Pilot Trial of Adoptive Transfer of Chimeric Antigen Receptor–transduced T Cells Targeting EGFRvIII in Patients With Glioblastoma

Goff, Stephanie L.; Morgan, Richard A.; Yang, James Chih‐Hsin; Sherry, Richard M.; Robbins, Paul F.; Restifo, Nicholas P.; Feldman, Steven A.; Lu, Yong-Chen; Lu, Lily; Zheng, Zhili; Xi, Liqiang; Epstein, Monica; McIntyre, Lori; Malekzadeh, Parisa; Raffeld, Mark; Fine, Howard A.; Rosenberg, Steven A.

doi:10.1097/cji.0000000000000260

Cited by 278 publications

(250 citation statements)

References 43 publications

Supporting

Mentioning

246

Contrasting

Unclassified

Order By: Relevance

“…At the highest dose levels of ≥10 10 T cells, pulmonary toxicities were observed, including one treatment‐related mortality after IV infusion of 6 × 10 10 cells, resulting in respiratory symptoms within hours of cell infusion. Post‐mortem analysis demonstrated significant pulmonary edema . In the majority of patients (14 of 18), low levels of CAR T cell persistence could be detected one month after infusion.…”

Section: Initial Clinical Experience With Car T Cell Therapy For Gbmmentioning

confidence: 97%

“…The NCI published results of a dose escalation study of EGFRvIII CAR T cells in recurrent EGFRvIII+ GBM utilizing a third‐generation human scFv‐based EGFRvIII CAR with CD28 and 4‐1BB costimulation (NCT01454596) . CAR T cells were delivered intravenously after lymphodepleting chemotherapy, followed by systemic IL‐2 support.…”

Section: Initial Clinical Experience With Car T Cell Therapy For Gbmmentioning

confidence: 99%

“…After treatment with IL13Rα2‐CAR T, one patient had a CR lasting about 7.5 months, which was remarkable given the aggressive multifocal nature of his recurrent disease. After treatment with EGFRvIII‐CAR T cells on the clinical trial NCT02209376, one of 10 patients had extended stable disease and remained alive more than 18 months, and on the NCT01454596 trial, one patient also had extended PFS of 12.5 months . Finally, after HER2‐CAR T treatment, 1 of 17 patients had a partial response and seven of 17 patients had stable disease (three extended stable disease).…”

Section: Initial Clinical Experience With Car T Cell Therapy For Gbmmentioning

confidence: 99%

“…Locoregional CNS delivery of CAR T cells may also reduce the risk of systemic toxicities associated with the therapeutic cells. For instance, in clinical trials of EGFRvIII‐ and HER2‐CAR T cells, high‐dose peripheral (IV) infusion increased the risk of serious pulmonary toxicities, and in the most severe cases resulted in death. Locoregional delivery is expected to limit intravenous first‐pass pulmonary toxicity as well as off‐tumor targeting of other systemic tissues.…”

Section: Getting Cars To Go: Car T Cell Trafficking To Brain Tumorsmentioning

confidence: 99%

“…While it is reasonable to assume that lymphodepletion will also augment CAR T cell clinical responses for brain tumors, particularly for IV delivery, its therapeutic benefit in the context of brain tumors requires further clinical validation, since most clinical studies to date have not included lymphodepleting regimens. Additionally, for the two reported EGFRvIII‐CAR clinical trials, the NCI study that included lymphodepletion pre‐conditioning (Fludarabine + Cyclophosphamide) and systemic IL‐2 cytokine support (NCT01454596) did not show significantly improved CAR T cell persistence, expansion, or patient outcomes compared with the University of Pennsylvania study that did not include lymphodepletion (https://clinicaltrials.gov/ct2/show/NCT02209376). While this could be due to many factors, such as CAR design, target selection, and patient enrollment, it highlights the need for further clinical assessment of the role lymphodepletion in the application of CAR T cells for brain tumors, particularly for locoregional delivery.…”

