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Recent Prospectives in CAR T-based Therapy for Solid and Hematological...
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Recent Prospectives in CAR T-based Therapy for Solid and Hematological Malignancies

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Gene and Cell Therapy".

Deadline for manuscript submissions: closed (15 October 2022) | Viewed by 41161

Special Issue Editors

Dr. Carlo Cenciarelli

E-Mail Website
Guest Editor
Institute of Translational Pharmacology, National Research Council of Italy, Rome, Italy
Interests: cancer; glioblastoma; T cell therapy; mAbs; signal transduction; cell growth
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Hany E. Marei

E-Mail Website
Guest Editor
Faculty of Veterinary Medicine, Department of Cytology and Histology, Mansoura University, Mansoura, Egypt
Interests: CAR T; scRNAseq for GBM; ribosome sequence for GBM; unannotated ORF for detection of neoantigens
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

CAR T-cell therapy has been demonstrated to be effective in CD19-positive blood cancers; thus, this offers great hope for a wide range of aggressive tumors that has so far demonstrated limited response to current treatments. CAR T-cell therapy is based on the use of patient-specific T cells that have been genetically engineered to express a single-chain variable fragment (scFv) of an antibody specific to a tumor-associated antigen, linked to intracellular co-stimulatory molecules. When CAR T cells interact with tumor cells, they cause cytotoxicity and the release of various inflammatory cytokines, resulting in the killing of target cells. Despite the great promise of CAR T-cell-based therapy, several challenges still exist such as cancer cells heterogeneity, abnormal signaling pathways involved in tumor progression, antigen escape, the hostile inhibitory tumor microenvironment and T cells’ dysfunction/exhaustion. All of these issues must be addressed before a full clinical application can begin. More recently, another T-cell therapy has taken hold, and we hope in this Special issue can provide advances in T cells engineered with Fcγ-chimeric receptors (CRs) redirected against solid tumors and blood malignancies. The engagement of Fcγ-CRs on the surface of effectors cells with the Fc region of tumor-bound antibodies can promote tumor elimination by antibody-dependent cellular cytotoxicity (ADCC). We also intend to highlight the most recent completed and ongoing clinical trials with a focus on the rationale for using different types of CAR T cells, emphasizing the various ways in which such trials are designed to overcome specific hurdles, as well as how outcomes are reflected in improving therapeutic arsenals against various cancer types.

Dr. Carlo Cenciarelli
Prof. Dr. Hany E. Marei
Guest Editors

Manuscript Submission Information

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Keywords

  • CAR
  • Fcγ-CR
  • T cells
  • solid tumors
  • blood malignancies
  • cancer immune evasion
  • cancer immunotherapy
  • clinical trials

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Published Papers (11 papers)

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Editorial

Jump to: Research, Review

3 pages, 172 KiB  
Editorial
Recent Prospective in CAR T-Based Therapy for Solid and Hematological Malignancies
by Hany E. Marei and Carlo Cenciarelli
Biomedicines 2023, 11(2), 627; https://doi.org/10.3390/biomedicines11020627 - 20 Feb 2023
Viewed by 1615
Abstract
Given that CAR-T cell therapy is effective in CD19-positive blood malignancies, it offers great hope for a variety of aggressive tumors that have thus far shown very little response to available therapies [...] Full article
(This article belongs to the Special Issue Recent Prospectives in CAR T-based Therapy for Solid and Hematological Malignancies)

