Search

Chimeric antigen receptor T‐cell (CAR‐T) therapy is becoming an effective technique for the treatment of patients with relapsed/refractory hematologic malignancies. After analyzing patients with tumor progression and sustained remission after CAR‐T cell therapy, many factors were found to be associated with the efficacy of CAR‐T therapy. This paper reviews the factors affecting the effect of CAR‐T such as tumor characteristics, tumor microenvironment and immune function of patients, CAR‐T cell structure, construction method and in vivo expansion values, lymphodepletion chemotherapy, and previous treatment, and provides a preliminary outlook on the corresponding therapeutic strategies. [ABSTRACT FROM AUTHOR]

Tumor immunotherapy, represented by immune checkpoint blocking and chimeric antigen receptor (CAR) T cell therapy, has achieved promising results in clinical applications. However, it faces challenges that hinder its further development, such as limited response rates and poor tumor permeability. The efficiency of tumor immunotherapy is also closely linked to the structure and function of the immune microenvironment where the tumor resides. Recently, nanoparticle‐based tumor immune microenvironment (TIME) modulation strategies have attracted a great deal of attention in cancer immunotherapy. This is primarily due to the distinctive physical characteristics of nanoparticles, which enable them to effectively infiltrate the TIME and selectively modulate its key constituents. This paper reviews recent advances in nanoparticle engineering to improve anti‐cancer immunotherapy. Emerging nanoparticle‐based approaches for modulating immune cells, tumor stroma, cytokines and immune checkpoints are discussed, aiming to overcome current challenges in the clinic. In addition, integrating immunotherapy with various treatment modalities such as chemotherapy and photodynamic therapy can be facilitated through the utilization of nanoparticles, thereby enhancing the efficacy of cancer treatment. The future challenges and opportunities of using nanomaterials to reeducate the suppressive immune microenvironment of tumors are also discussed, with the aim of anticipating further advancements in this growing field. [ABSTRACT FROM AUTHOR]

Heart diseases remain the primary cause of human mortality in the world. Although conventional therapeutic opportunities fail to halt or recover cardiac fibrosis, the promising clinical results and therapeutic efficacy of engineered chimeric antigen receptor (CAR) T cell therapy show several advancements. However, the current models of CAR‐T cells need further improvement since the T cells are associated with the triggering of excessive inflammatory cytokines that directly affect cardiac functions. Thus, the current study highlights the critical function of heart immune cells in tissue fibrosis and repair. The study also confirms CAR‐T cell as an emerging therapeutic for treating cardiac fibrosis, explores the current roadblocks to CAR‐T cell therapy, and considers future outlooks for research development. Significance statement: The necessity and importance of chimeric antigen receptor (CAR) T cells and their therapeutic efficiency in treating diseases other than cancer, mainly cardiovascular diseases, have emerged in recent years. However, there is still room for advancement in the current models of CAR‐T cell therapy. This paper highlights the evolution and roadblocks of CAR‐T technology at different levels, from technical concerns to clinical outcomes, in an attempt to improve the therapeutic efficiency of CAR‐T cell therapy in this area. [ABSTRACT FROM AUTHOR]

According to the latest evidence, the microbial metabolite Urolithin A (UA), known for its role in promoting cellular health, modulates CD8+ T cell‐mediated antitumor activity. However, the direct target protein of UA and its underlying mechanism remains unclear. Here, this research identifies ERK1/2 as the specific target crucial for UA‐mediated CD8+ T cell activation. Even at low doses, UA markedly enhances the persistence and effector functions of primary CD8+ cytotoxic T lymphocytes (CTLs) and human chimeric antigen receptor (CAR) T cells both in vitro and in vivo. Mechanistically, UA interacts directly with ERK1/2 kinases, enhancing their activation and subsequently facilitating T cell activation by engaging ULK1. The UA‐ERK1/2‐ULK1 axis promotes autophagic flux in CD8+ CTLs, enhancing cellular metabolism and maintaining reactive oxygen species (ROS) levels, as evidenced by increased oxygen consumption and extracellular acidification rates. UA‐treated CD8+ CTLs also display elevated ATP levels and enhanced spare respiratory capacity. Overall, UA activates ERK1/2, inducing autophagy and metabolic adaptation, showcasing its potential in tumor immunotherapy and interventions for diseases involving ERKs. [ABSTRACT FROM AUTHOR]

