CAR T-cells for colorectal cancer immunotherapy: Ready to go?
Ontology highlight
ABSTRACT:
SUBMITTER: Ghazi B
PROVIDER: S-EPMC9705989 | biostudies-literature | 2022
REPOSITORIES: biostudies-literature
Publications
CAR T-cells for colorectal cancer immunotherapy: Ready to go?
Ghazi Bouchra B El Ghanmi Adil A Kandoussi Sarah S Ghouzlani Amina A Badou Abdallah A
Frontiers in immunology 20221115
Chimeric antigen receptor (CAR) T-cells represent a new genetically engineered cell-based immunotherapy tool against cancer. The use of CAR T-cells has revolutionized the therapeutic approach for hematological malignancies. Unfortunately, there is a long way to go before this treatment can be developed for solid tumors, including colorectal cancer. CAR T-cell therapy for colorectal cancer is still in its early stages, and clinical data are scarce. Major limitations of this therapy include high t ...[more]
Similar Datasets
Project description:Chimeric antigen receptor (CAR) T cells face a unique set of challenges in the context of solid tumors. To induce a favorable clinical outcome, CAR T cells have to surmount a series of increasingly arduous tasks. First, they have to be made specific for an antigen whose expression clearly demarcates tumor from normal tissue. Then, they must be able to home and penetrate the desmoplastic stroma that surrounds the tumor. Once within the tumor, they must expand, persist, and mediate cytotoxicity in a hostile milieu largely composed of immunosuppressive modulators. Whereas a seemingly herculean task, all of the aforementioned requirements can potentially be met effectively through both intrinsic and/or extrinsic modifications of CAR T cells. In this review, we delineate the barriers imposed by solid tumors on CARs and strategies that have and should be undertaken to improve therapeutic response.
| S-EPMC4050065 | biostudies-literature
Project description:BackgroundColorectal cancer (CRC) is the third most common cancer worldwide, with highly variable prognosis and response to treatment. A large subset of patients does not respond to standard treatments or develops resistance. As an alternative, adoptive immunotherapy based on chimeric antigen receptor (CAR)-transduced immune cells has been proposed, however with significant adverse events. We therefore evaluated alternative CAR targets already tested in other tumour types and employed the natural killer cell line NK-92 for CAR transduction because of its more favourable toxicity profile.MethodsAs an alternative antigen, we considered mesothelin (MSLN), the most represented target in CAR-based clinical studies for solid tumours. MSLN RNA expression was analysed in large series of CRC tumours (n = 640) and cell lines (n = 150), to evaluate its distribution and to identify MSLN-overexpressing models. NK-92 cells were transduced with anti-MSLN CAR, and subsequently sorted and cloned. Activity of CAR-NK-92 cells against target-expressing ovarian and CRC cells was assessed in vitro and in vivo. Statistical significance of efficacy was evaluated by t-test and log-rank test.ResultsLarge-scale expression analysis highlighted that about 10% of CRCs overexpress MSLN at levels comparable to those of ovarian cancer, a typical target of MSLN-CAR-based therapy. Intriguingly, MSLN overexpression is more frequent in poor prognosis and KRAS/BRAF-mutant CRC. Lentiviral transduction of NK-92 cells with the MSLN-CAR, followed by sorting and cloning, led to the identification of one clone, MSLN.CAR.NK-92.cl45, stably expressing the CAR and retaining the NK phenotype. As expected, the clone demonstrated significant in vitro and in vivo activity against ovarian cancer cells. When repurposed against models of CRC expressing high MSLN levels, it displayed comparable efficacy, both in vitro and in vivo. Specificity of the clone was confirmed by the absence of activity on control models with low or absent MSLN.ConclusionsOur results provide preclinical evidence that a subset of colorectal cancers expressing high mesothelin levels can be effectively targeted by MSLN-CAR-based immunotherapy. The potential therapeutic impact of these findings is enhanced by the fact that frequently MSLN-overexpressing CRCs display worse prognosis and resistance to standard care.