Research

Jump to: Editorial, Review

23 pages, 5162 KiB  
Article
Development of a TGFβ—IL-2/15 Switch Receptor for Use in Adoptive Cell Therapy
by Carole Beck, Nicholas Paul Casey, Irene Persiconi, Neda Nejati Moharrami, Adam Sike, Yixin Jin and Jon Amund Kyte
Biomedicines 2023, 11(2), 459; https://doi.org/10.3390/biomedicines11020459 - 4 Feb 2023
Cited by 9 | Viewed by 2765
Abstract
Therapy employing T cells modified with chimeric antigen receptors (CARs) is effective in hematological malignancies but not yet in solid cancers. CAR T cell activity in solid tumors is limited by immunosuppressive factors, including transforming growth factor β (TGFβ). Here, we describe the [...] Read more.
Therapy employing T cells modified with chimeric antigen receptors (CARs) is effective in hematological malignancies but not yet in solid cancers. CAR T cell activity in solid tumors is limited by immunosuppressive factors, including transforming growth factor β (TGFβ). Here, we describe the development of a switch receptor (SwR), in which the extracellular domains of the TGFβ receptor are fused to the intracellular domains from the IL-2/15 receptor. We evaluated the SwR in tandem with two variants of a CAR that we have developed against STEAP1, a protein highly expressed in prostate cancer. The SwR-CAR T cell activity was assessed against a panel of STEAP1+/− prostate cancer cell lines with or without over-expression of TGFβ, or with added TGFβ, by use of flow cytometry cytokine and killing assays, Luminex cytokine profiling, cell counts, and flow cytometry phenotyping. The results showed that the SwR-CAR constructs improved the functionality of CAR T cells in TGFβ-rich environments, as measured by T cell proliferation and survival, cytokine response, and cytotoxicity. In assays with four repeated target-cell stimulations, the SwR-CAR T cells developed an activated effector memory phenotype with retained STEAP1-specific activity. In conclusion, the SwR confers CAR T cells with potent and durable in vitro functionality in TGFβ-rich environments. The SwR may be used as an add-on construct for CAR T cells or other forms of adoptive cell therapy. Full article
(This article belongs to the Special Issue Recent Prospectives in CAR T-based Therapy for Solid and Hematological Malignancies)
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23 pages, 6471 KiB  
Article
An Innovative PTD-IVT-mRNA Delivery Platform for CAR Immunotherapy of ErbB(+) Solid Tumor Neoplastic Cells
by Sofia K. Georgiou-Siafis, Androulla N. Miliotou, Charikleia Ntenti, Ioannis S. Pappas and Lefkothea C. Papadopoulou
Biomedicines 2022, 10(11), 2885; https://doi.org/10.3390/biomedicines10112885 - 10 Nov 2022
Cited by 3 | Viewed by 3212
Abstract
Chimeric antigen receptor (CAR) immunotherapy includes the genetic modification of immune cells to carry such a receptor and, thus, recognize cancer cell surface antigens. Viral transfection is currently the preferred method, but it carries the risk of off-target mutagenicity. Other transfection platforms [...] Read more.
Chimeric antigen receptor (CAR) immunotherapy includes the genetic modification of immune cells to carry such a receptor and, thus, recognize cancer cell surface antigens. Viral transfection is currently the preferred method, but it carries the risk of off-target mutagenicity. Other transfection platforms have thus been proposed, such the in vitro transcribed (IVT)-mRNAs. In this study, we exploited our innovative, patented delivery platform to produce protein transduction domain (PTD)-IVT-mRNAs for the expression of CAR on NK-92 cells. CAR T1E-engineered NK-92 cells, harboring the sequence of T1E single-chain fragment variant (scFv) to recognize the ErbB receptor, bearing either CD28 or 4-1BB as co-stimulatory signaling domains, were prepared and assessed for their effectiveness in two different ErbB(+) cancer cell lines. Our results showed that the PTD-IVT-mRNA of CAR was safely transduced and expressed into NK-92 cells. CAR T1E-engineered NK-92 cells provoked high levels of cell death (25–33%) as effector cells against both HSC-3 (oral squamous carcinoma) and MCF-7 (breast metastatic adenocarcinoma) human cells in the co-incubation assays. In conclusion, the application of our novel PTD-IVT-mRNA delivery platform to NK-92 cells gave promising results towards future CAR immunotherapy approaches. Full article
(This article belongs to the Special Issue Recent Prospectives in CAR T-based Therapy for Solid and Hematological Malignancies)
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Graphical abstract

