Glioblastoma > Ex-Vivo Expanded Autologous IL-8 Receptor (CXCR2) Modified CD70 CAR (8R-70CAR) T Cells
CAR T Cell Therapy for Glioblastoma
(IMPACT Trial)
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: University of Florida
Must not be taking: Immunosuppressants
Disqualifiers: HIV, Unstable angina, Autoimmune, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This trial tests a new treatment where a patient's own immune cells are modified to better attack brain cancer cells. It targets adults with a specific type of brain cancer (glioblastoma) that shows a certain marker (CD70). The modified cells are designed to recognize and kill the cancer more effectively. CD70 is a protein that is usually limited in normal tissue but appears in various cancers.
Will I have to stop taking my current medications?
The trial information does not specify whether you need to stop taking your current medications. However, if you are on immunosuppressants or other treatments for autoimmune diseases, you may need to stop them, as these conditions are part of the exclusion criteria.
What data supports the effectiveness of the treatment Ex-Vivo expanded autologous IL-8 receptor (CXCR2) modified CD70 CAR (8R-70CAR) T cells for glioblastoma?
Research shows that modifying CAR T cells with the IL-8 receptor (CXCR2) enhances their ability to move into tumors and stay there, leading to complete tumor regression and long-lasting immune memory in aggressive tumors like glioblastoma in pre-clinical models.
12345Is CAR T Cell Therapy for Glioblastoma safe?
The research on CAR T cell therapy, including modifications like IL-8 receptor (CXCR2) and RVG29, shows promising antitumor activity in preclinical models with no significant adverse effects reported. However, these findings are primarily from early-stage studies, and more research is needed to fully understand the safety profile in humans.
13467What makes the 8R-70CAR T cell treatment unique for glioblastoma?
The 8R-70CAR T cell treatment is unique because it uses T cells modified with the IL-8 receptor (CXCR2) to enhance their ability to migrate and persist within the tumor, potentially leading to complete tumor regression and long-lasting immune memory, which is a novel approach compared to other treatments for glioblastoma.
14589Eligibility Criteria
Adults over 18 with newly-diagnosed, high-grade glioblastoma without prior brain tumors, who've had a recent surgical resection leaving less than 9 cm2 tumor. They must have CD70 positive and MGMT-unmethylated tumors, good liver and kidney function, stable blood counts, no severe illnesses or immune conditions that could interfere with the treatment. Women of childbearing age must test negative for pregnancy and agree to contraception.Inclusion Criteria
My tumor is located in the upper part of my brain.
I have been newly diagnosed with a high-grade brain tumor without any previous brain tumor history.
CBC with differential with adequate bone marrow function: ANC ≥ 1500 cells/mm3, Platelet count ≥ 100,000 cells/mm3, Hemoglobin ≥ 10 g/dl
+10 more
Exclusion Criteria
I have been cancer-free for over 3 years, except for non-melanoma skin cancer.
I do not have HIV or any diseases that weaken my immune system.
My cancer has spread to the lining of my brain and spine, but it's limited.
+4 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Chemoradiation
Patients undergo standard of care chemoradiation
6-8 weeks
Treatment
Administration of a single dose of 8R-70CAR T cells after completion of radiation
1 day
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The trial is testing a new therapy using the patient's own T cells that are modified to target IL-8 receptor in CD70+ glioblastoma cells. It aims to evaluate if this personalized cellular therapy is safe and can be feasibly produced for each participant.
1Treatment groups
Experimental Treatment
Group I: 8R-70CAR T cellsExperimental Treatment1 Intervention
Cohort 1 will receive 1 x 10\^6 cells/kg. Cohort 2 will receive 1 x 10\^7 cells/kg. Cohort 3 will receive 1 x 10\^8 cells/kg. Cohort 4 will receive Cy/Flu + CAR T cells at established maximum tolerated dose.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of Florida HealthGainesville, FL
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Who Is Running the Clinical Trial?
