CAR T-cells to treat brain tumors

Guzman, Grace; Pellot, Karolina; Reed, Megan R.; Rodriguez, Analiz

doi:10.1016/j.brainresbull.2023.02.014

Cited by 10 publications

(5 citation statements)

References 236 publications

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“…Tumors of the CNS are perhaps the most challenging targets for CAR T-cell therapy, owing to several factors. 130,131 First, the difficulty inherent to accessing the CNS imposed by the presence of the blood brain barrier (BBB). Second, the heightened risk of adverse events related specifically to CAR T-cell therapies, as well as the heightened risk of those specific toxicities occurring in their more severe forms, imposed by the location of the primary disease within the CNS.…”

Section: Central Nervous System Tumorsmentioning

confidence: 99%

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The Implementation of Chimeric Antigen Receptor (CAR) T-cell Therapy in Pediatric Patients: Where Did We Come From, Where Are We Now, and Where are We Going?

Knight E,

Oluwole,

Kitko

2024

Clinical Hematology International

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CD19-directed Chimeric Antigen Receptor (CAR) T-cell therapy has revolutionized the treatment of patients with B-cell acute lymphoblastic leukemia (B-ALL). Somewhat uniquely among oncologic clinical trials, early clinical development occurred simultaneously in both children and adults. In subsequent years however, the larger number of adult patients with relapsed/refractory (r/r) malignancies has led to accelerated development of multiple CAR T-cell products that target a variety of malignancies, resulting in six currently FDA-approved for adult patients. By comparison, only a single CAR-T cell therapy is approved by the FDA for pediatric patients: tisagenlecleucel, which is approved for patients  25 years with refractory B-cell precursor ALL, or B-cell ALL in second or later relapse. Tisagenlecleucel is also under evaluation in pediatric patients with relapsed/refractory B-cell non-Hodgkin lymphoma, but is not yet been approved for this indication. All the other FDA-approved CD19-directed CAR-T cell therapies available for adult patients (axicabtagene ciloleucel, brexucabtagene autoleucel, and lisocabtagene maraleucel) are currently under investigations among children, with preliminary results available in some cases. As the volume and complexity of data continue to grow, so too does the necessity of rapid assimilation and implementation of those data. This is particularly true when considering “atypical” situations, e.g. those arising when patients do not precisely conform to the profile of those included in pivotal clinical trials, or when alternative treatment options (e.g. hematopoietic stem cell transplantation (HSCT) or bispecific T-cell engagers (BITEs)) are also available. We have therefore developed a relevant summary of the currently available literature pertaining to the use of CD19-directed CAR-T cell therapies in pediatric patients, and sought to provide guidance for clinicians seeking additional data about specific clinical situations.

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Section: Central Nervous System Tumorsmentioning

confidence: 99%

“…134 These challenges, as well as some of the means by which they may be overcome have recently been discussed in a pair of excellent review articles. 130,131 Despite these limitations, some early evidence of success in pediatric clinical trials has been seen.…”

Section: Central Nervous System Tumorsmentioning

confidence: 99%

The Implementation of Chimeric Antigen Receptor (CAR) T-cell Therapy in Pediatric Patients: Where Did We Come From, Where Are We Now, and Where are We Going?

Knight E,

Oluwole,

Kitko

2024

Clinical Hematology International

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“…On the other hand, regarding cellular therapies, autologous T cells can be engineered to express tumor‐reactive TCRs or chimeric antigen receptors derived from metastases or circulating cells, thereby enhancing their infiltration into brain metastases. While this approach has demonstrated efficacy in targeting refractory solid tumors in phase I clinical trials, [103] its effectiveness in brain tumor settings remains to be established [104] . There is potential to combine various strategies for synergistic therapeutic effects.…”