18 pages, 2863 KiB  
Article
Adapter CAR T Cell Therapy for the Treatment of B-Lineage Lymphomas
by Daniel Atar, Anna-Sophia Mast, Sophia Scheuermann, Lara Ruoff, Christian Martin Seitz and Patrick Schlegel
Biomedicines 2022, 10(10), 2420; https://doi.org/10.3390/biomedicines10102420 - 28 Sep 2022
Cited by 10 | Viewed by 3526
Abstract
CD19CAR T cells facilitate a transformational treatment in various relapsed and refractory aggressive B-lineage cancers. In general, encouraging response rates have been observed in B-lineage-derived non-Hodgkin’s lymphomas treated with CD19CAR T cells. The major cause of death in heavily pretreated NHL patients is [...] Read more.
CD19CAR T cells facilitate a transformational treatment in various relapsed and refractory aggressive B-lineage cancers. In general, encouraging response rates have been observed in B-lineage-derived non-Hodgkin’s lymphomas treated with CD19CAR T cells. The major cause of death in heavily pretreated NHL patients is lymphoma progression and lymphoma recurrence. Inefficient CAR T cell therapy is the result of the limited potency of the CAR T cell product or is due to loss of the targeted antigen. Target antigen loss has been identified as the key factor that can be addressed stringently by dual- or multitargeted CAR T cell approaches. We have developed a versatile adapter CAR T cell technology (AdCAR) that allows multitargeting. Screening of three different B-lineage lymphoma cell lines has revealed distinct immune target profiles. Cancer-specific adapter molecule combinations may be utilized to prevent antigen immune escape. In general, CD19CAR T cells become non-functional in CD19 negative lymphoma subsets; however, AdCAR T cells can be redirected to alternative target antigens beyond CD19, such as CD20, CD22, CD79B, and ROR-1. The capability to flexibly shift CAR specificity by exchanging the adapter molecule’s specificity broadens the application and significantly increases the anti-leukemic and anti-lymphoma activity. The clinical evaluation of AdCAR T cells in lymphoma as a new concept of CAR T cell immunotherapy may overcome treatment failure due to antigen immune escape in monotargeted conventional CAR T cell therapies. Full article
(This article belongs to the Special Issue Recent Prospectives in CAR T-based Therapy for Solid and Hematological Malignancies)
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Graphical abstract