University of FloridaLead Sponsor
AM Rosen FoundationCollaborator
United States Department of DefenseCollaborator
References
CXCR1- or CXCR2-modified CAR T cells co-opt IL-8 for maximal antitumor efficacy in solid tumors. [2021]Chimeric antigen receptor (CAR) T-cell therapy targeting solid tumors has stagnated as a result of tumor heterogeneity, immunosuppressive microenvironments, and inadequate intratumoral T cell trafficking and persistence. Early (≤3 days) intratumoral presentation of CAR T cells post-treatment is a superior predictor of survival than peripheral persistence. Therefore, we have co-opted IL-8 release from tumors to enhance intratumoral T-cell trafficking through a CAR design for maximal antitumor activity in solid tumors. Here, we demonstrate that IL-8 receptor, CXCR1 or CXCR2, modified CARs markedly enhance migration and persistence of T cells in the tumor, which induce complete tumor regression and long-lasting immunologic memory in pre-clinical models of aggressive tumors such as glioblastoma, ovarian and pancreatic cancer.
Antitumor activity of the third generation EphA2 CAR-T cells against glioblastoma is associated with interferon gamma induced PD-L1. [2022]Glioblastoma (GBM) is the most common and aggressive brain malignancy in adults and is currently incurable with conventional therapies. The use of chimeric antigen receptor (CAR) modified T cells has been successful in clinical treatment of blood cancers, except solid tumors such as GBM. This study generated two third-generation CARs targeting different epitopes of ephrin type-A receptor 2 (EphA2) and examined their anti-GBM efficacy in vitro and in tumor-bearing mice. We observed that these two types of T cells expressing CAR (CAR-T) targeting EphA2 could be activated and expanded by EphA2 positive tumor cells in vitro. The survival of tumor-bearing mice after EphA2 CAR-T cell treatment was significantly improved. T cells transduced with one of the two EphA2 CARs exhibited better anti-tumor activity, which is related to the upregulation of CXCR-1/2 and appropriate interferon-γ (IFN-γ) production. CAR-T cells expressed excessively high level of IFN-γ exhibited poor anti-tumor activity resulting from inducing the upregulation of PD-L1 in GBM cells. The combination of CAR-T cells with poor anti-tumor activity and PD1 blockade improved the efficacy in tumor-bearing mice. In conclusion, both types of EphA2 CAR-T cells eliminated 20%-50% of GBM in xenograft mouse models. The appropriate combination of IFN-γ and CXCR-1/2 levels is a key factor for evaluating the antitumor efficiency of CAR-T cells.
Constitutive Signaling from an Engineered IL7 Receptor Promotes Durable Tumor Elimination by Tumor-Redirected T Cells. [2022]Successful adoptive T-cell immunotherapy of solid tumors will require improved expansion and cytotoxicity of tumor-directed T cells within tumors. Providing recombinant or transgenic cytokines may produce the desired benefits but is associated with significant toxicities, constraining clinical use. To circumvent this limitation, we constructed a constitutively signaling cytokine receptor, C7R, which potently triggers the IL7 signaling axis but is unresponsive to extracellular cytokine. This strategy augments modified T-cell function following antigen exposure, but avoids stimulating bystander lymphocytes. Coexpressing the C7R with a tumor-directed chimeric antigen receptor (CAR) increased T-cell proliferation, survival, and antitumor activity during repeated exposure to tumor cells, without T-cell dysfunction or autonomous T-cell growth. Furthermore, C7R-coexpressing CAR T cells were active against metastatic neuroblastoma and orthotopic glioblastoma xenograft models even at cell doses that had been ineffective without C7R support. C7R may thus be able to enhance antigen-specific T-cell therapies against cancer.Significance: The constitutively signaling C7R system developed here delivers potent IL7 stimulation to CAR T cells, increasing their persistence and antitumor activity against multiple preclinical tumor models, supporting its clinical development. Cancer Discov; 7(11); 1238-47. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 1201.
Glioblastoma-targeted CD4+ CAR T cells mediate superior antitumor activity. [2019]Chimeric antigen receptor-modified (CAR-modified) T cells have shown promising therapeutic effects for hematological malignancies, yet limited and inconsistent efficacy against solid tumors. The refinement of CAR therapy requires an understanding of the optimal characteristics of the cellular products, including the appropriate composition of CD4+ and CD8+ subsets. Here, we investigated the differential antitumor effect of CD4+ and CD8+ CAR T cells targeting glioblastoma-associated (GBM-associated) antigen IL-13 receptor α2 (IL13Rα2). Upon stimulation with IL13Rα2+ GBM cells, the CD8+ CAR T cells exhibited robust short-term effector function but became rapidly exhausted. By comparison, the CD4+ CAR T cells persisted after tumor challenge and sustained their effector potency. Mixing with CD4+ CAR T cells failed to ameliorate the effector dysfunction of CD8+ CAR T cells, while surprisingly, CD4+ CAR T cell effector potency was impaired when coapplied with CD8+ T cells. In orthotopic GBM models, CD4+ outperformed CD8+ CAR T cells, especially for long-term antitumor response. Further, maintenance of the CD4+ subset was positively correlated with the recursive killing ability of CAR T cell products derived from GBM patients. These findings identify CD4+ CAR T cells as a highly potent and clinically important T cell subset for effective CAR therapy.
