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Metabolically fit chimeric antigen receptor (CAR) cells need to be generated for effective CAR immunotherapy. (A) When CAR immune cells reach their target, due to the paucity of nutrients, these cells can become exhausted. This prevents the CAR immune cells from functioning and allows for tumor growth. (B) Metabolically fit CAR immune cells can be generated by modifying the metabolic pathways that endow these immune cells to out-compete cancer cells for nutrients and thus remain active even in the TME for the eradication of cancer cells. (C) Metabolic pathways that are disrupted and can be modified to generate metabolically fit CAR-immune cells.
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Simple Summary
This review paper here describes the recent progress that has been made in chimeric antigen receptor (CAR) -based therapies for treatment of tumors and the role of metabolism in the tumor microenvironment in relation to these therapies. Moreover, this manuscript also discusses role of different CAR-based cells for treatment of solid...
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Citations
... In 2023, Zou et al. reported a patient with multiline-resistant refractory PCNSL who received decitabine-primed tandem CD19/CD22 CAR-T therapy with PD-1 and BTK Inhibitors maintenance and eventually maintained complete remission (CR) for a 35-month follow-up period (83). Besides improving the CAR structure, alternative cell lines with antigen specificity, such as CAR-NK cells and CARmacrophages, have been developed, demonstrating enhanced antitumor anti-tumor activity (84). Furthermore, phase I/II clinical trials have shown fewer adverse effects with CAR-NK therapy compared to regular CAR-T therapy in treating systemic lymphoma (85). ...
Primary central nervous system lymphoma (PCNSL) is non-Hodgkin’s lymphoma (NHL) confined to the central nervous system. Most of the patients eventually develop relapsed/refractory (R/R) PCNSL, and the overall prognosis for PCNSL remains dismal. Recently, gene sequencing, transcriptome sequencing, and single-cell sequencing platforms have provided a large amount of data revealing the mechanisms underlying the pathogenesis and drug resistance in PCNSL, including the activation of the NF-κB signaling pathway in tumor cells, tumor heterogeneity, and the immunosuppressive tumor microenvironment. Advances in molecular pathology studies for PCNSL have led to identifying new therapeutic targets and developing novel drugs. New therapeutic strategies, such as creating small molecule targeted agents, immunomodulatory drugs, immune checkpoint inhibitors, and chimeric antigen receptor T (CAR-T) cell therapy, have brought new hope for patients with PCNSL, especially for R/R PCNSL. This review presents recent advances in the treatment of PCNSL, reviews and discusses the efficacy and challenges of targeted therapy and immunotherapy, and provides an outlook on the future development of PCNSL treatment strategies.
... The impressive success of chimeric antigen receptor (CAR) T-cell-based immunotherapy in B-cell malignancies [1] has sparked extraordinary interest in the scientific and medical communities [2][3][4][5]. In contrast, CAR-T-cell-based immunotherapy for solid tumors has not been successful due to cellular, metabolic, and anatomical complexities and tissue heterogeneity, which contribute to shaping the hostile tumor microenvironment (TME) for resident immune cells [6][7][8][9]. Despite their doubtless antitumor activity, CAR-T cells have also shown some limitations. ...
Background
Recent studies have shown that CD32/CD8a/CD28/CD3ζ chimeric receptor cells directly kill breast cancer cells, suggesting the existence of cell surface myeloid FcγR alternative ligands (ALs). Here, we investigated the metabolism, ALs, cytotoxicity, and immunoregulatory functions of CD64/CD28/CD3ζ in colorectal cancer (CRC) and squamous cell carcinoma of the head and neck.
Methods
The CD64/CD28/CD3ζ -SFG retroviral vector was used to produce viruses for T-cell transduction. T-cell expansion and differentiation were monitored via flow cytometry. Gene expression was assessed by RNA-seq. Bioenergetics were documented on a Seahorse extracellular flux analyzer. CD64/CD28/CD3ζ polarization was identified via confocal microscopy. Cytotoxicity was determined by MTT assay and bioluminescent imaging, and flow cytometry. Tridimensional antitumor activity of CD64/CD28/CD3ζ T cells was achieved by utilizing HCT116-GFP 3D spheroids via the IncuCyte S3 Live-Cell Analysis system. The intraperitoneal distribution and antitumor activity of NIR-CD64/CD28/CD3ζ and NIR-nontransduced T cells were investigated in CB17-SCID mice bearing subcutaneous FaDu Luc + cells by bioluminescent and fluorescent imaging. IFNγ was assessed by ELISA.
