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Immune cell therapy based on chimeric antigen receptor (CAR) technology platform has been greatly developed. The types of CAR immune cell therapy have expanded from T cells to innate immune cells such as NK cells and macrophages, and the diseases treated have expanded from hematological malignancies to non-tumor fields such as infectious diseases and autoimmune diseases. Among them, CAR-T and CAR-NK therapy have observed examples of rapid remission in approved clinical trials, but the efficacy is unstable and plagued by tumor resistance. Trogocytosis is a special phenomenon of intercellular molecular transfer that is common in the immune system and is achieved by recipient cells through acquisition and internalization of donor cell-derived molecules and mediates immune effects. Recently, a novel short-term drug resistance mechanism based on trogocytosis has been proposed, and the bidirectional molecular exchange between CAR immune cells and tumor cells triggered by trogocytosis partially explains the long-term relapse phenomenon after treatment with CAR immune cells. In this review, we summarize the research progress of trogocytosis in CAR immunotherapy, discuss the influencing factors of trogocytosis and its direct and indirect interference with CAR immune cells and emphasize that the interference of trogocytosis can further release the potential of CAR immune cell therapy. [ABSTRACT FROM AUTHOR]

Durable response to chimeric antigen receptor T (CART) cell therapy remains limited in part due to CART cell exhaustion. Here, we investigate the regulation of CART cell exhaustion with three independent approaches including: a genome-wide CRISPR knockout screen using an in vitro model for exhaustion, RNA and ATAC sequencing on baseline and exhausted CART cells, and RNA and ATAC sequencing on pre-infusion CART cell products from responders and non-responders in the ZUMA-1 clinical trial. Each of these approaches identify interleukin (IL)-4 as a regulator of CART cell dysfunction. Further, IL-4-treated CD8+ CART cells develop signs of exhaustion independently of the presence of CD4+ CART cells. Conversely, IL-4 pathway editing or the combination of CART cells with an IL-4 monoclonal antibody improves antitumor efficacy and reduces signs of CART cell exhaustion in mantle cell lymphoma xenograft mouse models. Therefore, we identify both a role for IL-4 in inducing CART exhaustion and translatable approaches to improve CART cell therapy. The application and therapeutic success of CAR-T cell approaches are limited by the development of T cell exhaustion. Here, Stewart et al discover a role for IL-4 in driving CD8+ CAR-T cell exhaustion and demonstrate the improvement of CAR-T cell effectivity with interruption of IL-4 signalling. [ABSTRACT FROM AUTHOR]

Adoptive cell therapy has revolutionized cancer treatment, especially for hematologic malignancies. T cells are the most extensively utilized cells in adoptive cell therapy. Currently, tumor-infiltrating lymphocytes, T cell receptor-transgenic T cells and chimeric antigen receptor T cells are the three main adoptive T cell therapies. Tumor-infiltrating lymphocytes kill tumors by reinfusing enlarged lymphocytes that naturally target tumor-specific antigens into the patient. T cell receptor-transgenic T cells have the ability to specifically destroy tumor cells via the precise recognition of exogenous T cell receptors with major histocompatibility complex. Chimeric antigen receptor T cells transfer genes with specific antigen recognition structural domains and T cell activation signals into T cells, allowing T cells to attack tumors without the assistance of major histocompatibility complex. Many barriers have been demonstrated to affect the clinical efficacy of adoptive T cell therapy, such as tumor heterogeneity and antigen loss, hard trafficking and infiltration, immunosuppressive tumor microenvironment and T cell exhaustion. Several strategies to improve the efficacy of adoptive T cell therapy have been explored, including multispecific chimeric antigen receptor T cell therapy, combination with immune checkpoint blockade, targeting the immunosuppressive tumor microenvironment, etc. In this review, we will summarize the current status and clinical application, followed by major bottlenecks in adoptive T cell therapy. In addition, we will discuss the promising strategies to improve adoptive T cell therapy. Adoptive T cell therapy will result in even more incredible advancements in solid tumors if the aforementioned problems can be handled. [ABSTRACT FROM AUTHOR]

The application of chimeric antigen receptor (CAR) T cells in the management of hematological malignancies has emerged as a noteworthy therapeutic breakthrough. Nevertheless, the utilization and effectiveness of CAR-T cell therapy in solid tumors are still limited primarily because of the absence of tumor-specific target antigen, the existence of immunosuppressive tumor microenvironment, restricted T cell invasion and proliferation, and the occurrence of severe toxicity. This review explored the history of CAR-T and its latest advancements in the management of solid tumors. According to recent studies, optimizing the design of CAR-T cells, implementing logic-gated CAR-T cells and refining the delivery methods of therapeutic agents can all enhance the efficacy of CAR-T cell therapy. Furthermore, combination therapy shows promise as a way to improve the effectiveness of CAR-T cell therapy. At present, numerous clinical trials involving CAR-T cells for solid tumors are actively in progress. In conclusion, CAR-T cell therapy has both potential and challenges when it comes to treating solid tumors. As CAR-T cell therapy continues to evolve, further innovations will be devised to surmount the challenges associated with this treatment modality, ultimately leading to enhanced therapeutic response for patients suffered solid tumors. [ABSTRACT FROM AUTHOR]