Background: The efficacy of CD22 or CD19 chimeric antigen receptor T (CAR‐T) cells in the management of acute lymphoblastic leukemia (ALL) and non‐Hodgkin lymphoma (NHL) was observed. Because antigen loss and lack of CAR‐T‐cell persistence are the leading causes of progressive disease following single‐antigen targeting, we evaluated CD22/CD19 dual‐targeting CAR‐T‐cell therapy efficacy and safety in relapsed/refractory B‐cell malignancies. Methods: The Web of Science, PubMed, Cochrane, and Embase databases were searched until July 2022. Patients confirmed with any relapsed/refractory B‐cell hematological malignancies were included regardless of age, gender, or ethnicity, receiving CD22 and CD19‐dual‐targeting CAR‐T‐cell therapy. The studies conducted on patients with coexisting other cancer were excluded. We used random‐effect models to explore the outcome, and heterogeneity was investigated by subgroup analysis. Results: Fourteen studies (405 patients) were included. The pooled overall response (OR) and complete remission (CR) were 97% and 93%, respectively, for ALL patients. The 1‐year proportions of overall survival (OS) and progression‐free survival (PFS) were 70% and 49%, respectively. For NHL, OR occurred in 85% of patients, and 57% experienced CR. The results illustrated that the 1‐year OS and 1‐year PFS were 77% and 65%, respectively. The subgroup analysis showed that the dual‐targeting modality achieved higher CR in the following cases: coadministration of CD22/CD19‐CAR‐T cells and third‐generation CAR‐T cells combined with ASCT and BEAM pretreatment. The ALL and NHL groups seemed similar in treatment‐related toxicity: all grade cytokine release syndrome (CRS), severe CRS, and neurotoxicity occurred in 86%, 7%, and 12% of patients, respectively. Conclusions: Our meta‐analysis demonstrated that the CD22/CD19 dual‐targeting CAR‐T‐cell strategy has high efficiency with tolerable adverse effects in B‐cell malignancies. This meta‐analysis demonstrates very high responses by using dual‐targeting CAR‐T therapy with a tolerable safety profile in treating R/R B‐cell hematologic malignancies.Although further studies are warranted, these findings may help immunologists and clinicians design proper CAR structure and/or combine with important target therapies to improve clinical outcomes. [ABSTRACT FROM AUTHOR]

The robust and stable expression of CD38 in T‐cell acute lymphoblastic leukemia (T‐ALL) blasts makes CD38 chimeric antigen receptor (CAR)‐T/natural killer (NK) a potential therapy for T‐ALL. However, CD38 expression in normal T/NK cells causes fratricide of CD38 CAR‐T/NK cells. Here a "2‐in‐1" gene editing strategy is developed to generate fratricide‐resistant locus‐specific CAR‐T/NK cells. CD38‐specific CAR is integrated into the disrupted CD38 locus by CRISPR/Cas9, and CAR is placed under the control of either endogenous CD38 promoter (CD38KO/KI) or exogenous EF1α promoter (CD38KO/KIEF1α). CD38 knockout reduces fratricide and allows the expansion of CAR‐T cells. Meanwhile, CD38KO/KIEF1α results in higher CAR expression than CD38KO/KI in both CAR‐T and CAR‐NK cells. In a mouse T‐ALL model, CD38KO/KIEF1α CAR‐T cells eradicate tumors better than CD38KO/KI CAR‐T cells. Surprisingly, CD38KO/KI CAR‐NK cells show superior tumor control than CD38KO/KIEF1α CAR‐NK cells. Further investigation reveals that endogenous regulatory elements in NK cells lead to higher expression of CD38 CAR than in T cells, and the expression levels of CAR affect the therapeutic outcome of CAR‐T and CAR‐NK cells differently. Therefore, these results support the efficacy of CD38 CAR‐T/NK against T‐ALL and demonstrate that the "2‐in‐1" strategy can resolve fratricide and enhance tumor eradication, paving the way for clinical translation. [ABSTRACT FROM AUTHOR]

