Generation of Murine Chimeric Antigen Receptor-Modified T Cells for In Vivo Studies in Syngeneic Tumor Models.

CAR-T cell therapy has emerged as a potent and effective tool in the immunotherapy of refractory cancers. However, challenges exist in their clinical application, necessitating extensive preclinical research to optimize their function. Various preclinical in vitro and in vivo models have been proposed for such purpose; among which immunocompetent mouse models serve as an invaluable tool in studying host immune interactions within a more realistic simulation of the tumor milieu.

Simultaneous targeting of Tim3 and A2a receptors modulates MSLN-CAR T cell antitumor function in a human cervical tumor xenograft model.

Introduction: Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of hematological malignancies. However, its efficacy in solid tumors is limited by the immunosuppressive tumor microenvironment that compromises CAR T cell antitumor function in clinical settings. To overcome this challenge, researchers have investigated the potential of inhibiting specific immune checkpoint receptors, including A2aR (Adenosine A2 Receptor) and Tim3 (T cell immunoglobulin and mucin domain-containing protein 3), to enhance CAR T cell function.

PX-478, an HIF-1α inhibitor, impairs mesoCAR T cell antitumor function in cervical cancer.

Introduction: Chimeric Antigen Receptor (CAR) T cell therapy has demonstrated remarkable success in treating hematological malignancies. However, its efficacy against solid tumors, including cervical cancer, remains a challenge. Hypoxia, a common feature of the tumor microenvironment, profoundly impacts CAR T cell function, emphasizing the need to explore strategies targeting hypoxia-inducible factor-1α (HIF-1α).

Anti-CTLA-4 nanobody as a promising approach in cancer immunotherapy.

Cancer is one of the most common diseases and causes of death worldwide. Since common treatment approaches do not yield acceptable results in many patients, developing innovative strategies for effective treatment is necessary. Immunotherapy is one of the promising approaches that has been highly regarded for preventing tumor recurrence and new metastases.

Crosstalk between autophagy and metabolic regulation of (CAR) T cells: therapeutic implications.

Despite chimeric antigen receptor (CAR) T cell therapy's extraordinary success in subsets of B-cell lymphoma and leukemia, various barriers restrict its application in solid tumors. This has prompted investigating new approaches for producing CAR T cells with superior therapeutic potential. Emerging insights into the barriers to CAR T cell clinical success indicate that autophagy shapes the immune response via reprogramming cellular metabolism and vice versa.

PGE2-EP2/EP4 signaling elicits mesoCAR T cell immunosuppression in pancreatic cancer.

Introduction: For many years, surgery, adjuvant and combination chemotherapy have been the cornerstone of pancreatic cancer treatment. Although these approaches have improved patient survival, relapse remains a common occurrence, necessitating the exploration of novel therapeutic strategies. CAR T cell therapies are now showing tremendous success in hematological cancers.

The inhibitory receptors PD1, Tim3, and A2aR are highly expressed during mesoCAR T cell manufacturing in advanced human epithelial ovarian cancer.

Background: Chemotherapy and surgery have been the mainstays of epithelial ovarian cancer (EOC) treatment so far. Cellular immunotherapies such as CAR T cell therapy have recently given hope of a cure for solid tumors like EOC. However, extrinsic factors associated with the CAR T cell manufacturing process and/or intrinsic dysregulation of patient-derived T cells, which could be associated with cancer itself, cancer stage, and treatment regimen, may hamper the efficacy of CAR T cell therapy and promote their exhaustion or dysfunction.

MicroRNA-124 Enhances T Cells Functions by Manipulating the Lactic Acid Metabolism of Tumor Cells.

High production of lactic acid is a common feature of various tumors. Lactic acid is an immunosuppressive molecule with crucial roles in tumor cells' immune escape, which could largely be attributed to its negative effects on the T cells present in the tumor microenvironment (TME). Strategies that decrease the glycolysis rate of tumor cells could enhance immunosurveillance and limit tumor growth.

Soluble and Immobilized Anti-CD3/28 Distinctively Expand and Differentiate Primary Human T Cells: An Implication for Adoptive T Cell Therapy.