Section: From Bench To Bedside: Clinical Trial Considerationsmentioning

confidence: 99%

See 4 more Smart Citations

CAR T cells for brain tumors: Lessons learned and road ahead

Akhavan

Alizadeh

Wang

et al. 2019

Immunological Reviews

173

161

View full text Add to dashboard Cite

Malignant brain tumors, including glioblastoma, represent some of the most difficult to treat of solid tumors. Nevertheless, recent progress in immunotherapy, across a broad range of tumor types, provides hope that immunological approaches will have the potential to improve outcomes for patients with brain tumors. Chimeric antigen receptors (CAR) T cells, a promising immunotherapeutic modality, utilizes the tumor targeting specificity of any antibody or receptor ligand to redirect the cytolytic potency of T cells. The remarkable clinical response rates of CD19‐targeted CAR T cells and early clinical experiences in glioblastoma demonstrating safety and evidence for disease modifying activity support the potential of further advancements ultimately providing clinical benefit for patients. The brain, however, is an immune specialized organ presenting unique and specific challenges to immune‐based therapies. Remaining barriers to be overcome for achieving effective CAR T cell therapy in the central nervous system (CNS) include tumor antigenic heterogeneity, an immune‐suppressive microenvironment, unique properties of the CNS that limit T cell entry, and risks of immune‐based toxicities in this highly sensitive organ. This review will summarize preclinical and clinical data for CAR T cell immunotherapy in glioblastoma and other malignant brain tumors, including present obstacles to advancement.

show abstract

Section: Initial Clinical Experience With Car T Cell Therapy For Gbmmentioning

confidence: 97%

Section: Initial Clinical Experience With Car T Cell Therapy For Gbmmentioning

confidence: 99%

Section: Initial Clinical Experience With Car T Cell Therapy For Gbmmentioning

confidence: 99%

Section: Getting Cars To Go: Car T Cell Trafficking To Brain Tumorsmentioning

confidence: 99%

Section: From Bench To Bedside: Clinical Trial Considerationsmentioning

confidence: 99%

See 3 more Smart Citations

CAR T cells for brain tumors: Lessons learned and road ahead

Akhavan

Alizadeh

Wang

et al. 2019

Immunological Reviews

173

161

View full text Add to dashboard Cite

show abstract

Current and Future Roles of Chimeric Antigen Receptor T-Cell Therapy in Neurology

Ismail,

Gallus,

Meuth

et al. 2024

JAMA Neurol

View full text Add to dashboard Cite

ImportanceAdvancements in molecular engineering have facilitated the creation of engineered T cells that express synthetic receptors, termed chimeric antigen receptors (CARs). This is promising not only in cancer treatment but also in addressing a spectrum of other conditions. This review provides a comprehensive overview of the current approaches and future potential of CAR T-cell therapy in the field of neurology, particularly for primary brain tumors and autoimmune neurological disorders.ObservationsCAR T-cell therapy for glioblastoma is promising; however, first-in-human trials did not yield significant success or showed only limited success in a subset of patients. To date, the efficacy of CAR T-cell therapies has been demonstrated in animal models of multiple sclerosis, but larger human studies to corroborate the efficacy remain pending. CAR T cells showed efficacy in treatment of patients with relapsed or refractory aquaporin 4–immunoglobulin G–seropositive neuromyelitis optica spectrum disorders. Further studies with larger patient populations are needed to confirm these results. Success was reported also for treatment of cases with generalized myasthenia gravis using CAR T cells. Chimeric autoantibody receptor T cells, representing a modified form of CAR T cells directed against autoreactive B cells secreting autoantibodies, were used to selectively target autoreactive anti–N-methyl-d-aspartate B cells under in vitro and in vivo conditions, providing the basis for human studies and application to other types of autoimmune encephalitis associated with neuronal or glial antibodies.Conclusions and RelevanceCAR T cells herald a new era in the therapeutic landscape of neurological disorders. While their application in solid tumors, such as glioblastoma, has not universally yielded robust success, emerging innovative strategies show promise, and there is optimism for their effectiveness in certain autoimmune neurological disorders.