Cellular immunotherapy, particularly CAR-T cells, has shown potential in the improvement of outcomes in patients with refractory and recurrent malignancies of the blood. However, achieving sustainable long-term complete remission for blood cancer remains a challenge, with resistance and relapse being expected outcomes for many patients. Although many studies have attempted to clarify the mechanisms of CAR-T cell therapy failure, the mechanism remains unclear. In this article, we discuss and describe the current state of knowledge regarding these factors, which include elements that influence the CAR-T cell, cancer cells as a whole, and the microenvironment surrounding the tumor. In addition, we propose prospective approaches to overcome these obstacles in an effort to decrease recurrence rates and extend patient survival subsequent to CAR-T cell therapy. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR-T) cell therapy has been widely used in hematological malignancies and has achieved remarkable results, but its longterm efficacy in solid tumors is greatly limited by factors such as the tumor microenvironment (TME). In this paper, we discuss the latest research and future views on CAR-T cell cancer immunotherapy, compare the different characteristics of traditional immunotherapy and CAR-T cell therapy, introduce the latest progress in CAR-T cell immunotherapy, and analyze the obstacles that hinder the efficacy of CAR-T cell therapy, including immunosuppressive factors, metabolic energy deficiency, and physical barriers. We then further discuss the latest therapeutic strategies to overcome these barriers, as well as management decisions regarding the possible safety issues of CAR-T cell therapy, to facilitate solutions to the limited use of CAR-T immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Chimeric antigen receptor (CAR)-T cell therapy has been used to treat pediatric refractory or relapsed mature B-cell non-Hodgkin lymphoma (r/r MB-NHL) with significantly improved outcomes, but a proportion of patients display no response or experience relapse after treatment. To investigate whether tumor-intrinsic somatic genetic alterations have an impact on CAR-T cell treatment, the genetic features and treatment outcomes of 89 children with MB-NHL were analyzed. Methods: 89 pediatric patients treated at multiple clinical centers of the China Net Childhood Lymphoma (CNCL) were included in this study. Targeted next-generation sequencing for a panel of lymphoma-related genes was performed on tumor samples. Survival rates and relapse by genetic features and clinical factors were analyzed. Survival curves were calculated using a log-rank (Mantel-Cox) test. The Wilcox sum-rank test and Fisher's exact test were applied to test for group differences. Results: A total of 89 driver genes with somatic mutations were identified. The most frequently mutated genes were TP53 (66%), ID3 (55%), and ARID1A (31%). The incidence of ARID1A mutation and co-mutation of TP53 and ARID1A was high in patients with r/r MB-NHL (P = 0.006; P = 0.018, respectively). CAR-T cell treatment significantly improved survival in r/r MB-NHL patients (P = 0.00081), but patients with ARID1A or ARID1A and TP53 co-mutation had poor survival compared to those without such mutations. Conclusion: These results indicate that children with MB-NHL harboring ARID1A or TP53 and ARID1A co-mutation are insensitive to initial conventional chemotherapy and subsequent CAR-T cell treatment. Examination of ARID1A and TP53 mutation status at baseline might have prognostic value, and risk-adapted or more effective therapies should be considered for patients with these high-risk genetic alterations. [ABSTRACT FROM AUTHOR]

Summary: Cell therapies are powerful technologies in which human cells are reprogrammed for therapeutic applications such as killing cancer cells or replacing defective cells. The technologies underlying cell therapies are increasing in effectiveness and complexity, making rational engineering of cell therapies more difficult. Creating the next generation of cell therapies will require improved experimental approaches and predictive models. Artificial intelligence (AI) and machine learning (ML) methods have revolutionized several fields in biology including genome annotation, protein structure prediction, and enzyme design. In this review, we discuss the potential of combining experimental library screens and AI to build predictive models for the development of modular cell therapy technologies. Advances in DNA synthesis and high‐throughput screening techniques enable the construction and screening of libraries of modular cell therapy constructs. AI and ML models trained on this screening data can accelerate the development of cell therapies by generating predictive models, design rules, and improved designs. [ABSTRACT FROM AUTHOR]

T cell differentiation is a highly regulated, multi-step process necessary for the progressive establishment of effector functions, immunological memory, and long-term control of pathogens. In response to strong stimulation, as seen in severe or chronic infections or cancer, T cells acquire a state of hypo-responsiveness known as exhaustion, limiting their effector function. Recent advances in autologous chimeric antigen receptor (CAR)-T cell therapies have revolutionized the treatment of hematologic malignancies by taking advantage of the basic principles of T cell biology to engineer products that promote long-lasting T cell response. However, many patients' malignancies remain unresponsive to treatment or are prone to recur. Discoveries in T cell biology, including the identification of key regulators of differentiation and exhaustion, offer novel opportunities to have a durable impact on the fate of CAR-T cells after infusion. Such next-generation CAR-T cell therapies and their clinical implementation may result in the next leap forward in cancer treatment for selected patients. In this context, this review summarizes the foundational principles of T cell differentiation and exhaustion and describes how they can be utilized and targeted to further improve the design and efficacy of CAR-T cell therapies. [ABSTRACT FROM AUTHOR]

Adoptive cell therapies continually evolve through science-based innovation. Specialized innovations for TCR-T therapies are described here that are embedded in an End-to-End Platform for TCR-T Therapy Development which aims to provide solutions for key unmet patient needs by addressing challenges of TCR-T therapy, including selection of target antigens and suitable T cell receptors, generation of TCR-T therapies that provide long term, durable efficacy and safety and development of efficient and scalable production of patient-specific (personalized) TCR-T therapy for solid tumors. Multiple, combinable, innovative technologies are used in a systematic and sequential manner in the development of TCR-T therapies. One group of technologies encompasses product enhancements that enable TCR-T therapies to be safer, more specific and more effective. The second group of technologies addresses development optimization that supports discovery and development processes for TCR-T therapies to be performed more quickly, with higher quality and greater efficiency. Each module incorporates innovations layered onto basic technologies common to the field of immunology. An active approach of "evolution by innovation" supports the overall goal to develop best-in-class TCR-T therapies for treatment of patients with solid cancer. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is the most common cause of cancer death in women. According to the American Cancer Society's yearly cancer statistics, BC constituted almost 15% of all the newly diagnosed cancer cases in 2022 for both sexes. Metastatic disease occurs in 30% of patients with BC. The currently available treatments fail to cure metastatic BC, and the average survival time for patients with metastatic BC is approximately 2 years. Developing a treatment method that terminates cancer stem cells without harming healthy cells is the primary objective of novel therapeutics. Adoptive cell therapy is a branch of cancer immunotherapy that utilizes the immune cells to attack cancer cells. Natural killer (NK) cells are an essential component of innate immunity and are critical in destroying tumor cells without prior stimulation with antigens. With the advent of chimeric antigen receptors (CARs), the autologous or allogeneic use of NK/CAR–NK cell therapy has raised new hopes for treating patients with cancer. Here, we describe recent developments in NK and CAR–NK cell immunotherapy, including the biology and function of NK cells, clinical trials, different sources of NK cells and their future perspectives on BC. [ABSTRACT FROM AUTHOR]