Results
Compared to CD16/CD8a/CD28/CD3ζ T cells, CD32/CD8a/CD28/CD3ζ T cells, and non-transduced T cells, CD64/CD28/CD3ζ T cells exhibited the highest levels of cell expansion and persistence capacity. A total of 235 genes linked to cell division and 52 genes related to glycolysis were overexpressed. The glycolytic phenotype was confirmed by functional in vitro studies accompanied by preferential T-cell effector memory differentiation. Interestingly, oxamic acid was found to inhibit CD64-CR T cell proliferation, indicating the involvement of lactate. Upon CD64/CD28/CD3ζ T-cell conjugation with CRC cells, CD64/CD28/CD3ζ cells polarize at immunological synapses, leading to CRC cell death. CD64/CD28/CD3ζ T cells kill SCCHN cells, and in combination with the anti-B7-H3 mAb (376.96) or anti-EGFR mAb, these cells trigger antibody-dependent cellular cytotoxicity (ADCC) in vitro under 2D and 3D conditions. The 376.96 mAb combined with CD64/CD28/CD3ζ T cells had anti-SCCHN activity in vivo. In addition, they induce the upregulation of PD-L1 and HLA-DR expression in cancer cells via IFNγ. PD-L1 positive SCCHN cells in combination with anti-PD-L1 mAb and CD64-CR T cells were killed by ADCC, which enhanced direct cytotoxicity. These findings indicate that the glycolytic phenotype is involved in CD64-CR T cell proliferation/expansion. These cells mediate long-lasting HLA-independent cytotoxicity and ADCC in CRC and SCCHN cells.
Conclusions
CD64/CD28/CD3ζ T cells could significantly impact the rational design of personalized studies to treat CRC and SCCHN and the identification of novel FcγR ALs in cancer and healthy cells.
... 120 Recent data suggest that the costimulatory domain has an impact on T cell subsets within the CAR-T product; however, the optimal costimulatory domain remains to be clarified. 121 The available data thus far indicate that there are functional distinctions between various T cell subsets concerning in vivo proliferation and activity, which consequently impacts clinical outcomes. ...
CD19‐directed autologous chimeric antigen receptor T cell (CAR‐T) therapy has transformed the management of relapsed/refractory (R/R) large B cell lymphoma (LBCL). Initially approved in the third line and beyond setting, CAR‐T is now standard of care (SOC) for second‐line treatment in patients with refractory disease or early relapse (progression within 12 months) following primary chemoimmunotherapy. Despite becoming SOC, most patients do not achieve complete response, and long‐term cure is only observed in approximately 40% of patients. Accordingly, there is an urgent need to better understand the mechanisms of treatment failure and to identify patients that are unlikely to benefit from SOC CAR‐T. The field needs robust biomarkers to predict treatment outcome, as better understanding of prognostic factors and mechanisms of resistance can inform on the design of novel treatment approaches for patients predicted to respond poorly to SOC CAR‐T. This review aims to provide a comprehensive overview of clinical, molecular, imaging, and cellular features that have been shown to influence outcomes of CAR‐T therapy in patients with R/R LBCL.
... Third-generation CARs improved costimulation by including two co-stimulatory signaling domains ( Figure 2C) [16]. Incorporating the OX40, ICOS, or CD27 as secondary costimulatory domains increases the expansion and persistence of resting T cells through proinflammatory pathways [48]. In murine models, third-generation CARs mount a more robust antitumor response and contribute to longer-surviving mice [49]. ...