Section: Design Of Next‐generation Therapeuticsmentioning

confidence: 99%

“…While this approach has demonstrated efficacy in targeting refractory solid tumors in phase I clinical trials, [103] its effectiveness in brain tumor settings remains to be established. [104] There is potential to combine various strategies for synergistic therapeutic effects. These combined approaches might involve transfecting T cells to efficiently express tumor-reactive TCRs using nanovesicle cargos, [105] utilizing T cells to directly deliver drugs to the tumor site, [106] or pairing T cells with helper cells, such as stem cell-derived endothelial progenitors.…”

Section: Transcriptomic Biomarkers (References) Protein Biomarkers An...mentioning

confidence: 99%

Understanding the heterogeneous immune repertoire of brain metastases for designing next‐gen therapeutics

Wang,

Chen

2023

Brain-X

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Approximately 20% of cancer patients experience brain metastases in the advanced stages as circulating tumor cells migrate to and colonize the brain microvasculature. Due to the challenges associated with biopsies, our understanding of the tumor microenvironment and heterogeneity in brain metastases remains limited, hindering the development of systemic approaches for detection and treatment. Emerging evidence suggests that specific brain metastases induce a substantial level of immune activation and infiltration, which provides an opportunity to design specific immunotherapies targeting brain metastases. This perspective aims to summarize recent advancements in molecular profiling of the immune repertoires of brain metastases using biopsy‐based approaches, with an emphasis on tumor‐reactive T cells. Additionally, we discuss the potential of alternative tissues and technologies that offer improved temporal resolution, throughput, and fidelity for tracking tumor dynamics.

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“…Despite this progress, many limitations remain. For example, existing CAR T therapies are ineffective against solid tumors due to the immunosuppressive tumor microenvironment and low rate of tumor infiltration (Feigl et al 2023 ; Guzman et al 2023 ). Additionally, CAR T therapy can cause severe side effects, such as cytokine release syndrome and on-target, off-tumor toxicity (Chen et al 2023 ).…”

Section: Introductionmentioning

confidence: 99%

Information-Theoretic Analysis of a Model of CAR-4-1BB-Mediated NFκB Activation

Tserunyan,

Finley

2023

Bull Math Biol

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Systems biology utilizes computational approaches to examine an array of biological processes, such as cell signaling, metabolomics and pharmacology. This includes mathematical modeling of CAR T cells, a modality of cancer therapy by which genetically engineered immune cells recognize and combat a cancerous target. While successful against hematologic malignancies, CAR T cells have shown limited success against other cancer types. Thus, more research is needed to understand their mechanisms of action and leverage their full potential. In our work, we set out to apply information theory on a mathematical model of NFκB signaling initiated by the CAR following antigen encounter. First, we estimated channel capacity for CAR-4-1BB-mediated NFκB signal transduction. Next, we evaluated the pathway’s ability to distinguish contrasting “low” and “high” antigen concentration levels, depending on the amount of variability in protein concentrations. Finally, we assessed the fidelity by which NFκB activation reflects the encountered antigen concentration, depending on the prevalence of antigen-positive targets in tumor population. We found that in most scenarios, fold change in the nuclear concentration of NFκB carries a higher channel capacity for the pathway than NFκB’s absolute response. Additionally, we found that most errors in transducing the antigen signal through the pathway skew towards underestimating the concentration of encountered antigen. Finally, we found that disabling IKKβ deactivation could increase signaling fidelity against targets with antigen-negative cells. Our information-theoretic analysis of signal transduction can provide novel perspectives on biological signaling, as well as enable a more informed path to cell engineering.Kindly check and confirm whether the corresponding affiliation is correctly identified.this is correct

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CAR T-cells to treat brain tumors

Cited by 10 publications

References 236 publications

The Implementation of Chimeric Antigen Receptor (CAR) T-cell Therapy in Pediatric Patients: Where Did We Come From, Where Are We Now, and Where are We Going?

The Implementation of Chimeric Antigen Receptor (CAR) T-cell Therapy in Pediatric Patients: Where Did We Come From, Where Are We Now, and Where are We Going?

Understanding the heterogeneous immune repertoire of brain metastases for designing next‐gen therapeutics

Information-Theoretic Analysis of a Model of CAR-4-1BB-Mediated NFκB Activation

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