Cell-based cancer therapies have led to a paradigm shift in the treatment of patients with various cancers. To date, a vast majority of cancer immunotherapies have used genetically engineered T cells to target tumors. Stimulation and ex vivo expansion of T cells, as one of the crucial starting materials for T cell manufacturing, have always been a critical part of adoptive T-cell therapy (ACT).

Identification of the Optimal Pattern of the Injection and Dosage of DC Immunotherapy Using the Mathematical Models Based on Ordinary Differential Equations.

Background: Mathematical modeling offers the possibility to select the optimal dose of a drug or vaccine. Considerable evidence show that many bacterial components can activate dendritic cells (DCs). Our previous report showed that multiple doses of DCs matured with Listeria monocytogenes led to tumor regression whereas multiple doses of CpG-matured DCs affected tumor reversely.

Restricting tumor lactic acid metabolism using dichloroacetate improves T cell functions.

Background: Lactic acid produced by tumors has been shown to overcome immune surveillance, by suppressing the activation and function of T cells in the tumor microenvironment. The strategies employed to impair tumor cell glycolysis could improve immunosurveillance and tumor growth regulation. Dichloroacetate (DCA) limits the tumor-derived lactic acid by altering the cancer cell metabolism.

CRISPR/Cas9-mediated TGFβRII disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells in vitro.

Background: CAR T-cell therapy has been recently unveiled as one of the most promising cancer therapies in hematological malignancies. However, solid tumors mount a profound line of defense to escape immunosurveillance by CAR T-cells. Among them, cytokines with an inhibitory impact on the immune system such as IL-10 and TGFβ are of great importance: TGFβ is a pleiotropic cytokine, which potently suppresses the immune system and is secreted by a couple of TME resident and tumor cells.

Targeting hypoxia and hypoxia-inducible factor-1 in the tumor microenvironment for optimal cancer immunotherapy.

The development of new strategies of anticancer immunotherapies has provided promising approaches in the treatment of solid tumors. However, despite the improved survival in responders, most of the patients show incomplete responses with a lack of remarkable clinical improvement. Hypoxia has been identified as a common characteristic of solid tumors contributing to different aspects of tumor progression, including invasion, metastasis, and the creation of the immunosuppressive tumor microenvironment.

Prediction of anti-CD25 and 5-FU treatments efficacy for pancreatic cancer using a mathematical model.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with rising incidence and with 5-years overall survival of less than 8%. PDAC creates an immune-suppressive tumor microenvironment to escape immune-mediated eradication. Regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSC) are critical components of the immune-suppressive tumor microenvironment.

Genetic Modification of Cytokine Signaling to Enhance Efficacy of CAR T Cell Therapy in Solid Tumors.

Chimeric antigen receptor (CAR) T cell therapy has shown unprecedented success in treating advanced hematological malignancies. Its effectiveness in solid tumors has been limited due to heterogeneous antigen expression, a suppressive tumor microenvironment, suboptimal trafficking to the tumor site and poor CAR T cell persistence. Several approaches have been developed to overcome these obstacles through various strategies including the genetic engineering of CAR T cells to blunt the signaling of immune inhibitory receptors as well as to modulate signaling of cytokine/chemokine molecules and their receptors.

Targeted knockdown of Tim3 by short hairpin RNAs improves the function of anti-mesothelin CAR T cells.

T-cell immunoglobulin mucin 3 (Tim3) is an immune checkpoint receptor that plays a central role in chimeric antigen receptor (CAR) T cell exhaustion within the tumor microenvironment. This study was aimed to evaluate the effects of targeted-knockdown of Tim3 on the antitumor function of anti-mesothelin (MSLN)-CAR T cells. To knockdown Tim3 expression, three different shRNA sequences specific to different segments of the human Tim3 gene were designed and co-inserted with an anti-MSLN-CAR transgene into lentiviral vectors.

Epigenetic strategies to boost CAR T cell therapy.

Chimeric antigen receptor (CAR) T cell therapy has led to a paradigm shift in cancer immunotherapy, but still several obstacles limit CAR T cell efficacy in cancers. Advances in high-throughput technologies revealed new insights into the role that epigenetic reprogramming plays in T cells. Mechanistic studies as well as comprehensive epigenome maps revealed an important role for epigenetic remodeling in T cell differentiation.