| S-EPMC11616334 | biostudies-literature
Project description:Chimeric antigen receptor T-cell (CAR-T) therapy is the result of combining genetic engineering-based cancer immunotherapy with adoptive cell therapy (ACT). CAR-T therapy has been successful in treating various types of hematological cancers. CARs are receptors made of an extracellular domain, a membrane-spanning domain, and an intracellular domain. The extracellular domain of CARs harbors an antigen-targeting domain responsible for recognizing and binding cell surface-expressed target antigens. Conventionally, the single-chain fragment variable (scFv) of a monoclonal antibody (mAb) is used as the antigen-targeting domain of CARs. However, of late, researchers have exploited nanobodies for this aim based on numerous rationales including the small size of nanobodies, their stability, specificity, and high affinity, and their easy and feasible development process. Many findings have confirmed that nanobody-based CAR-Ts can be as functional as scFv-based CAR-Ts in preclinical and clinical settings. In this review, we discuss the advantages and disadvantages of scFvs and nanobodies in regards to their application as the targeting domain of CARs. Ultimately, we discuss various CAR target antigens which have been targeted using nanobody-based CAR-T cells for the treatment of different types of malignancies.
| S-EPMC9036779 | biostudies-literature
Project description:As of April 2021, there are five commercially available chimeric antigen receptor (CAR) T cell therapies for hematological malignancies. With the current transition of CAR T cell manufacturing from academia to industry, there is a shift toward Good Manufacturing Practice (GMP)-compliant closed and automated systems to ensure reproducibility and to meet the increased demand for cancer patients. In this review we describe current CAR T cells clinical manufacturing models and discuss emerging technological advances that embrace scaling and production optimization. We summarize measures being used to shorten CAR T-cell manufacturing times and highlight regulatory challenges to scaling production for clinical use.Statement of significance ∣As the demand for CAR T cell cancer therapy increases, several closed and automated production platforms are being deployed, and others are in development.This review provides a critical appraisal of these technologies that can be leveraged to scale and optimize the production of next generation CAR T cells.
| S-EPMC8462122 | biostudies-literature
Project description:T cells engineered to express chimeric antigen receptors (CARs) can recognize and engage with target cancer cells with redirected specificity for cancer immunotherapy. However, there is a lack of ideal CARs for solid tumor antigens, which may lead to severe adverse effects. Here, we developed a light-inducible nuclear translocation and dimerization (LINTAD) system for gene regulation to control CAR T activation. We first demonstrated light-controllable gene expression and functional modulation in human embryonic kidney 293T and Jurkat T cell lines. We then improved the LINTAD system to achieve optimal efficiency in primary human T cells. The results showed that pulsed light stimulations can activate LINTAD CAR T cells with strong cytotoxicity against target cancer cells, both in vitro and in vivo. Therefore, our LINTAD system can serve as an efficient tool to noninvasively control gene activation and activate inducible CAR T cells for precision cancer immunotherapy.
| S-EPMC7030928 | biostudies-literature
Project description:Natural Killer (NK) cells and CD8+ cytotoxic T cells are two types of immune cells that can kill target cells through similar cytotoxic mechanisms. With the remarkable success of chimeric antigen receptor (CAR)-engineered T (CAR-T) cells for treating haematological malignancies, there is a rapid growing interest in developing CAR-engineered NK (CAR-NK) cells for cancer therapy. Compared to CAR-T cells, CAR-NK cells could offer some significant advantages, including: (1) better safety, such as a lack or minimal cytokine release syndrome and neurotoxicity in autologous setting and graft-versus-host disease in allogenic setting, (2) multiple mechanisms for activating cytotoxic activity, and (3) high feasibility for 'off-the-shelf' manufacturing. CAR-NK cells could be engineered to target diverse antigens, enhance proliferation and persistence in vivo, increase infiltration into solid tumours, overcome resistant tumour microenvironment, and ultimately achieve an effective anti-tumour response. In this review, we focus on recent progress in genetic engineering and clinical application of CAR-NK cells, and discuss current challenges and future promise of CAR-NK cells as a novel cellular immunotherapy in cancer.
| S-EPMC7452675 | biostudies-literature
Project description:The first CD19 CAR T-cell products, Kymriah and Yescarta, are entering the US market and also being evaluated for marketing authorization in the EU. This breakthrough has expanded the interest and also investments towards novel chimeric antigen receptor (CAR) designs, both for hematological malignancies and solid tumors. At the same time, there is active development in moving from autologous products to allogeneic, off-the-shelf -products. New manufacturing technologies are also emerging for production of these complex genetically-modified cells and even decentralized manufacturing in hospitals is under consideration. However, the high potency of CAR T-cells is associated with toxicity and not all patients respond to the treatment. In addition, the number of patient and product variables impacting the clinical outcome is high. The race towards novel CAR T treatment options for cancer patients has begun, but without careful design of the constructs and overall understanding of the factors that impact the ultimate outcome in each case, the road towards commercial success may be long and winding. This review discusses the product- and patient-related variables that may pose challenges for the industry and developers both from the scientific and regulatory perspective.