Chimeric antigen receptor T (CAR-T) cell therapy has transformed the field of immunology by redirecting T lymphocytes toward tumor antigens. Despite successes in attaining high remission rates as high as 90%, the performance of CAR therapy is limited by the survival of T cells. T cell persistence is crucial as it sustains immune response against malignancies, playing a critical role in cancer treatment outcomes. This review explores various approaches to improve CAR-T cell persistence, focusing on the choice between autologous and allogeneic cell sources, optimization of culture conditions for T cell subsets, metabolite adjustments to modify T cell metabolism, the use of oncolytic viruses (OVs), and advancements in CAR design. Autologous CAR-T cells generally exhibit longer persistence but are less accessible and cost-effective than their allogeneic counterparts. Optimizing culture conditions by promoting TSCM and TCM cell differentiation has also demonstrated increased persistence, as seen with the use of cytokine combinations like IL-7 and IL-15. Metabolic adjustments, such as using 2-deoxy-D-glucose (2-DG) and L-arginine, have enhanced the formation of memory T cells, leading to improved antitumor activity. OVs, when combined with CAR-T therapy, can amplify CAR-T cell penetration and persistence in solid tumors, although further clinical validation is needed. Advances in CAR design from second to fifth generations have progressively improved T cell activation and survival, with fifth-generation CARs demonstrating strong cytokine-mediated signaling and long-lasting persistence. Understanding the underlying mechanisms behind these strategies is essential for maximizing the potential of CAR-T therapy in treating cancer. Further research is needed to improve safety and efficacy and seamlessly integrate the discussed strategies into the manufacturing process.
... Chimeric antigen receptor (CAR) T cells and immune checkpoint inhibitors are examples of immunotherapies that use the immune system to identify and destroy cancer cells. The goal of metabolic targeting techniques is to hinder the proliferation of cancer cells by depriving them of energy sources or by disrupting important metabolic processes [31]. Photodynamic therapy (PDT) uses light-activated photosensitizing drugs to specifically target and kill cancer cells by taking advantage of their optical characteristics. ...
Despite the recent successes of cancer therapy, numerous obstacles remain. The medical community of the 16th century believed that magnets might be used to cure or prevent illness. However, this concept has only recently been put into practice in the treatment of cancer. Cancers vary greatly not only at the patient, tissue, and cellular levels but also at the molecular level. Because of this multiscale heterogeneity, effective treatments that not only differentiate between cancerous and healthy tissues but also target a wide variety of tumor subclones are difficult to develop. Most treatments either take advantage of a specific biological characteristic shared by cancer cells (e.g., their propensity for rapid division) or indiscriminately eradicate every cell in an area of interest. In this article, we review the physical, chemical, electrical, optical, and magnetic properties of cancer cells, before discussing how these properties may be modulated by current and future cancer therapies.
... The purpose of bridge therapy is to buy time for patients while waiting for the preparation and production of CAR-T cell therapy (54). Once the CAR-T cells are expanded to a sufficient number and the patient is prepared for treatment, the doctor injects the CAR-T cells into the patient through an intravenous infusion (55). Patients are closely observed and monitored after receiving CAR-T cell therapy; this includes monitoring for adverse reactions, evaluation of tumor response and monitoring CAR-T cell activity and survival in the body (55). ...
... Once the CAR-T cells are expanded to a sufficient number and the patient is prepared for treatment, the doctor injects the CAR-T cells into the patient through an intravenous infusion (55). Patients are closely observed and monitored after receiving CAR-T cell therapy; this includes monitoring for adverse reactions, evaluation of tumor response and monitoring CAR-T cell activity and survival in the body (55). ...
... For example, CAR-T cells designed against the CD19 antigen have achieved therapeutic effects by targeting and killing CD19 + leukemia cells (62). In addition, CAR-T cell therapy has shown notable efficacy in the treatment of relapsed/refractory B-cell non-Hodgkin's lymphoma (B-NHL) (63), B-cell acute lymphoblastic leukemia (B-ALL) and chronic lymphocytic leukemia, with ~40-60% of patients with B-NHL obtaining durable remission and survival after receiving CAR-T cell therapy, and ~80-90% of patients with B-ALL obtaining durable remission and survival or complete remission, after receiving CAR-T cell therapy (55,64). The application of CAR-T cell therapy in the treatment of solid tumors, as opposed to hematological tumors, continues to be investigated, and despite a number of challenges and limitations, positive advances have been made (65). ...
