Chimeric Antigen Receptors for the Tumour Microenvironment

Habib, Rosemary; Nagrial, Adnan; Micklethwaite, Kenneth; Gowrishankar, Kavitha

doi:10.1007/978-3-030-44518-8_8

Cited by 8 publications

(9 citation statements)

References 160 publications

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“…This technology will be a significant game changer allowing for clinicians to target intracellular oncogenic pathways. Besides targeting cancer cells, considerations of how to target the microenvironment to enhance anti-tumor activity is underway (183). In pediatric brain tumors, further work is needed to delinate the tumor microenvironment taking into account subtype variability.…”

Section: Discussion and Future Directionsmentioning

confidence: 99%

CAR T Cell Therapy for Pediatric Brain Tumors

et al. 2020

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Chimeric Antigen Receptor (CAR) T cell therapy has recently begun to be used for solid tumors such as glioblastoma multiforme. Many children with pediatric malignant brain tumors develop extensive long-term morbidity of intensive multimodal curative treatment. Others with certain diagnoses and relapsed disease continue to have limited therapies and a dismal prognosis. Novel treatments such as CAR T cells could potentially improve outcomes and ameliorate the toxicity of current treatment. In this review, we discuss the potential of using CAR therapy for pediatric brain tumors. The emerging insights on the molecular subtypes and tumor microenvironment of these tumors provide avenues to devise strategies for CAR T cell therapy. Unique characteristics of these brain tumors, such as location and associated morbid treatment induced neuro-inflammation, are novel challenges not commonly encountered in adult brain tumors. Despite these considerations, CAR T cell therapy has the potential to be integrated into treatment schema for aggressive pediatric malignant brain tumors in the future.

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Section: Discussion and Future Directionsmentioning

confidence: 99%

CAR T Cell Therapy for Pediatric Brain Tumors

et al. 2020

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“…Currently, successful tumor control through ACT is mainly restricted to hematologic malignancies, while major hurdle still exist for solid tumors (6)(7)(8)(9). Besides problems in entering the solid tumor milieu, adoptively transferred T cells develop functional deficits inside the tumor milieu (14,16,17,19,59). Preventing the development of T cell deficits in the TME holds the promise to improve the portion of patients that respond to ACT (12,21,59,60).…”

Section: Discussion and Relevance For Immunotherapymentioning

confidence: 99%

“…Besides problems in entering the solid tumor milieu, adoptively transferred T cells develop functional deficits inside the tumor milieu ( 14 , 16 , 17 , 19 , 59 ). Preventing the development of T cell deficits in the TME holds the promise to improve the portion of patients that respond to ACT ( 12 , 21 , 59 , 60 ).…”

Section: Discussion and Relevance For Immunotherapymentioning

confidence: 99%

Tumor Lactic Acidosis: Protecting Tumor by Inhibiting Cytotoxic Activity Through Motility Arrest and Bioenergetic Silencing

et al. 2020

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Adoptive T cell therapy (ACT) is highly effective in the treatment of hematologic malignancies, but shows limited success in solid tumors. Inactivation of T cells in the tumor milieu is a major hurdle to a wider application of ACT. Cytotoxicity is the most relevant activity for tumor eradication. Here, we document that cytotoxic T cells (CTL) in lactic acidosis exhibited strongly reduced tumor cell killing, which could be compensated partly by increasing the CTL to tumor cell ratio. Lactic acid intervened at multiple steps of the killing process. Lactic acid repressed the number of CTL that performed lytic granule exocytosis (degranulation) in tumor cell co-culture, and, additionally impaired the quality of the response, as judged by the reduced intensity of degranulation and lower secretion of cytotoxins (perforin, granzyme B, granzyme A). CTL in lactic acid switched to a low bioenergetic profile with an inability to metabolize glucose efficiently. They responded to anti-CD3 stimulation poorly with less extracellular acidification rate (ECAR). This might explain their repressed granule exocytosis activity. Using live cell imaging, we show that CTL in lactic acid have reduced motility, resulting in lower field coverage. Many CTL in lactic acidosis did not make contact with tumor cells; however, those which made contact, adhered to the tumor cell much longer than a CTL in normal medium. Reduced motility together with prolonged contact duration hinders serial killing, a defining feature of killing potency, but also locally confines cytotoxic activity, which helps to reduce the risk of collateral organ damage. These activities define lactic acid as a major signaling molecule able to orchestrate the spatial distribution of CTL inside inflamed tissue, such as cancer, as well as moderating their functional response. Lactic acid intervention and strategies to improve T cell metabolic fitness hold promise to improve the clinical efficacy of T cell–based cancer immunotherapy.

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“…However, CAR-T cell therapy has not yet had similar results in solid tumors [8][9][10]. Solid tumors have a more complex immunosuppressive microenvironment and there are many immunosuppressive cells and cytokines which inhibit the activation and survival of CAR-T cells within the tumor [11,12]. The dense extracellular matrix (ECM) also prevents CAR-T cells from in ltrating into solid tumors and can affect CAR-T cell activity [13,14].…”

Section: Introductionmentioning

confidence: 99%

Co-expression of IL-7 and PH20 Promote anti-GPC3 CAR-T Tumor Suppressor Activity in Vivo and in Vitro

Liu

Wang

Jiang

et al. 2020

Preprint

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While CAR-T therapy has successfully treated hematological malignancies, it has proved sub-optimal for solid tumors. The main limitation is the inability of CAR-T cells to infiltrate and then proliferate within tumors. In this study, we co-expressed IL-7 and PH20, a type of hyaluronidase, with CAR targeting GPC3 (G3CAR-7×20) to address these issues. We found (G3CAR-7×20) exhibited better proliferation in vivo and in vitro than G3CAR, reduced the level of apoptosis after stimulation by tumor cells, and maintained the memory phenotype of CAR-T cells. G3CAR-7×20 also increased the ability of CAR-T cells to infiltrate tumor tissue. G3CAR-7×20 may significantly enhance the efficacy of CAR-T cells in solid tumors.

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Chimeric Antigen Receptors for the Tumour Microenvironment

Cited by 8 publications

References 160 publications

CAR T Cell Therapy for Pediatric Brain Tumors

CAR T Cell Therapy for Pediatric Brain Tumors

Tumor Lactic Acidosis: Protecting Tumor by Inhibiting Cytotoxic Activity Through Motility Arrest and Bioenergetic Silencing

Co-expression of IL-7 and PH20 Promote anti-GPC3 CAR-T Tumor Suppressor Activity in Vivo and in Vitro

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