| S-EPMC5982434 | biostudies-other
Project description:Chimeric antigen receptor (CAR) T-cell therapy is emerging as an effective cancer treatment, such as for hematological malignancies, however its effectiveness as an approach to treat solid tumors, such as in colorectal cancer (CRC), remains to be better developed. One area of intense development has been in the identification and characterization of novel cancer-related ligand receptors for CAR design and evaluation. It is known that the CD6 receptors CD166 and CD318 are highly expressed in CRC, and several CAR-Ts have also been explored in preclinical and clinical studies for the treatment of CRC, with promising safety and efficacy findings. Here, we constructed a CAR based on the extracellular domain of CD6 and demonstrate its cytotoxic effect in target positive human CRC cell lines. Unexpectedly, we found that CD6-CAR-T cells targeted CD166 instead of CD318. Furthermore, CD6-CAR-T cells show robust cytotoxicity to CD166-positive cell lines in a dose-dependent manner with cytokine IFN-γ significantly released. Particularly, CD6-CAR-T cells show potent cytotoxicity targeting CRC cancer stem cells (CSCs), highlighting that CD6-CAR-T is a promising approach for the therapy of CRC.
| S-EPMC9637812 | biostudies-literature
Project description:Natural killer (NK) cells are unique innate immune cells and manifest rapid and potent cytotoxicity for cancer immunotherapy and pathogen removal without the requirement of prior sensitization or recognition of peptide antigens. Distinguish from the T lymphocyte-based cythotherapy with toxic side effects, chimeric antigen receptor-transduced NK (CAR-NK) cells are adequate to simultaneously improve efficacy and control adverse effects including acute cytokine release syndrome (CRS), neurotoxicity and graft-versus-host disease (GVHD). Moreover, considering the inherent properties of NK cells, the CAR-NK cells are "off-the-shelf" product satisfying the clinical demand for large-scale manufacture for cancer immunotherapy attribute to the cytotoxic effect via both NK cell receptor-dependent and CAR-dependent signaling cascades. In this review, we mainly focus on the latest updates of CAR-NK cell-based tactics, together with the opportunities and challenges for cancer immunotherapies, which represent the paradigm for boosting the immune system to enhance antitumor responses and ultimately eliminate malignancies. Collectively, we summarize and highlight the auspicious improvement in CAR-NK cells and will benefit the large-scale preclinical and clinical investigations in adoptive immunotherapy.
| S-EPMC8932134 | biostudies-literature
Project description:Chimeric antigen receptor (CAR) - and T-cell receptor (TCR) - modified T-cells are rapidly emerging as a viable treatment option for cancer patients. While initial clinical trials for these CAR T cells showed response rates of over 90% in some cases, retrospective studies have revealed a wide variability in patient responses as well as a significant proportion of patients relapsing after an initial response. In addition, patients often have severe adverse reactions to this therapy (e.g., cytokine release and neurologic syndromes). As a result, much research is still needed to be able to predict both therapeutic outcomes and possible toxicities. Furthermore, little success has been seen in treating solid tumors with engineered T cells and uncovering modes of failure is a topic of much research. Finally, little is known about the T cells' pharmacokinetics after infusion into the patient, as standard methods of tracking the cells analyze peripheral blood and tumor biopsies - both of which lack spatiotemporal information. Herein, we propose that reporter gene-based imaging of engineered T cells in humans would be tremendously valuable in elucidating the fate of the transplanted T cells and would greatly facilitate clinical translation of new CAR and TCR technologies. Currently, there are no FDA-approved reporter genes and few methods have advanced to human studies. Herein, we outline current reporter gene approaches to track engineered cells in vivo, analyze why current reporter genes have not progressed into the clinic, and propose "rules" for designing a widely applicable reporter gene for use in humans.
| S-EPMC7518311 | biostudies-literature