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.
... Previous studies have shown that stably CAR expressing NKs can be achieved through lentiviral and retroviral expressional systems [61]. Others have also reported the use of nonviral expression systems for this purpose [62][63][64]. ...
NK cells are the first sentinels of the immune system that can recognize and eradicate transformed cells. Their activation without a need for additional signaling have attracted great attention on the use of NK cells as a promising option in cancer immunotherapy. However, the large-scale production of NK cells for successful NK cells therapy is a challenge that needs to be tackled. Engineering NK cells to avoid tumor escape and improve their antitumor potency are the other matters of focus that have widely been studied in the recent years. This paper reviews the most recent advances in the stem cell-derived NK cell technology and discusses the potential of the engineered NK cells for clinical applications in cancer immunotherapy.
... Recently, targeting tumor immunity has been regarded as a critical approach to improving therapeutic efficacy [8,9]. Based on the capability of regulating immune cell activation, chimeric antigen receptor T (CAR-T) cells and immune checkpoint inhibitors have achieved impressive efficacy in patients with R/R B-ALL [10,11]. Therefore, molecular mechanisms of tumor immunoregulation associated with tumorigenesis and progression deserve in-depth exploration. ...
Background
As an essential regulator of type I interferon (IFN) response, TMEM173 participates in immune regulation and cell death induction. In recent studies, activation of TMEM173 has been regarded as a promising strategy for cancer immunotherapy. However, transcriptomic features of TMEM173 in B-cell acute lymphoblastic leukemia (B-ALL) remain elusive.
Methods
Quantitative real-time PCR (qRT-PCR) and western blotting (WB) were applied to determine the mRNA and protein levels of TMEM173 in peripheral blood mononuclear cells (PBMCs). TMEM173 mutation status was assessed by Sanger sequencing. Single-cell RNA sequencing (scRNA-seq) analysis was performed to explore the expression of TMEM173 in different types of bone marrow (BM) cells.
Results
The mRNA and protein levels of TMEM173 were increased in PBMCs from B-ALL patients. Besides, frameshift mutation was presented in TMEM173 sequences of 2 B-ALL patients. ScRNA-seq analysis identified the specific transcriptome profiles of TMEM173 in the BM of high-risk B-ALL patients. Specifically, expression levels of TMEM173 in granulocytes, progenitor cells, mast cells, and plasmacytoid dendritic cells (pDCs) were higher than that in B cells, T cells, natural killer (NK) cells, and dendritic cells (DCs). Subset analysis further revealed that TMEM173 and pyroptosis effector gasdermin D (GSDMD) restrained in precursor-B (pre-B) cells with proliferative features, which expressed nuclear factor kappa-B (NF-κB), CD19, and Bruton’s tyrosine kinase (BTK) during the progression of B-ALL. In addition, TMEM173 was associated with the functional activation of NK cells and DCs in B-ALL.
Conclusions
Our findings provide insights into the transcriptomic features of TMEM173 in the BM of high-risk B-ALL patients. Targeted activation of TMEM173 in specific cells might provide new therapeutic strategies for B-ALL patients.
... Commercial approval of several CAR T cell therapies by the FDA [277] T cells are more suitable for bioengineering by classical viral vector transduction [257] No need for cells of autologous origin [172] Less prone to GVHD [172] CAR designs and metabolic fitness 4-1BB-containing CAR: OXPHOS metabolism [75] and longer in vivo persistence [72] CD28-containing CAR: glycolytic metabolism [75] and shorter in vivo persistence [72] NKG2D-expressing CAR resistant to the immune and metabolic suppressor TGFβ drives MDSCs clearance and better tumor burden control of CAR T cells targeting neuroblastoma in mice [261]. ...