Summary: Mechanisms of prolonged cytopenia (PC) after chimeric antigen receptor (CAR) T‐cell therapy, an emerging therapy for relapsed or refractory diffuse large B‐cell lymphoma, remain elusive. Haematopoiesis is tightly regulated by the bone marrow (BM) microenvironment, called the 'niche'. To investigate whether alterations in the BM niche cells are associated with PC, we analysed CD271+ stromal cells in BM biopsy specimens and the cytokine profiles of the BM and serum obtained before and on day 28 after CAR T‐cell infusion. Imaging analyses of the BM biopsy specimens revealed that CD271+ niche cells were severely impaired after CAR T‐cell infusion in patients with PC. Cytokine analyses after CAR T‐cell infusion showed that CXC chemokine ligand 12 and stem cell factor, niche factors essential for haematopoietic recovery, were significantly decreased in the BM of patients with PC, suggesting reduced niche cell function. The levels of inflammation‐related cytokines on day 28 after CAR T‐cell infusion were consistently high in the BM of patients with PC. Thus, we demonstrate for the first time that BM niche disruption and sustained elevation of inflammation‐related cytokines in the BM following CAR T‐cell infusion are associated with subsequent PC. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T‐cells (CAR‐T) are widely used for the treatment of relapsed/refractory diffuse large B cell lymphoma (DLBCL). The data for CAR‐T cell therapy in patients with extra‐nodal (EN) lymphoma is restricted. We included 126 consecutive patients with DLBCL treated with commercially available CAR‐T cells (tisagenlecleucel, n = 100, 79.4% and axicabtagene ciloleucel, n = 26, 20.6%). At lymphodepletion, 72 of 126 (57%) patients had EN disease, 42 of 126 (33%) patients had nodal disease (ND)‐only and 12 of 126 (10%) showed no disease assessed by PET‐CT. There were no significant differences in CAR‐T related toxicities and in the median Progression free survival (PFS) between EN patients and ND (10.76 [95% CI: 7.8–13.6] vs. 14.1 [95% CI: 10–18.1] months, p =.126). Similarly, median overall survival (OS) was not significantly different (15.36 [95% CI 12.5–18.2] vs. 18.4 [95% CI 14.8–22.1] months, p =.100). Subgroup analysis according to the number of EN involved sites showed that median PFS and OS were significantly higher in patients with <3 EN sites (12.3 months [95% CI 9–15.5] vs. 4.28 months [95% CI 0.6–7.9], p =.010) compared to patients with >2 EN sites, respectively (16.5 months [95% CI 13.4–19.6] vs. 8.7 months [95% CI 4.6–12.8], p =.05). In multivariate cox regression analysis, increased number sites of EN disease and high lactate dehydrogenase (LDH) at lymphodepletion negatively impacted PFS (p =.021 and <.001, respectively), while sex, type of product administered, age and performance status did not predict PFS and OS. Of note, all the patients with involvement of gastrointestinal tract (n = 9), urinary tract (n = 9), or pharynx (n = 3) at lymphodepletion, progressed or had an early relapse. In conclusions, patients with >2 EN sites at lymphodepletion have significantly worse clinical outcomes compared to patients with <3 EN sites. Patients with specific sites of EN disease may demonstrate grim prognosis. [ABSTRACT FROM AUTHOR]