Adoptive cell therapies (ACTs) have existed for decades. From the initial infusion of tumor-infiltrating lymphocytes to the subsequent specific enhanced T cell receptor (TCR)-T and chimeric antigen receptor (CAR)-T cell therapies, many novel strategies for cancer treatment have been developed. Owing to its promising outcomes, CAR-T cell therapy has revolutionized the field of ACTs, particularly for hematologic malignancies. Despite these advances, CAR-T cell therapy still has limitations in both autologous and allogeneic settings, including practicality and toxicity issues. To overcome these challenges, researchers have focused on the application of CAR engineering technology to other types of immune cell engineering. Consequently, several new cell therapies based on CAR technology have been developed, including CAR-NK, CAR-macrophage, CAR-γδT, and CAR-NKT. In this review, we describe the development, advantages, and possible challenges of the aforementioned ACTs and discuss current strategies aimed at maximizing the therapeutic potential of ACTs. We also provide an overview of the various gene transduction strategies employed in immunotherapy given their importance in immune cell engineering. Furthermore, we discuss the possibility that strategies capable of creating a positive feedback immune circuit, as healthy immune systems do, could address the flaw of a single type of ACT, and thus serve as key players in future cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Purpose: Chimeric antigen receptor (CAR)-T cells against CD19 have been proven to be effective in treating B-cell hematological malignancies. However, the efficacy of this promising therapy is limited by many factors. Methods: In this study, the germinal center B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) cell line OCI-Ly1, and patient-derived xenografted (PDX) mice (CY-DLBCL) were used as the CAR-T cell-resistant model. Meanwhile, the activated B-cell-like (ABC) DLBCL cell line OCI-Ly3 and PDX mice (ZML-DLBCL) were defined as the CAR-T sensitive model. The enhancement of CAR-T cell function by lenalidomide (LEN) was examined in vitro and in vivo. Results: Lenalidomide effectively enhanced the function of third-generation CD19-CAR-T cells by polarizing CD8+ CAR-T cells to CD8 early-differentiated stage and Th1 type, reducing CAR-T cell exhaustion and improving cell expansion. It was further demonstrated that CAR-T cells combined with LEN substantially reduce the tumor burden and prolong the survival time in various DLBCL mouse models. LEN was also found to promote the infiltration of CD19-CAR-T cells into the tumor site by modulating the tumor microenvironment. Conclusion: In summary, the results of the present study suggest that LEN can improve the function of CD19-CAR-T cells, providing a basis for clinical trials using this combination therapy against DLBCL. [ABSTRACT FROM AUTHOR]

The most common kind of acute leukemia in adults is acute myeloid leukemia (AML), which is often treated with induction chemotherapy regimens followed by consolidation or allogeneic hematopoietic stem cell transplantation (HSCT). However, some patients continue to develop relapsed or refractory AML (R/R-AML). Small molecular targeted drugs require long-time administration. Not all the patients hold molecular targets. Novel medicines are therefore needed to enhance treatment outcomes. T cells and natural killer (NK) cells engineered with chimeric antigen receptors (CARs) that target antigens associated with AML have recently been produced and are currently being tested in both pre-clinical and clinical settings. This review provides an overview of CAR-T/NK treatments for AML. [ABSTRACT FROM AUTHOR]

Summary: Regulatory T cells (Tregs) have enormous therapeutic potential to treat a variety of immunopathologies characterized by aberrant immune activation. Adoptive transfer of ex vivo expanded autologous Tregs continues to progress through mid- to late-phase clinical trials in several disease spaces and has generated promising preliminary safety and efficacy signals to date. However, the practicalities of this strategy outside of the clinical trial setting remain challenging. Here, we review the current landscape of regulatory T-cell therapy, considering emergent approaches and technologies presenting novel ways to engage Tregs, and reflect on the progress necessary to deliver their therapeutic potential to patients. Regulatory T cells (Tregs) have enormous therapeutic potential to treat a variety of immunopathologies characterized by aberrant immune activation. However, the practicalities of Treg cell therapy outside of the clinical trial setting remain challenging. Here, we review the current landscape of Treg cell therapy, considering emergent approaches and technologies presenting novel ways to engage Tregs, and reflect on the progress necessary to deliver their therapeutic capabilities to patients. [ABSTRACT FROM AUTHOR]

In the last decade, Chimeric Antigen Receptor (CAR)-T cell therapy has emerged as a promising immunotherapeutic approach to fight cancers. This approach consists of genetically engineered immune cells expressing a surface receptor, called CAR, that specifically targets antigens expressed on the surface of tumor cells. In hematological malignancies like leukemias, myeloma, and non-Hodgkin B-cell lymphomas, adoptive CAR-T cell therapy has shown efficacy in treating chemotherapy refractory patients. However, the value of this therapy remains inconclusive in the context of solid tumors and is restrained by several obstacles including limited tumor trafficking and infiltration, the presence of an immunosuppressive tumor microenvironment, as well as adverse events associated with such therapy. Recently, CAR-Natural Killer (CAR-NK) and CAR-macrophages (CAR-M) were introduced as a complement/alternative to CAR-T cell therapy for solid tumors. CAR-NK cells could be a favorable substitute for CAR-T cells since they do not require HLA compatibility and have limited toxicity. Additionally, CAR-NK cells might be generated in large scale from several sources which would suggest them as promising off-the-shelf product. CAR-M immunotherapy with its capabilities of phagocytosis, tumor-antigen presentation, and broad tumor infiltration, is currently being investigated. Here, we discuss the emerging role of CAR-T, CAR-NK, and CAR-M cells in solid tumors. We also highlight the advantages and drawbacks of CAR-NK and CAR-M cells compared to CAR-T cells. Finally, we suggest prospective solutions such as potential combination therapies to enhance the efficacy of CAR-cells immunotherapy. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T-cell (CAR-T-cell) therapy has been well researched to date because of its ability to target malignant tumor cells. The most common CART cells are CD19 CAR-T cells, which play a large role in B-cell leukemia treatment. However, most CAR-T cells are associated with relapse after clinical treatment, so the quality and persistence of CAR-T cells need to be improved. With continuous optimization, there have been four generations of CARs and each generation of CARs has better quality and durability than the previous generation. In addition, it is important to increase the proportion of memory cells in CAR-T cells. Studies have shown that an immunosuppressive tumor microenvironment (TME) can lead to dysfunction of CAR-T cells, resulting in decreased cell proliferation and poor persistence. Thus, overcoming the challenges of immunosuppressive molecules and targeting cytokines in the TME can also improve CAR-T cell persistence. In this paper, we explored how to improve the durability of CAR-T cell therapy by improving the structure of CARs, increasing the proportion of memory CAR-T cells and improving the TME. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T cell therapy is a clinically approved cancer immunotherapy approach using genetically engineered T cells. The success of CAR T cells has been met with challenges regarding efficacy and safety. Although a broad spectrum of CAR T cell variants and applications is emerging, this review focuses on CAR T cells for the treatment of cancer. In the first part, the general principles of adoptive cell transfer, the architecture of the CAR molecule, and the effects of design on function are presented. The second part describes five conceptual challenges that hinder the success of CAR T cells; immunosuppressive tumour microenvironment, T cell intrinsic properties, tumour targeting, manufacturing cellular product, and immune-related adverse events. Throughout the review, selected current approaches to address these issues are presented. Cancer immunotherapy with CAR T cells represents a paradigm shift in the treatment of certain blood cancers that do not respond to other available treatment options. Well-trodden paths taken by pioneers led to the first clinical approval, and now the journey continues down lesser-known paths to treat a variety of cancers and other serious diseases with CAR T cells. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T (CAR-T) cell therapy has significantly improved the life expectancy for patients with refractory or relapse B cell lymphoma. As for B cell acute lymphoblastic leukemia (B-ALL), although the primary response rate is promising, the high incidence of early relapse has caused modest long-term survival with CAR-T cell alone. One of the main challenges is the limited persistence of CAR-T cells. To further optimize the clinical effects of CAR-T cells, many studies have focused on modifying the CAR structure and regulating CAR-T cell differentiation. In this review, we focus on CAR-T cell persistence and summarize the latest progress and strategies adopted during the in vitro culture stage to optimize CAR-T immunotherapy by improving long-term persistence. Such strategies include choosing a suitable cell source, improving culture conditions, combining CAR-T cells with conventional drugs, and applying genetic manipulations, all of which may improve the survival of patients with hematologic malignancies by reducing the probability of recurrence after CAR-T cell infusion and provide clues for solid tumor CAR-T cell therapy development. [ABSTRACT FROM AUTHOR]