show abstract

Systemic Anti–PD-1 Immunotherapy Results in PD-1 Blockade on T Cells in the Cerebrospinal Fluid

et al. 2020

View full text Add to dashboard Cite

IMPORTANCE Little is known about the penetration and bioactivity of systemically administered programmed cell death 1 (PD-1) antibodies in the central nervous system. Such information is critical for advancing checkpoint antibody therapies for treatment of brain tumors. OBJECTIVE To evaluate pembrolizumab concentrations and PD-1 blockade on T cells in the cerebrospinal fluid (CSF) after intravenous administration. DESIGN, SETTING, AND PARTICIPANTS Cerebrospinal fluid and blood samples were collected from 10 adult patients with high-grade gliomas who were participating in clinical trials of intracranially administered chimeric antigen receptor (CAR) T cells and intravenous pembrolizumab at City of Hope in Duarte, California, from 2017 through 2019. Neuropharmacokinetic and immunologic correlative studies were performed on CSF and serum samples. INTERVENTIONS OR EXPOSURES Pembrolizumab, 200 mg, was given intravenously every 3 weeks with a median of 2 cycles (range, 1-8). CAR T cells were administered intracranially every 1 to 4 weeks. Cerebrospinal fluid and blood samples were collected on the day of CAR T-cell administration and then 24 hours later for a total of 100 paired samples. MAIN OUTCOMES AND MEASURES Pembrolizumab concentrations were measured by enzyme-linked immunosorbent assay, PD-1 blocking on T cells by flow cytometry, and results of PD-1 blockade on CAR T-cell function by in vitro tumor rechallenge assays. RESULTS Of the 10 patients included in this study, the mean (SD) age was 45.7 (11.0) years, and 6 (60%) were women. Steady-state pembrolizumab concentrations in the CSF were achieved by 24 hours after initial intravenous administration, with a mean CSF:serum ratio of 0.009 (95% CI, 0.004-0.014). The CSF concentrations of pembrolizumab effectively blocked PD-1 on both endogenous T cells and intracranially administered CAR T cells in the CSF, with flow cytometric detection of surface PD-1 on the T cells decreasing from a mean (SD) of 39.3% (20.2%) before pembrolizumab to a mean (SD) of 3.8% (5.8%) 24 hours after pembrolizumab infusion. Steady-state concentrations in the CSF were maintained throughout the 21-day cycle of pembrolizumab, as was the PD-1 blocking effect, evidenced by no increase in detectable surface PD-1 on T cells in the CSF during that time period. Incubation of PD-1-expressing T cells with CSF samples from patients treated with pembrolizumab also resulted in PD-1 blockade. CONCLUSIONS AND RELEVANCE Results of this study demonstrate steady-state concentrations of pembrolizumab in CSF after intravenous administration as well as CSF concentrations that are sufficient for blocking PD-1 on endogenous and adoptively transferred T cells. This provides mechanistic insight regarding the ability of systemically administered PD-1 blocking antibodies to modulate T-cell activity in the brain.

show abstract

Pilot Trial of Adoptive Transfer of Chimeric Antigen Receptor–transduced T Cells Targeting EGFRvIII in Patients With Glioblastoma

Cited by 278 publications

References 43 publications

CAR T cells for brain tumors: Lessons learned and road ahead

CAR T cells for brain tumors: Lessons learned and road ahead

Current and Future Roles of Chimeric Antigen Receptor T-Cell Therapy in Neurology

Systemic Anti–PD-1 Immunotherapy Results in PD-1 Blockade on T Cells in the Cerebrospinal Fluid

Contact Info

Product

Resources

About