Nutritional interventions are investigated in the context of non-communicable diseases such as cancer. Dietary regimens such as caloric restriction, fasting, ketogenic and protein-restricted diets have shown benefits to control tumor progression. Indeed, we have previously reported the protective effect of an isocaloric diet partially reduced in protein in several cancer mouse models. Beyond a stronger anticancer immunosurveillance dependent on cytotoxic T cells, the low protein diet limited tumor growth in an IRE1α-dependent manner.Inositol-requiring enzyme 1α (IRE1α) is the most evolutionally conserved ER (endoplasmic reticulum) stress sensor induced as part of the Unfolded Protein Response (UPR). The UPR is activated by accumulation of misfolded proteins in the ER, lipidic disturbances in the ER membrane, hypoxia and nutrient deprivation. IRE1α activates downstream targets via its endoribonuclease activity resulting in XBP1 splicing as well as degradation of RNAs by a process known as the Regulated IRE1-Dependent Decay (RIDD). While XBP1 splicing recovers cellular homeostasis, massive RIDD induction leads to apoptosis under chronic ER stress.The IRE1α signaling has been described to play dual roles in most hallmarks of cancer. While the IRE1α-XBP1 axis in tumor cells supports tumor progression in several solid and liquid oncogenic malignancies, the IRE1α-RIDD branch has been suggested as tumor-suppressive in glioblastoma. Since our previous findings showed that IRE1 is implicated in the tumor-protective effects of a low protein diet, we investigated the effect of the exogenous expression of IRE1 in tumor cells implanted in immunocompetent mice.We found that overexpression of IRE1 and self-induction of its full RNAse activity was detrimental for subcutaneous tumor growth of colorectal and Lewis lung carcinomas. Tumors with higher IRE1 activity were characterized by active IRE1α-XBP1 and IRE1α-RIDD branches, a higher anticancer immunosurveillance and tumor cells undergoing apoptosis. The enhanced anti-cancer immune response elicits upon IRE1α overexpression was mainly dependent on T cell-mediated-cytotoxicity. In conclusion, our findings support the notion that IRE1α with a full RNAse activity can have tumor-suppressive roles.
... The currently approved FDA therapies Kymriah and Yescarta belong to this second-generation CAR-T cells. The experience gained from the application of secondgeneration CAR-T cells highlighted the relevance of the costimulatory molecule on the function and fate of the engineered cells within the TME (85). The addition of the 4-1BB (CD137) domain to CAR constructs promoted the induction of CD8 + T cells with increased respiratory capacity and heightened mitochondrial biogenesis, two characteristics of the least differentiated memory T cells (24,25,86). ...
... Third-generation CARs incorporated a second co-stimulatory signaling domain to achieve greater functional potency ( Figure 3C) (90,91). For example, the addition of the CD28 and OX40 domains to a CD3z chain leads to the sustained activation, proliferation, and effector function of resting T cells through the NFkB signaling pathway (85). Furthermore, ICOS-dependent signaling in CAR-T cells has been shown to result in an enhanced cell survival following the ACT. ...
... Specific metabolic and epigenetic changes must occur in cells in order to proliferate and differentiate. As can be seen, metabolism is intimately linked to cell activation, proliferation, migration, and function, and therefore to the very fate of T cells (85,161,162). ...
Adoptive cell therapy with T cells reprogrammed to express chimeric antigen receptors (CAR-T cells) has been highly successful in patients with hematological neoplasms. However, its therapeutic benefits have been limited in solid tumor cases. Even those patients who respond to this immunotherapy remain at risk of relapse due to the short-term persistence or non-expansion of CAR-T cells; moreover, the hostile tumor microenvironment (TME) leads to the dysfunction of these cells after reinfusion. Some research has shown that, in adoptive T-cell therapies, the presence of less differentiated T-cell subsets within the infusion product is associated with better clinical outcomes. Naive and memory T cells persist longer and exhibit greater antitumor activity than effector T cells. Therefore, new methods are being studied to overcome the limitations of this therapy to generate CAR-T cells with these ideal phenotypes. In this paper, we review the characteristics of T-cell subsets and their implications in the clinical outcomes of adoptive therapy with CAR-T cells. In addition, we describe some strategies developed to overcome the reduced persistence of CAR T-cells and alternatives to improve this therapy by increasing the expansion ability and longevity of modified T cells. These methods include cell culture optimization, incorporating homeostatic cytokines during the expansion phase of manufacturing, modulation of CAR-T cell metabolism, manipulating signaling pathways involved in T-cell differentiation, and strategies related to CAR construct designs.