16 pages, 2635 KiB  
Article
Comparing Intraperitoneal and Intravenous Personalized ErbB2CAR-T for the Treatment of Epithelial Ovarian Cancer
by Naamit Deshet-Unger, Galit Horn, Moran Rawet-Slobodkin, Tova Waks, Ido Laskov, Nadav Michaan, Yael Raz, Vered Bar, Adi Zundelevich, Sara Aharon, Lubov Turovsky, Giuseppe Mallel, Seth Salpeter, Guy Neev, Kenneth Samuel Hollander, Ben-Zion Katz, Dan Grisaru and Anat Globerson Levin
Biomedicines 2022, 10(9), 2216; https://doi.org/10.3390/biomedicines10092216 - 7 Sep 2022
Cited by 5 | Viewed by 2618
Abstract
High-grade serous ovarian carcinoma (HGSOC) is the most common type of epithelial ovarian cancer. The majority of cases are diagnosed at advanced stages, when intraperitoneal (IP) spread has already occurred. Despite significant surgical and chemotherapeutic advances in HGSOC treatment over the past decades, [...] Read more.
High-grade serous ovarian carcinoma (HGSOC) is the most common type of epithelial ovarian cancer. The majority of cases are diagnosed at advanced stages, when intraperitoneal (IP) spread has already occurred. Despite significant surgical and chemotherapeutic advances in HGSOC treatment over the past decades, survival rates with HGSOC have only modestly improved. Chimeric antigen receptor (CAR)-T cells enable T cells to directly bind to tumor-associated antigens in a major histocompatibility complex-independent manner, thereby inducing tumor rejection. While CAR-T cell therapy shows great promise in hematological malignancies, its use in solid tumors is limited. Therefore, innovative approaches are needed to increase the specificity of CAR-modified T cells against solid tumors. The aim of this study was to assess the efficacy and safety of intraperitoneal (IP) versus intravenous (IV) CAR-T cell therapy in the treatment of HGSOC. We constructed a CAR that targets the ErbB2/HER2 protein (ErbB2CAR), which is overexpressed in HGSOC, and evaluated the functionality of ErbB2CAR on ovarian cancer cell lines (OVCAR8, SKOV3, and NAR). Our findings show that an IP injection of ErbB2CAR-T cells to tumor-bearing mice led to disease remission and increased survival compared to the IV route. Moreover, we found that IP-injected ErbB2CART cells circulate to a lesser extent, making them safer for non-tumor tissues than IV-injected cells. Further supporting our findings, we show that the effect of ErbB2CAR-T cells on primary HGSOC tumors is correlated with ErbB2 expression. Together, these data demonstrate the advantages of an IP administration of CAR-T cells over IV administration, offering not only a safer strategy but also the potential for counteracting the effect of ErbB2CAR in HGSOC. Significance: IP-injected ErbB2CAR-T cells led to disease remission and increased survival compared to the IV route. These findings demonstrate the advantages of IP administration, offering a safe treatment strategy with the potential for counteracting the effect of ErbB2CAR in HGSOC. Full article
(This article belongs to the Special Issue Recent Prospectives in CAR T-based Therapy for Solid and Hematological Malignancies)
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14 pages, 1621 KiB  
Article
Binding and Efficacy of Anti-Robo4 CAR-T Cells against Solid Tumors
by Sachiko Hirobe, Seina Nagai, Masashi Tachibana and Naoki Okada
Biomedicines 2022, 10(6), 1273; https://doi.org/10.3390/biomedicines10061273 - 30 May 2022
Cited by 1 | Viewed by 2757
Abstract
Chimeric antigen receptor expression T (CAR-T) cell therapy has been shown be efficacious against relapsed/refractory B-cell malignant lymphoma and has attracted attention as an innovative cancer treatment. However, cells of solid tumors are less accessible to CAR-T cells; moreover, CAR-T function is decreased [...] Read more.
Chimeric antigen receptor expression T (CAR-T) cell therapy has been shown be efficacious against relapsed/refractory B-cell malignant lymphoma and has attracted attention as an innovative cancer treatment. However, cells of solid tumors are less accessible to CAR-T cells; moreover, CAR-T function is decreased in the immunosuppressive state of the tumor microenvironment. Since most tumors induce angiogenesis, we constructed CAR-T cells targeting roundabout homolog 4 (Robo4), which is expressed at high levels in tumor vascular endothelial cells, by incorporating three anti-Robo4 single-chain variable fragments (scFv) that were identified using phage display. We found that binding affinities of the three CARs to mouse and human Robo4 reflected their scFv affinities. More importantly, when each CAR-T cell was assayed in vitro, antigen-specific cytotoxicity, cytokine-producing ability, and proliferation were correlated with binding affinity for Robo4. In vivo, all three T-cells inhibited tumor growth in a B16BL6 murine model, which also correlated with Robo4 binding affinities. However, growth inhibition of mouse Robo4-expressing tumors was observed only in the model with CAR-T cells with the lowest Robo4 affinity. Therefore, at high Robo4 expression, CAR-T in vitro and in vivo were no longer correlated, suggesting that clinical tumors will require Robo4 expression assays. Full article
(This article belongs to the Special Issue Recent Prospectives in CAR T-based Therapy for Solid and Hematological Malignancies)
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Review

