strategies in counteracting TGF‐β in the adoptive cell therapy warrant exploration. We here discuss the most recent advances in the field and draw future developments to make CAR T‐cell therapy more potent in the treatment of solid cancer. [ABSTRACT FROM AUTHOR]