Despite substantial advancements in development of cancer treatments, lack of standardized and physiologically‐relevant in vitro testing platforms limit the early screening of anticancer agents. A major barrier is the complex interplay between the tumor microenvironment and immune response. To tackle this, a dynamic‐flow based 3D bioprinted multi‐scale vascularized breast tumor model, responding to chemo and immunotherapeutics is developed. Heterotypic tumors are precisely bioprinted at pre‐defined distances from a perfused vasculature, exhibit tumor angiogenesis and cancer cell invasion into the perfused vasculature. Bioprinted tumors treated with varying dosages of doxorubicin for 72 h portray a dose‐dependent drug response behavior. More importantly, a cell based immune therapy approach is explored by perfusing HER2‐targeting chimeric antigen receptor (CAR) modified CD8+ T cells for 24 or 72 h. Extensive CAR‐T cell recruitment to the endothelium, substantial T cell activation and infiltration to the tumor site, resulted in up to ≈70% reduction in tumor volumes. The presented platform paves the way for a robust, precisely fabricated, and physiologically‐relevant tumor model for future translation of anti‐cancer therapies to personalized medicine. [ABSTRACT FROM AUTHOR]

Cell‐based immunotherapy, for example, chimeric antigen receptor T (CAR‐T) cell immunotherapy, has revolutionized cancer treatment, particularly for blood cancers. However, factors such as insufficient T cell tracking, tumour heterogeneity, inhibitory tumour microenvironment (TME) and T cell exhaustion limit the broad application of CAR‐based immunotherapy for solid tumours. In particular, the TME is a complex and evolving entity, which is composed of cells of different types (e.g., cancer cells, immune cells and stromal cells), vasculature, soluble factors and extracellular matrix (ECM), with each component playing a critical role in CAR‐T immunotherapy. Thus, developing approaches to mitigate the inhibitory TME factors is critical for future success in applying CAR‐T cells for solid tumour treatment. Accordingly, understanding the bilateral interaction of CAR‐T cells with the TME is in pressing need to pave the way for more efficient therapeutics. In the following review, we will discuss TME‐associated aspects with an emphasis on T cell trafficking, ECM barriers, abnormal vasculature, solid tumour heterogenicity and immune suppressive microenvironment. We will then summarize current engineering strategies to overcome the challenges posed by the TME‐associated factors. Lastly, the future directions for engineering efficient CAR‐T cells for solid tumour therapy will be discussed. [ABSTRACT FROM AUTHOR]

Genetically arming new chimeric antigen receptors (CARs) on T cells is a prevalent method to fulfill CAR‐T immunotherapy. However, this approach fails to completely address the poor infiltration, complex immunosuppressive tumor microenvironment (ITM), and insufficient immune cells, which are recognized as the three dominant hurdles to discouraging the trafficking and persistence of CAR‐T and immune checkpoint blockade (ICB) immunotherapies against solid tumors. To address the three hurdles, a sonoimmunity‐engineered nanoplatform is designed in which a rattle‐type‐structured carrier enables intraparticle‐double‐scattering to generate massive reactive oxygen species (ROS) during the sonodynamic process. Abundant ROS accumulation can directly kill tumor cells, release antigens, and activate systematic immune responses for expanding effector T or CAR‐T cells, while alleviating ITM via immunosuppressive macrophage polarization and reduction in pro‐tumorigenic cytokine secretion. Furthermore, the co‐loaded phosphodiesterase‐5 inhibitors release nitric oxide (NO) to impel vascular normalization and open the infiltration barrier (IB) for allowing more T cells to enter into the tumor. Systematic experiments demonstrate the feasibility of such intraparticle‐double‐scattering‐decoded sonogenetics in the sonoimmunity‐engineered nanoplatforms for expanding effector T or CAR‐T cells, thereby promoting their infiltration into tumors and alleviating ITM. These compelling actions lead to excellent CAR‐T and ICB immunotherapies against solid tumors with repressed tumor metastasis. [ABSTRACT FROM AUTHOR]