Jump to: Editorial, Research

15 pages, 1061 KiB  
Review
Recent Advances in the Development of Anti-FLT3 CAR T-Cell Therapies for Treatment of AML
by Maya Graham Pedersen, Bjarne Kuno Møller and Rasmus O. Bak
Biomedicines 2022, 10(10), 2441; https://doi.org/10.3390/biomedicines10102441 - 30 Sep 2022
Cited by 7 | Viewed by 2806
Abstract
Following the success of the anti-CD19 chimeric antigen receptor (CAR) T-cell therapies against B-cell malignancies, the CAR T-cell approach is being developed towards other malignancies like acute myeloid leukemia (AML). Treatment options for relapsed AML patients are limited, and the upregulation of the [...] Read more.
Following the success of the anti-CD19 chimeric antigen receptor (CAR) T-cell therapies against B-cell malignancies, the CAR T-cell approach is being developed towards other malignancies like acute myeloid leukemia (AML). Treatment options for relapsed AML patients are limited, and the upregulation of the FMS-like tyrosine kinase 3 (FLT3) in malignant T-cells is currently not only being investigated as a prognostic factor, but also as a target for new treatment options. In this review, we provide an overview and discuss different approaches of current anti-FLT3 CAR T-cells under development. In general, these therapies are effective both in vitro and in vivo, however the safety profile still needs to be further investigated. The first clinical trials have been initiated, and the community now awaits clinical evaluation of the approach of targeting FLT3 with CAR T-cells. Full article
(This article belongs to the Special Issue Recent Prospectives in CAR T-based Therapy for Solid and Hematological Malignancies)
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19 pages, 359 KiB  
Review
CAR T-Based Therapies in Lymphoma: A Review of Current Practice and Perspectives
by Semira Sheikh, Denis Migliorini and Noémie Lang
Biomedicines 2022, 10(8), 1960; https://doi.org/10.3390/biomedicines10081960 - 12 Aug 2022
Cited by 7 | Viewed by 3765
Abstract
While more than half of non-Hodgkin lymphomas (NHL) can be cured with modern frontline chemoimmunotherapy regimens, outcomes of relapsed and/or refractory (r/r) disease in subsequent lines remain poor, particularly if considered ineligible for hematopoietic stem cell transplantation. Hence, r/r NHLs represent a population [...] Read more.
While more than half of non-Hodgkin lymphomas (NHL) can be cured with modern frontline chemoimmunotherapy regimens, outcomes of relapsed and/or refractory (r/r) disease in subsequent lines remain poor, particularly if considered ineligible for hematopoietic stem cell transplantation. Hence, r/r NHLs represent a population with a high unmet medical need. This therapeutic gap has been partially filled by adoptive immunotherapy. CD19-directed autologous chimeric antigen receptor (auto-CAR) T cells have been transformative in the treatment of patients with r/r B cell malignancies. Remarkable response rates and prolonged remissions have been achieved in this setting, leading to regulatory approval from the U.S. Food and Drug Administration (FDA) of four CAR T cell products between 2017 and 2021. This unprecedented success has created considerable enthusiasm worldwide, and autologous CAR T cells are now being moved into earlier lines of therapy in large B cell lymphoma. Herein, we summarize the current practice and the latest progress of CD19 auto-CAR T cell therapy and the management of specific toxicities and discuss the place of allogeneic CAR T development in this setting. Full article
(This article belongs to the Special Issue Recent Prospectives in CAR T-based Therapy for Solid and Hematological Malignancies)
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Graphical abstract