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]

B-cell acute lymphoblastic leukemia (B-ALL) is the most common childhood malignancy. The cure rate has reached 90% after conventional chemotherapy and hematopoietic stem cell transplantation (HSCT), but the prognosis of patients with relapsed and refractory (R/R) leukemia is still poor after conventional treatment. Since FDA approved CD19 CAR-T cell (Kymriah) for the treatment of R/R B-ALL, increasing studies have been conducted on CAR-T cells for R/R ALL. Herein, we report the treatment of a patient with ALL who relapsed after allogeneic HSCT, had a complete remission (CR) to murine scFv CD19 CAR-T but relapsed 15 months later. Partial response was achieved after humanized CD19 CAR-T treatment, and the patient finally achieved diseasefree survival after sequential CD22 CAR-T treatment. By comparing the treatment results of different CAR-T cells in the same patient, this case suggests that multiple CAR-T therapies are effective and safe in intramedullary and extramedullary recurrence in the same patient, and the expansion of CAR-T cells and the release of inflammatory cytokines are positively correlated with their efficacy. However, further clinical studies with large sample sizes are still needed for further clarification. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T cell (CAR-T cell) therapy based on gene editing technology represents a significant breakthrough in personalized immunotherapy for human cancer. This strategy uses genetic modification to enable T cells to target tumor-specific antigens, attack specific cancer cells, and bypass tumor cell apoptosis avoidance mechanisms to some extent. This method has been extensively used to treat hematologic diseases, but the therapeutic effect in solid tumors is not ideal. Tumor antigen escape, treatment-related toxicity, and the immunosuppressive tumor microenvironment (TME) limit their use of it. Target selection is the most critical aspect in determining the prognosis of patients receiving this treatment. This review provides a comprehensive summary of all therapeutic targets used in the clinic or shown promising potential. We summarize CAR-T cell therapies' clinical trials, applications, research frontiers, and limitations in treating different cancers. We also explore coping strategies when encountering sub-optimal tumor-associated antigens (TAA) or TAA loss. Moreover, the importance of CAR-T cell therapy in cancer immunotherapy is emphasized. [ABSTRACT FROM AUTHOR]

Background: Breast cancer (BC) is a highly prevalent solid cancer with a high-rise infiltration of immune cells, turning it into a significant candidate for tumor-specific immunotherapies. Chimeric antigen receptor (CAR)-T cells are emerging as immunotherapeutic tools with genetically engineered receptors to efficiently recognize and attack tumor cells that express specific target antigens. Technological advancements in CAR design have provided five generations of CAR-T cells applicable to a wide range of cancer patients while boosting CAR-T cell therapy safety. However, CAR-T cell therapy is ineffective against breast cancer because of the loss of specified antigens, the immunosuppressive nature of the tumor and CAR-T cell-induced toxicities. Next-generation CAR-T cells actively pass through the tumor vascular barriers, persist for extended periods and disrupt the tumor microenvironment (TME) to block immune escape. Conclusion: CAR-T cell therapy embodies advanced immunotherapy for BC, but further pre-clinical and clinical assessments are recommended to achieve maximized efficiency and safety. [ABSTRACT FROM AUTHOR]

In the past decade, the emergence of chimeric antigen receptor (CAR) T-cell therapy has led to a cellular immunotherapy revolution against various cancers. Although CAR-T cell therapies have demonstrated remarkable efficacy for patients with certain B cell driven hematological malignancies, further studies are required to broaden the use of CAR-T cell therapy against other hematological malignancies. Moreover, treatment failure still occurs for a significant proportion of patients. CAR antigen loss on cancer cells is one of the most common reasons for cancer relapse. Additionally, immune evasion can arise due to the hostile immunosuppressive tumor microenvironment and the impaired CAR-T cells in vivo persistence. Other than direct antitumor activity, the adverse effects associated with CAR-T cell therapy are another major concern during treatment. As a newly emerged treatment approach, numerous novel preclinical studies have proposed different strategies to enhance the efficacy and attenuate CAR-T cell associated toxicity in recent years. The major obstacles that impede promising outcomes for patients with hematological malignancies during CAR-T cell therapy have been reviewed herein, along with recent advancements being made to surmount them. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the third most common cancer, with a high mortality rate and a serious impact on people’s life and health. In recent years, adoptive chimeric antigen receptor T (CAR-T) cells therapy has shown well efficacy in the treatment of hematological malignancies, but there are still many problems and challenges in solid tumors such as CRC. For example, the tumor immunosuppressive microenvironment, the low targeting of CAR-T cells, the short time of CAR-T cells in vivo, and the limited proliferation capacity of CAR-T cells, CAR-T cells can not effectively infiltrate into the tumor and so on. New approaches have been proposed to address these challenges in CRC, and this review provides a comprehensive overview of the current state of CAR-T cells therapy in CRC. [ABSTRACT FROM AUTHOR]