Advances in immuno‐oncology have provided a variety of novel therapeutics that harness the innate immune system to identify and destroy neoplastic cells. It is noteworthy that acceptable safety profiles accompany the development of these targeted therapies, which result in efficacious cancer treatment with higher survival rates and lower toxicities. Adoptive cellular therapy (ACT) has shown promising results in inducing sustainable remissions in patients suffering from refractory diseases. Two main types of ACT include engineered Chimeric Antigen Receptor (CAR) T cells and T cell receptor (TCR) T cells. The application of these immuno‐therapies in the last few years has been successful and has demonstrated a safe and rapid treatment regimen for solid and non‐solid tumors. The current review presents an insight into the clinical pharmacology aspects of immuno‐therapies, especially CAR‐T cells. Here, we summarize the current knowledge of TCR and CAR‐T cell immunotherapy with particular focus on the structure of CAR‐T cells, the effects and toxicities associated with these therapies in clinical trials, risk mitigation strategies, dose selection approaches, and cellular kinetics. Finally, the quantitative approaches and modeling techniques used in the development of CAR‐T cell therapies are described. [ABSTRACT FROM AUTHOR]

Summary: Treatment with high‐dose chemotherapy followed by autologous stem cell transplantation (ASCT) is considered standard of care (SOC) second‐line treatment for relapsed or refractory large B‐cell lymphoma (LBCL). However, outcomes remain suboptimal. A systematic review and meta‐analysis of randomised controlled trials comparing efficacy and safety of SOC versus chimeric antigen receptor T‐cell (CAR‐T) therapy as second‐line for patients with LBCL refractory or relapsing within 12 months. Outcomes included overall survival (OS), event‐free survival (EFS), overall response rate (ORR) and safety. Three trials published in 2021 (involving 865 participants) fulfilled the eligibility criteria. EFS as well as OS were significantly improved with CAR‐T therapy as compared to SOC, hazard ratio (HR) 0.57 (95% confidence interval [CI] 0.49–0.68) and HR 0.77 (95% CI 0.60–0.98) respectively. CAR‐T therapy was associated with significantly better ORR, relative risk (RR) 1.55 (95% CI 1.12–2.13, p = 0.001). The risk of Grade III/IV adverse event was comparable between the two arms, RR 1.03 (95% CI 0.93–1.14). In summary, CAR‐T therapy has superior outcomes as compared to SOC in patients with LBCL refractory or relapsing within 12 months, without excess of toxicity. Longer follow‐up is needed to confirm these results and determine the optimal sequencing of CAR‐T therapy in the management of LBCL. [ABSTRACT FROM AUTHOR]

Advances made in chimeric antigen receptor (CAR) T cell therapy have revolutionized the treatment and management of certain cancers. Currently, B cell malignancies have been among the few cancers to which CAR T cells have shown persistent and resilient anti‐tumor responses. A growing body of evidence suggests that the persistence of CAR T cells within patients following infusion is linked to the mitochondrial fitness of the CAR T cell, which could affect clinical outcomes. Analysis of CAR T cells from patients undergoing successful treatment has shown an increase in mitochondrial mass and fusion events, and a reduction in aerobic metabolism, highlighting the importance of mitochondria in CAR T cell function. Consequently, there has been recent interest and investment in approaches that focus on mitochondrial programming. In this regard, miRNAs are promising agents in mitochondrial reprogramming for several reasons: (1) natural and artificial miRNAs are non‐immunogenic, (2) one miRNA can simultaneously modulate the expression of multiple genes within a pathway, (3) the small size of a sequence required for producing mature miRNA is ideal for use in viral vectors and (4) different precursor miRNAs (pre‐miRNAs) hairpins can be incorporated into a polycistronic miRNA cluster to create a miRNA cocktail. In this perspective, we describe the latest genetic engineering strategies that can be used to achieve the optimal expression of candidate miRNAs alongside a CAR construct. In addition, we include an in silico analysis of rational candidate miRNAs that could promote the mitochondrial fitness of CAR T cells. [ABSTRACT FROM AUTHOR]