18 pages, 1467 KiB  
Review
Site-Specific Considerations on Engineered T Cells for Malignant Gliomas
by Nirmeen Elmadany, Obada T. Alhalabi, Michael Platten and Lukas Bunse
Biomedicines 2022, 10(7), 1738; https://doi.org/10.3390/biomedicines10071738 - 19 Jul 2022
Cited by 11 | Viewed by 4731
Abstract
Immunotherapy has revolutionized cancer treatment. Despite the recent advances in immunotherapeutic approaches for several tumor entities, limited response has been observed in malignant gliomas, including glioblastoma (GBM). Conversely, one of the emerging immunotherapeutic modalities is chimeric antigen receptors (CAR) T cell therapy, which [...] Read more.
Immunotherapy has revolutionized cancer treatment. Despite the recent advances in immunotherapeutic approaches for several tumor entities, limited response has been observed in malignant gliomas, including glioblastoma (GBM). Conversely, one of the emerging immunotherapeutic modalities is chimeric antigen receptors (CAR) T cell therapy, which demonstrated promising clinical responses in other solid tumors. Current pre-clinical and interventional clinical studies suggest improved efficacy when CAR-T cells are delivered locoregionally, rather than intravenously. In this review, we summarize possible CAR-T cell administration routes including locoregional therapy, systemic administration with and without focused ultrasound, direct intra-arterial drug delivery and nanoparticle-enhanced delivery in glioma. Moreover, we discuss published as well as ongoing and planned clinical trials involving CAR-T cell therapy in malignant glioma. With increasing neoadjuvant and/or adjuvant combinatorial immunotherapeutic concepts and modalities with specific modes of action for malignant glioma, selection of administration routes becomes increasingly important. Full article
(This article belongs to the Special Issue Recent Prospectives in CAR T-based Therapy for Solid and Hematological Malignancies)
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31 pages, 2867 KiB  
Review
Alternative CAR Therapies: Recent Approaches in Engineering Chimeric Antigen Receptor Immune Cells to Combat Cancer
by Carlos Moreno, Christopher Haynie, Abigail Cheever and K. Scott Weber
Biomedicines 2022, 10(7), 1493; https://doi.org/10.3390/biomedicines10071493 - 24 Jun 2022
Cited by 21 | Viewed by 5150
Abstract
For nearly three decades, chimeric antigen receptors (CARs) have captivated the interest of researchers seeking to find novel immunotherapies to treat cancer. CARs were first designed to work with T cells, and the first CAR T cell therapy was approved to treat B [...] Read more.
For nearly three decades, chimeric antigen receptors (CARs) have captivated the interest of researchers seeking to find novel immunotherapies to treat cancer. CARs were first designed to work with T cells, and the first CAR T cell therapy was approved to treat B cell lymphoma in 2017. Recent advancements in CAR technology have led to the development of modified CARs, including multi-specific CARs and logic gated CARs. Other immune cell types, including natural killer (NK) cells and macrophages, have also been engineered to express CARs to treat cancer. Additionally, CAR technology has been adapted in novel approaches to treating autoimmune disease and other conditions and diseases. In this article, we review these recent advancements in alternative CAR therapies and design, as well as their mechanisms of action, challenges in application, and potential future directions. Full article
(This article belongs to the Special Issue Recent Prospectives in CAR T-based Therapy for Solid and Hematological Malignancies)
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21 pages, 1179 KiB  
Review
CAR-T Cells/-NK Cells in Cancer Immunotherapy and the Potential of MSC to Enhance Its Efficacy: A Review
by Ler Yie Chan, Sylvia Annabel Dass, Gee Jun Tye, Siti A. M. Imran, Wan Safwani Wan Kamarul Zaman and Fazlina Nordin
Biomedicines 2022, 10(4), 804; https://doi.org/10.3390/biomedicines10040804 - 30 Mar 2022
Cited by 18 | Viewed by 6520
Abstract
The chimeric antigen receptor (CAR) plays a dynamic role in targeting tumour-associated antigens in cancer cells. This novel therapeutic discovery combines fragments of monoclonal antibodies with the signalling and co-stimulatory domains that have been modified to its current fourth generation. CAR has been [...] Read more.
The chimeric antigen receptor (CAR) plays a dynamic role in targeting tumour-associated antigens in cancer cells. This novel therapeutic discovery combines fragments of monoclonal antibodies with the signalling and co-stimulatory domains that have been modified to its current fourth generation. CAR has been widely implemented in T-cells and natural killer (NK) cells immunotherapy. The significant advancement in CAR technology is evident based on numerous ongoing clinical trials on CAR-T/-NK cells and successful CAR-related products such as Kymriah (Novartis) and Yescarta (Kite Pharma, Gilead). Another important cell-based therapy is the engineering of mesenchymal stem cells (MSC). Researchers have been exploring MSCs and their innate homing abilities to tumour sites and secretion cytokines that bridge both CAR and MSC technologies as a therapeutic agent. This combination allows for both therapies to overcome each one’s flaw as an immunotherapy intervention. Herein, we have provided a concise review on the background of CAR and its applications in different cancers, as well as MSCs’ unique ability as delivery vectors for cancer therapy and the possibility of enhancing the CAR-immune cells’ activity. Hence, we have highlighted throughout this review the synergistic effects of both interventions. Full article
(This article belongs to the Special Issue Recent Prospectives in CAR T-based Therapy for Solid and Hematological Malignancies)
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