Advancements in adoptive cell therapy over the last four decades have revealed various new therapeutic strategies, such as chimeric antigen receptors (CARs), which are dedicated immune cells that are engineered and administered to eliminate cancer cells. In this context, CAR T-cells have shown significant promise in the treatment of hematological malignancies. However, many obstacles limit the efficacy of CAR T-cell therapy in both solid tumors and hematological malignancies. Consequently, CAR-NK and CAR-M cell therapies have recently emerged as novel therapeutic options for addressing the challenges associated with CAR T-cell therapies. Currently, many CAR immune cell trials are underway in various human malignancies around the world to improve antitumor activity and reduce the toxicity of CAR immune cell therapy. This review will describe the comprehensive literature of recent findings on CAR immune cell therapy in a wide range of human malignancies, as well as the challenges that have emerged in recent years. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the therapeutic landscape of haematological malignancies. However, resistance and relapse remain prominent limitations, and they are related to the limited persistence and efficacy of CAR T cells, downregulation or loss of tumour antigens, intrinsic resistance of tumours to death signalling, and immune suppressive microenvironment. Rational combined modality treatments are regarded as a promising strategy to further unlock the antitumor potential of CAR T cell therapy, which can be applied before CAR T cell infusion as a conditioning regimen or in ex vivo culture settings as well as concomitant with or after CAR T cell infusion. In this review, we summarize the combinatorial strategies, including chemotherapy, radiotherapy, haematopoietic stem cell transplantation, targeted therapies and other immunotherapies, in an effort to further enhance the effectiveness of this impressive therapy and benefit more patients. [ABSTRACT FROM AUTHOR]

Cell therapies have emerged as a promising new class of "living" therapeutics over the last decade and have been particularly successful for treating hematological malignancies. Increasingly, cellular therapeutics are being developed with the aim of treating almost any disease, from solid tumors and autoimmune disorders to fibrosis, neurodegenerative disorders and even aging itself. However, their therapeutic potential has remained limited due to the fundamental differences in how molecular and cellular therapies function. While the structure of a molecular therapeutic is directly linked to biological function, cells with the same genetic blueprint can have vastly different functional properties (e.g., secretion, proliferation, cell killing, migration). Although there exists a vast array of analytical and preparative separation approaches for molecules, the functional differences among cells are exacerbated by a lack of functional potency-based sorting approaches. In this context, we describe the need for next-generation single-cell profiling microtechnologies that allow the direct evaluation and sorting of single cells based on functional properties, with a focus on secreted molecules, which are critical for the in vivo efficacy of current cell therapies. We first define three critical processes for single-cell secretion-based profiling technology: (1) partitioning individual cells into uniform compartments; (2) accumulating secretions and labeling via reporter molecules; and (3) measuring the signal associated with the reporter and, if sorting, triggering a sorting event based on these reporter signals. We summarize recent academic and commercial technologies for functional single-cell analysis in addition to sorting and industrial applications of these technologies. These approaches fall into three categories: microchamber, microfluidic droplet, and lab-on-a-particle technologies. Finally, we outline a number of unmet needs in terms of the discovery, design and manufacturing of cellular therapeutics and how the next generation of single-cell functional screening technologies could allow the realization of robust cellular therapeutics for all patients. [ABSTRACT FROM AUTHOR]

Regulatory T cell (Treg) adoptive cell therapy (ACT) represents an emerging strategy for restoring immune tolerance in autoimmune diseases. Tregs are commonly purified using a CD4+CD25+CD127lo/- gating strategy, which yields a mixed population: 1) cells expressing the transcription factors, FOXP3 and Helios, that canonically define lineage stable thymic Tregs and 2) unstable FOXP3+Helios- Tregs. Our prior work identified the autoimmune disease risk-associated locus and costimulatory molecule, CD226, as being highly expressed not only on effector T cells but also, interferon-γ (IFN-γ) producing peripheral Tregs (pTreg). Thus, we sought to determine whether isolating Tregs with a CD4+CD25+CD226- strategy yields a population with increased purity and suppressive capacity relative to CD4+CD25+CD127lo/- cells. After 14d of culture, expanded CD4+CD25+CD226- cells displayed a decreased proportion of pTregs relative to CD4+CD25+CD127lo/- cells, as measured by FOXP3+Helios- expression and the epigenetic signature at the FOXP3 Treg-specific demethylated region (TSDR). Furthermore, CD226- Tregs exhibited decreased production of the effector cytokines, IFN-γ, TNF, and IL-17A, along with increased expression of the immunoregulatory cytokine, TGF-β1. Lastly, CD226- Tregs demonstrated increased in vitro suppressive capacity as compared to their CD127lo/- counterparts. These data suggest that the exclusion of CD226-expressing cells during Treg sorting yields a population with increased purity, lineage stability, and suppressive capabilities, which may benefit Treg ACT for the treatment of autoimmune diseases. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T-cells (CAR-Ts) are known as revolutionary living drugs that have turned the tables of conventional cancer treatments in certain hematologic malignancies such as B-cell acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL) by achieving US Food and Drug Administration (FDA) approval based on their successful clinical outcomes. However, this type of therapy has not seen the light of victory in the fight against solid tumors because of various restricting caveats including heterogeneous tumor antigen expression and the immunosuppressive tumor microenvironments (TME) that negatively affect the tumor-site accessibility, infiltration, stimulation, activation, and persistence of CAR-Ts. In this review, we explore strategic twists including boosting vaccines and designing implementations that can support CAR-T expansion, proliferation, and tumoricidal capacity. We also step further by underscoring novel strategies for triggering endogenous antitumor responses and overcoming the limitation of poor CAR-T tumor-tissue infiltration and the lack of definitive tumor-specific antigens. Ultimately, we highlight how these approaches can address the mentioned arduous hurdles. [ABSTRACT FROM AUTHOR]

Cancer immunotherapies utilize the capabilities of the immune system to efficiently target malignant cells. In recent years, chimeric antigen receptor (CAR) equipped T cells showed promising results against B cell lymphomas. Autologous CAR-T cells require patient-specific manufacturing and thus extensive production facilities, resulting in high priced therapies. Along with potentially severe side effects, these are the major drawbacks of CAR-T cells therapies. Natural Killer (NK) cells pose an alternative for CAR equipped immune cells. Since NK cells can be safely transferred from healthy donors to cancer patients, they present a suitable platform for an allogeneic "off-the-shelf" immunotherapy. However, administration of activated NK cells in cancer therapy has until now shown poor anti-cancer responses, especially in solid tumors. Genetic modifications such as CARs promise to enhance recognition of tumor cells, thereby increasing anti-tumor effects and improving clinical efficacy. Although the cell biology of T and NK cells deviates in many aspects, the development of CAR-NK cells frequently follows within the footsteps of CAR-T cells, meaning that T cell technologies are simply adopted to NK cells. In this review, we underline the unique properties of NK cells and their potential in CAR therapies. First, we summarize the characteristics of NK cell biology with a focus on signaling, a fine-tuned interaction of activating and inhibitory receptors. We then discuss why tailored NK cell-specific CAR designs promise superior efficacy compared to designs developed for T cells. We summarize current findings and developments in the CAR-NK landscape: different CAR formats and modifications to optimize signaling, to target a broader pool of antigens or to increase in vivo persistence. Finally, we address challenges beyond NK cell engineering, including expansion and manufacturing, that need to be addressed to pave the way for CAR-NK therapies from the bench to the clinics. [ABSTRACT FROM AUTHOR]