Although chimeric antigen receptor (CAR) T cells have demonstrated significant promise in suppressing hematopoietic cancers, their applications in treating solid tumors have been limited by onset of CAR T cell exhaustion that accompanies continuous CAR T cell exposure to tumor antigen. To address this limitation, we have exploited the abilities of recently designed universal CARs to bind fluorescein and internalize a fluorescein‐TLR7 agonist conjugate by CAR‐mediated endocytosis. We demonstrate here that anti‐fluorescein CAR‐mediated uptake of a fluorescein‐TLR7‐3 conjugate can reactivate exhausted CAR T cells, leading to dramatic reduction in T cell exhaustion markers (PD‐1+Tim‐3+) and shrinkage of otherwise resistant tumors without inducing systemic activation of the immune system. We conclude that CAR T cell exhaustion can be reversed by administration of a CAR‐targeted TLR7 agonist, thereby enabling the CAR T cells to successfully treat solid tumors without incurring the systemic toxicity that commonly accompanies administration of nontargeted TLR7 agonists. [ABSTRACT FROM AUTHOR]

As a revolutionary cancer treatment, the chimeric antigen receptor (CAR) T cell therapy suffers from complications such as cytokine release syndromes and T cell exhaustion. Their mitigation desires controllable activation of CAR‐T cells that is achievable through regulatory display of CARs. By embedding the hepatitis C virus NS3 protease (HCV‐NS3) between the single‐chain variable fragment (scFv) and the hinge domain, we showed that the display of anti‐CD19 scFv on CAR‐T cells was positively correlated to the presence of a clinical HCV‐NS3 inhibitor asunaprevir (ASV). This novel CAR design that allows the display of anti‐CD19 scFv in the presence of ASV and its removal in the absence of ASV creates a practically reversible chemical switch. We demonstrated that the intact CAR on T cells can be repeatedly turned on and off by controlling the presence of ASV in a dose dependent manner both in vitro and in vivo, which enables delicate modulation of CAR‐T activation during cancer treatment. [ABSTRACT FROM AUTHOR]

The development of gene editing technologies over the past years has allowed the precise and efficient insertion of transgenes into the genome of various cell types. Knock‐in approaches using homology‐directed repair and designer nucleases often rely on viral vectors, which can considerably impact the manufacturing cost and timeline of gene‐edited therapeutic products. An attractive alternative would be to use naked DNA as a repair template. However, such a strategy faces challenges such as cytotoxicity from double‐stranded DNA (dsDNA) to primary cells. Here, we sought to study the kinetics of transcription activator‐like effector nuclease (TALEN)‐mediated gene editing in primary T cells to improve nonviral gene knock‐in. Harnessing this knowledge, we developed a rapid and efficient gene insertion strategy based on either short single‐stranded oligonucleotides or large (2 Kb) linear naked dsDNA sequences. We demonstrated that a time‐controlled two‐step transfection protocol can substantially improve the efficiency of nonviral transgene integration in primary T cells. Using this approach, we achieved modification of up to ˜ 30% of T cells when inserting a chimeric antigen receptor (CAR) at the T‐cell receptor alpha constant region (TRAC) locus to generate 'off‐the shelf' CAR‐T cells. [ABSTRACT FROM AUTHOR]

Despite remarkable advances in different types of cancer therapies, an effective therapeutic strategy is still a major and significant challenge. One of the most promising approaches in this regard is immunotherapy, which takes advantage of the patients' immune system; however, the many mechanisms that cancerous cells harbor to extend their survival make it impossible to gain perfect eradication of tumors. The response rate to cancer immunotherapies, especially checkpoint inhibitors and adoptive T cell therapy, substantially differs in various cancer types with the highest rates in advanced melanoma and non‐small cell lung cancer. Indeed, the lack of response in many tumors indicates primary resistance that can originate from either tumor cells (intrinsic) or tumor microenvironment (extrinsic). On the other hand, some tumors show an initial response to immunotherapy followed by relapse in few months (acquired resistance). Understanding the underlying molecular mechanisms of immunotherapy resistance makes it possible to develop effective strategies to overcome this hurdle and boost therapy outcomes. In this review, we take a look at immunotherapy strategies and go through a number of primary and acquired resistance mechanisms. Also, we present various ongoing methods to overcoming resistance and introduce some promising fields to improve the outcome of immunotherapy in patients affected with cancer. [ABSTRACT FROM AUTHOR]