Chimeric Antigen Receptor (CAR) T Cell Therapy for Metastatic Melanoma: Challenges and Road Ahead.

Metastatic melanoma is the most aggressive and difficult to treat type of skin cancer, with a survival rate of less than 10%. Metastatic melanoma has conventionally been considered very difficult to treat; however, recent progress in understanding the cellular and molecular mechanisms involved in the tumorigenesis, metastasis and immune escape have led to the introduction of new therapies. These include targeted molecular therapy and novel immune-based approaches such as immune checkpoint blockade (ICB), tumor-infiltrating lymphocytes (TILs), and genetically engineered T-lymphocytes such as chimeric antigen receptor (CAR) T cells.

Dendritic cells loaded with exosomes derived from cancer stem cell-enriched spheroids as a potential immunotherapeutic option.

Cancer stem cells (CSCs) are responsible for therapeutic resistance and recurrence in colorectal cancer. Despite advances in immunotherapy, the inability to specifically eradicate CSCs has led to treatment failure. Hence, identification of appropriate antigen sources is a major challenge in designing dendritic cell (DC)-based therapeutic strategies against CSCs.

A metabolic switch to memory CAR T cells: Implications for cancer treatment.

Therapeutic efficacy of chimeric antigen receptor (CAR) T cells is associated with their expansion, persistence and effector function. Although CAR T cell therapy has shown remarkable therapeutic effects in hematological malignancies, its therapeutic efficacy has been limited in some types of cancers - in particular, solid tumors - partially due to the cells' inability to persist and the acquisition of T cell dysfunction within a harsh immunosuppressive tumor microenvironment. Therefore, it would be expected that generation of CAR T cells with intrinsic properties for functional longevity, such as the cells with early-memory phenotypes, could beneficially enhance antitumor immunity.

Highly Efficient Generation of Transgenically Augmented CAR NK Cells Overexpressing CXCR4.

Natural killer (NK) cells are a noteworthy lymphocyte subset in cancer adoptive cell therapy. NK cells initiate innate immune responses against infections and malignancies with natural cytotoxicity, which is independent of foreign antigen recognition. Based on these substantive features, genetically modifying NK cells is among the prime goals in immunotherapy but is currently difficult to achieve.

Construction and Functional Characterization of a Fully Human Anti-mesothelin Chimeric Antigen Receptor (CAR) Expressing T Cell.

Chimeric antigen receptor (CAR) T cell therapy is considered as an encouraging approach for the treatment of hematological malignancies. However, its efficacy in solid tumors has not been satisfying, mainly in the immunosuppressive network of the tumor microenvironment and paucity of appropriate target antigens. Mesothelin (MSLN) is a tumor-associated antigen (TAA) expressed in numerous types of solid tumors such as gastrointestinal, ovarian, and pancreatic tumors.

Prolonged Persistence of Chimeric Antigen Receptor (CAR) T Cell in Adoptive Cancer Immunotherapy: Challenges and Ways Forward.

CAR T cell qualities, such as persistence and functionality play important roles in determining the outcome of cancer immunotherapy. In spite of full functionality, it has been shown that poor persistence of CAR T cells can limit an effective antitumor immune response. Here, we outline specific strategies that can be employed to overcome intrinsic and extrinsic barriers to CAR T cell persistence.

Pharmacological targeting of immune checkpoint A2aR improves function of anti-CD19 CAR T cells in vitro.

In spite of impressive results in the treatment of acute lymphoblastic B cell leukemia (B-ALL) with chimeric antigen receptor (CAR) T cells, the clinical outcome of some hematological cancers like follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL) has not been very promising likely due to immunosuppressive networks within tumor microenvironment. Hypoxia in the microenvironment of hematological malignancies and consequently generation of adenosine molecule is appeared to be correlated with immunosuppression, tumor progression, and relapse. Herein, we hypothesized that whether pharmacological targeting of adenosine 2a receptor (A2aR) can enhance antitumor activity of anti-CD19 CAR T cells in vitro.