Advances from novel adoptive cellular therapies have yet to be fully realized for the treatment of children and young adults with solid tumors. This review discusses the strategies and preliminary results, including T-cell, NK-cell and myeloid cell-based therapies. While each of these approaches have shown some early promise, there remain challenges. These include poor trafficking to the tumor as well as a hostile tumor microenvironment with numerous immunosuppressive mechanisms which result in exhaustion of cellular therapies. We then turn our attention to new strategies proposed to address these challenges including novel clinical trials that are ongoing and in development. [ABSTRACT FROM AUTHOR]

Cell therapy is an innovative therapeutic concept where viable cells are implanted, infused, or grafted into a patient to treat impaired or malignant tissues. The term was first introduced circa the 19th century and has since resulted in multiple breakthroughs in different fields of medicine, such as neurology, cardiology, and oncology. Lately, cell and gene therapy are merging to provide cell products with additional or enhanced properties. In this context, adoptive transfer of genetically modified cytotoxic lymphocytes has emerged as a novel treatment option for cancer patients. To this day, five cell therapy products have been FDA approved, four of which for CD19-positive malignancies and one for B-cell maturation antigen (BCMA)-positive malignancies. These are personalized immunotherapies where patient T cells are engineered to express chimeric antigen receptors (CARs) with the aim to redirect the cells against tumor-specific antigens. CAR-T cell therapies show impressive objective response rates in clinical trials that, in certain instances, may reach up to 80%. However, the life-threatening side effects associated with T cell toxicity and the manufacturing difficulties of developing personalized therapies hamper their widespread use. Recent literature suggests that Natural Killer (NK) cells, may provide a safer alternative and an 'off-the-shelf' treatment option thanks to their potent antitumor properties and relatively short lifespan. Here, we will discuss the potential of NK cells in CAR-based therapies focusing on the applications of CAR-NK cells in cancer therapy and beyond. [ABSTRACT FROM AUTHOR]

The most common adverse event associated with chimeric antigen receptor T-cell therapy is cytokine release syndrome, which is characterized by fever, hypoxia, and hypotension in varying degrees of severity. In severe cases, cytokine release syndrome can result in life-threatening symptoms such as multi-organ failure. The widely accepted first-line therapy for cytokine release syndrome management is tocilizumab with or without corticosteroids, but there is very limited guidance on the proper management of patients unresponsive to this regimen. There are emerging strategies that target cytokine release syndrome through novel mechanisms, showing promise in treating or preventing severe cytokine release syndrome. Although further clinical investigation is necessary to assess the applicability of the emerging approaches, these exploratory therapies may shape the future landscape of chimeric antigen receptor T-cell induced cytokine release syndrome management. This review article provides a comprehensive overview of the current and emerging therapies for the management of chimeric antigen receptor T-cell induced cytokine release syndrome, especially cases that are refractory to tocilizumab and steroids. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T (CAR-T) cell therapy achieved extraordinary achievements results in antitumor treatments, especially against hematological malignancies, where it leads to remarkable, long-term antineoplastic effects with higher target specificity. Nevertheless, some limitations persist in autologous CAR-T cell therapy, such as high costs, long manufacturing periods, and restricted cell sources. The development of a universal CAR-T (UCAR-T) cell therapy is an attractive breakthrough point that may overcome most of these drawbacks. Here, we review the progress and challenges in CAR-T cell therapy, especially focusing on comprehensive comparison in UCAR-T cell therapy to original CAR-T cell therapy. Furthermore, we summarize the developments and concerns about the safety and efficiency of UCAR-T cell therapy. Finally, we address other immune cells, which might be promising candidates as a complement for UCAR-T cells. Through a detailed overview, we describe the current landscape and explore the prospect of UCAR-T cell therapy. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T (CART) cell immunotherapy has yielded significant clinical success in treating certain hematological malignancies. However, despite high initial response rates, most patients eventually relapse. Resistance to CART cell therapy can stem from tumor cell mutations, T cell defects, and tumor microenvironment (TME) immunosuppression. Tumor cells can downregulate target antigen expression to evade CART cell detection or mutate death receptor pathways to resist CART cell cytotoxicity. Patient T cells can be intrinsically defective, and CART cells often undergo exhaustion. The TME is abundant with immunosuppressive cells and factors which contribute to suboptimal CART cell activity. Collectively, issues originating in tumor cells, T cells, and the TME present significant hurdles to long-term remission after CART cell therapy. Various strategies to combat CART cell resistance have shown promise in preclinical studies and early clinical trials and are crucial to achieving durable responses. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma is one of the most common malignancies globally. It not only has a hidden onset but also progresses rapidly. Most HCC patients are already in the advanced stage of cancer when they are diagnosed, and have even lost the opportunity for surgical treatment. As an inflammation-related tumor, the immunosuppressive microenvironment of HCC can promote immune tolerance through a variety of mechanisms. Immunotherapy can activate tumor-specific immune responses, which brings a new hope for the treatment of HCC. At the present time, main immunotherapy strategies of HCC include immune checkpoint inhibitors, tumor vaccines, adoptive cell therapy, and so on. This article reviews the application and research progress of immune checkpoint inhibitors, tumor vaccines, and adoptive cell therapy in the treatment of HCC. [ABSTRACT FROM AUTHOR]

CAR-T-cell therapy against MM currently shows promising results, but usually with serious toxicities. CAR-NK cells may exert less toxicity when redirected against resistant myeloma cells. CARs can be designed through the use of receptors, such as NKG2D, which recognizes a wide range of ligands to provide broad target specificity. Here, we test this approach by analyzing the antitumor activity of activated and expanded NK cells (NKAE) and CD45RA− T cells from MM patients that were engineered to express an NKG2D-based CAR. NKAE cells were cultured with irradiated Clone9.mbIL21 cells. Then, cells were transduced with an NKG2D-4-1BB-CD3z-CAR. CAR-NKAE cells exhibited no evidence of genetic abnormalities. Although memory T cells were more stably transduced, CAR-NKAE cells exhibited greater in vitro cytotoxicity against MM cells, while showing minimal activity against healthy cells. In vivo, CAR-NKAE cells mediated highly efficient abrogation of MM growth, and 25% of the treated mice remained disease free. Overall, these results demonstrate that it is feasible to modify autologous NKAE cells from MM patients to safely express a NKG2D-CAR. Additionally, autologous CAR-NKAE cells display enhanced antimyeloma activity demonstrating that they could be an effective strategy against MM supporting the development of NKG2D-CAR-NK-cell therapy for MM. [ABSTRACT FROM AUTHOR]

Engineered T cell therapies such as chimeric antigen receptor (CAR) expressing T cells (CAR-T cells) have great potential to treat many human diseases; however, inflammatory toxicities associated with these therapies present safety risks and can greatly limit its widespread use. This article briefly reviews our current understanding of mechanisms for inflammatory toxicities during CAR T-cell therapy, current strategies for management and mitigation of these risks and highlights key areas of knowledge gap for future research. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR)-T cell therapy is an innovative approach to immune cell therapy that works by modifying the T cells of a patient to express the CAR protein on their surface, and thus induce their recognition and destruction of cancer cells. CAR-T cell therapy has shown some success in treating hematological tumors, but it still faces a number of challenges in the treatment of solid tumors, such as antigen selection, tolerability and safety. In response to these issues, studies continue to improve the design of CAR-T cells in pursuit of improved therapeutic efficacy and safety. In the future, CAR-T cell therapy is expected to become an important cancer treatment, and may provide new ideas and strategies for individualized immunotherapy. The present review provides a comprehensive overview of the principles, clinical applications, therapeutic efficacy and challenges of CAR-T cell therapy. [ABSTRACT FROM AUTHOR]

The switchable chimeric antigen receptors (CARs) have shown many advantages in CAR T-cell therapy. However, human primary T-cells are required to evaluate antigen-specific adaptors by IFN-γ assay or FACS analysis, which limits the throughput of adaptor screening. A sensitive and robust CD16-CAR Jurkat NFAT-eGFP reporter system has been developed to assess the therapeutic efficacy of antibody-targeted CAR-T-cell by effectively evaluating the T-cell activation by various tumor cells and the impact of immune checkpoint inhibitor antibodies. This reporter system facilitates the screening of targeted antibodies in a high throughput manner for the development of improved T-cell immunotherapy. [ABSTRACT FROM AUTHOR]

Successful CAR T cell therapy for the treatment of solid tumors requires exemplary CAR T cell expansion, persistence and fitness, and the ability to target tumor antigens safely. Here we address this constellation of critical attributes for successful cellular therapy by using integrated technologies that simplify development and derisk clinical translation. We have developed a CAR-CD19 T cell that secretes a CD19-anti-Her2 bridging protein. This cell therapy strategy exploits the ability of CD19-targeting CAR T cells to interact with CD19 on normal B cells to drive expansion, persistence and fitness. The secreted bridging protein potently binds to Her2-positive tumor cells, mediating CAR-CD19 T cell cytotoxicity in vitro and in vivo. Because of its short half-life, the secreted bridging protein will selectively accumulate at the site of highest antigen expression, ie. at the tumor. Bridging proteins that bind to multiple different tumor antigens have been created. Therefore, antigen-bridging CAR-CD19 T cells incorporate critical attributes for successful solid tumor cell therapy. This platform can be exploited to attack tumor antigens on any cancer. [ABSTRACT FROM AUTHOR]

CAR-T cell therapy is effective for hematologic malignancies. However, considerable numbers of patients relapse after the treatment, partially due to poor expansion and limited persistence of CAR-T cells in vivo. Here, we demonstrate that human CAR-T cells polarized and expanded under a Th9-culture condition (T9 CAR-T) have an enhanced antitumor activity against established tumors. Compared to IL2-polarized (T1) cells, T9 CAR-T cells secrete IL9 but little IFN-γ, express central memory phenotype and lower levels of exhaustion markers, and display robust proliferative capacity. Consequently, T9 CAR-T cells mediate a greater antitumor activity than T1 CAR-T cells against established hematologic and solid tumors in vivo. After transfer, T9 CAR-T cells migrate effectively to tumors, differentiate to IFN-γ and granzyme-B secreting effector memory T cells but remain as long-lived and hyperproliferative T cells. Our findings are important for the improvement of CAR-T cell-based immunotherapy for human cancers. Antigen-specific IL9-secreting CD4 Th9 and CD8 Tc9 cells have been previously characterized for their anti-tumour properties. Here, the authors show that ex vivo polarized Th9/Tc9 human CAR-T cells display increased anti-tumor activity in pre-clinical haematological and solid cancer models compared to conventional IL-2 activated CAR-T cells. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy represents the most dynamic field of biomedical research currently, with thoracic immuno-oncology as a forerunner. PD-(L)1 inhibitors are already part of standard first-line treatment for both non-small-cell and small-cell lung cancer, while unprecedented 5-year survival rates of 15–25% have been achieved in pretreated patients with metastatic disease. Evolving strategies are mainly aiming for improvement of T-cell function, increase of immune activation in the tumor microenvironment (TME), and supply of tumor-reactive lymphocytes. Several novel therapeutics have demonstrated preclinical efficacy and are increasingly used in rational combinations within clinical trials. Two overarching trends dominate: extension of immunotherapy to earlier disease stages, mainly as neoadjuvant treatment, and a shift of focus towards multivalent, individualized, mutatome-based antigen-specific modalities, mainly adoptive cell therapies and cancer vaccines. The former ensures ample availability of treated and untreated patient samples, the latter facilitates deeper mechanistic insights, and both in combination build an overwhelming force that is accelerating progress and driving the greatest revolution cancer medicine has seen so far. Today, immune modulation represents the most potent therapeutic modality in oncology, the most important topic in clinical and translational cancer research, and arguably our greatest, meanwhile justified hope for achieving cure of pulmonary neoplasms and other malignancies in the next future. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T (CART) cell immunotherapy has been remarkably successful in treating certain relapsed/refractory hematological cancers. However, CART cell therapy is also associated with toxicities which present an obstacle to its wider adoption as a mainstay for cancer treatment. The primary toxicities following CART cell administration are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). New insights into the mechanisms of these toxicities have spurred novel treatment options. In this review, we summarize the available literature on the clinical manifestations, mechanisms, and treatments of CART-associated CRS and ICANS. [ABSTRACT FROM AUTHOR]

Chimeric Antigen Receptor (CAR) T cell therapy targeting CD19 has introduced a paradigmatic shift in our treatment approach for advanced B cell malignancies. A major advance has been in the field of pediatric B-ALL where complete responses have been achieved across clinical trials with rates of 65–90% in the relapsed/refractory setting. These striking early response rates led to FDA approval of Tisagenlecleucel, CD19-specific CAR T cells, in August 2017. With broadened access and available longitudinal follow up, it is imperative to study the true durability of CAR-mediated responses and establish long-term relapse free and survival outcomes following CAR therapy. Phase I and II clinical trials have reported event-free survival rates of 50% at 1 year following CD19-CAR infusion in children and young adults with B-ALL. Here, we review some of the major challenges accounting for the discrepancy between early response rates and long term outcomes. In specific, relapse with CD19+ or CD19– disease has emerged as a major challenge following CD19-CAR T cell therapy. Related, is the issue of CAR persistence which has been shown to correlate with long-term outcomes. We highlight select efforts to optimize clinical strategies and CAR design to promote enhanced persistence. To date, we do not have robust predictors of response durability and relapse following CAR therapy. The ability to identify patients at risk of relapse in an a priori manner may introduce an interventional window to consolidate CAR-mediated remissions and enhance response durability. This review highlights the need to bridge the gap between the remarkable early complete responses achieved with CD19-CAR T cell therapy and the long-term survival outcomes. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T cell therapies have demonstrated remarkable efficacy for the treatment of hematological malignancies. However, in patients with solid tumors, objective responses to CAR-T cell therapy remain sporadic and transient. A major obstacle for CAR-T cells is the intrinsic ability of tumors to evade immune responses. Advanced solid tumors are largely composed of desmoplastic stroma and immunosuppressive modulators, and characterized by aberrant cell proliferation and vascularization, resulting in hypoxia and altered nutrient availability. To mount a curative response after infusion, CAR-T cells must infiltrate the tumor, recognize their cognate antigen and perform their effector function in this hostile tumor microenvironment, to then differentiate and persist as memory T cells that confer long-term protection. Fortunately, recent advances in synthetic biology provide a wide set of tools to genetically modify CAR-T cells to overcome some of these obstacles. In this review, we provide a comprehensive overview of the key tumor intrinsic mechanisms that prevent an effective CAR-T cell antitumor response and we discuss the most promising strategies to prevent tumor escape to CAR-T cell therapy. [ABSTRACT FROM AUTHOR]

Introduction: Since epithelial growth factor receptor (EGFR) overexpression is linked to a variety of malignancies, it is an attractive target for immune therapy including chimeric antigen receptor (CAR)-engineered T cells. Unfortunately, CAR T cell therapy harbors the risk of severe, even life-threatening side effects. Adaptor CAR T cell platforms such as the previously described UniCAR system might be able to overcome these problems. In contrast to conventional CARs, UniCAR T cells are per se inert. Their redirection towards target cells occurs only in the presence of a tumor-specific target molecule (TM). TMs are bifunctional molecules being able to recognize a tumor-associated antigen and to cross-link the CAR T cell via a peptide epitope recognized by the UniCAR domain. Materials and Methods: Here, we compare αEGFR TMs: a nanobody (nb)-based αEGFR TM derived from the camelid αEGFR antibody 7C12 with a murine and humanized single-chain fragment variable (scFv) based on the clinically used antibody Cetuximab®. Results: In principle, both the nb- and scFv-based TM formats are able to redirect UniCAR T cells to eliminate EGFR-expressing tumor cells in an antigen-specific and TM-dependent manner. However, the scFv-based αEGFR TM was significantly superior to the nb-based TM especially with respect to lysis of tumor cells. Discussion: Improved efficiency of the scFv-based TM allowed the redirection of UniCAR T cells towards tumor cells expressing high as well as low EGFR levels in comparison to nb-based αEGFR TMs. [ABSTRACT FROM AUTHOR]

Research on CAR T cells has achieved enormous progress in recent years. After the impressive results obtained in relapsed and refractory B-cell acute lymphoblastic leukemia and aggressive B-cell lymphomas, two constructs, tisagenlecleucel and axicabtagene ciloleucel, were approved by FDA. The role of CAR T cells in the treatment of B-cell disorders, however, is rapidly evolving. Ongoing clinical trials aim at comparing CAR T cells with standard treatment options and at evaluating their efficacy earlier in the disease course. The use of CAR T cells is still limited by the risk of relevant toxicities, most commonly cytokine release syndrome and neurotoxicity, whose management has nonetheless significantly improved. Some patients do not respond or relapse after treatment, either because of poor CAR T-cell expansion, lack of anti-tumor effects or after the loss of the target antigen on tumor cells. Investigators are trying to overcome these hurdles in many ways: by testing constructs which target different and/or multiple antigens or by improving CAR T-cell structure with additional functions and synergistic molecules. Alternative cell sources including allogeneic products (off-the-shelf CAR T cells), NK cells, and T cells obtained from induced pluripotent stem cells are also considered. Several trials are exploring the curative potential of CAR T cells in other malignancies, and recent data on multiple myeloma and chronic lymphocytic leukemia are encouraging. Given the likely expansion of CAR T-cell indications and their wider availability over time, more and more highly specialized clinical centers, with dedicated clinical units, will be required. Overall, the costs of these cell therapies will also play a role in the sustainability of many health care systems. This review will focus on the major clinical trials of CAR T cells in B-cell malignancies, including those leading to the first FDA approvals, and on the new settings in which these constructs are being tested. Besides, the most promising approaches to improve CAR T-cell efficacy and early data on alternative cell sources will be reviewed. Finally, we will discuss the challenges and the opportunities that are emerging with the advent of CAR T cells into clinical routine. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T cells targeting CD19 have been successful treating patients with relapsed/refractory B cell acute lymphoblastic leukemia (ALL) and B cell lymphomas. However, relapse after CAR T cell therapy is still a challenge. In addition, preclinical and early clinical studies targeting acute myeloid leukemia (AML) have not been as successful. This can be attributed in part to the presence of an AML microenvironment that has a dampening effect on the antitumor activity of CAR T cells. The AML microenvironment includes cellular interactions, soluble environmental factors, and structural components. Suppressive immune cells including myeloid derived suppressor cells and regulatory T cells are known to inhibit T cell function. Environmental factors contributing to T cell exhaustion, including immune checkpoints, anti-inflammatory cytokines, chemokines, and metabolic alterations, impact T cell activity, persistence, and localization. Lastly, structural factors of the bone marrow niche, secondary lymphoid organs, and extramedullary sites provide opportunities for CAR T cell evasion by AML blasts, contributing to treatment resistance and relapse. In this review we discuss the effect of the AML microenvironment on CAR T cell function. We highlight opportunities to enhance CAR T cell efficacy for AML through manipulating, targeting, and evading the anti-inflammatory leukemic microenvironment. [ABSTRACT FROM AUTHOR]