IL7 and IL7 Flt3L co-expressing CAR T cells improve therapeutic efficacy in mouse EGFRvIII heterogeneous glioblastoma. [2023]Chimeric antigen receptor (CAR) T cell therapy in glioblastoma faces many challenges including insufficient CAR T cell abundance and antigen-negative tumor cells evading targeting. Unfortunately, preclinical studies evaluating CAR T cells in glioblastoma focus on tumor models that express a single antigen, use immunocompromised animals, and/or pre-treat with lymphodepleting agents. While lymphodepletion enhances CAR T cell efficacy, it diminishes the endogenous immune system that has the potential for tumor eradication. Here, we engineered CAR T cells to express IL7 and/or Flt3L in 50% EGFRvIII-positive and -negative orthotopic tumors pre-conditioned with non-lymphodepleting irradiation. IL7 and IL7 Flt3L CAR T cells increased intratumoral CAR T cell abundance seven days after treatment. IL7 co-expression with Flt3L modestly increased conventional dendritic cells as well as the CD103+XCR1+ population known to have migratory and antigen cross-presenting capabilities. Treatment with IL7 or IL7 Flt3L CAR T cells improved overall survival to 67% and 50%, respectively, compared to 9% survival with conventional or Flt3L CAR T cells. We concluded that CAR T cells modified to express IL7 enhanced CAR T cell abundance and improved overall survival in EGFRvIII heterogeneous tumors pre-conditioned with non-lymphodepleting irradiation. Potentially IL7 or IL7 Flt3L CAR T cells can provide new opportunities to combine CAR T cells with other immunotherapies for the treatment of glioblastoma.
Optimizing EphA2-CAR T Cells for the Adoptive Immunotherapy of Glioma. [2020]Glioblastoma is the most aggressive primary brain tumor in humans and is virtually incurable with conventional therapies. Chimeric antigen receptor (CAR) T cell therapy targeting the glioblastoma antigen EphA2 is an attractive approach to improve outcomes because EphA2 is expressed highly in glioblastoma but only at low levels in normal brain tissue. Building upon our previous findings in this area, we generated and evaluated a panel of EphA2-specific CARs. We demonstrate here that T cells expressing CD28.ζ and 41BB.ζ CARs with short spacers had similar effector function, resulting in potent antitumor activity. In addition, incorporating the 41BB signaling domain into CD28.ζ CARs did not improve CAR T cell function. While we could not determine functional differences between CD28.ζ, 41BB.ζ, and CD28.41BB.ζ CAR T cells, we selected CD28.ζ CAR T cells for further clinical development based on safety consideration.
Rabies virus glycoprotein 29 (RVG29) promotes CAR-T immunotherapy for glioma. [2023]Chimeric antigen receptor T cell (CAR-T) therapy has limited efficacy for treating glioma because of the infiltrative nature of the blood-brain barrier (BBB) and T cell exhaustion. Conjugation with rabies virus glycoprotein (RVG) 29 enhances the brain-related efficacy of various agents. Here we assess whether RVG enhances the ability of CAR-T cells to cross the BBB and improves their immunotherapy. We generated 70R CAR-T cells (anti-CD70 CAR-T modified with RVG29) and validated their tumor-killing efficacy in vitro and in vivo. We validated their effects on tumor regression in a human glioma mouse orthotopic xenograft model as well as in patient-derived orthotopic xenograft (PDOX) models. The signaling pathways activated in 70R CAR-T cells were revealed by RNA sequencing. The 70R CAR-T cells we generated showed effective antitumor function against CD70+ glioma cells both in vitro and in vivo. 70R CAR-T cells were better able to cross the BBB into the brain than CD70 CAR-T cells under the same treatment conditions. Moreover, 70R CAR-T cells significantly promote the regression of glioma xenografts and improve the physical characteristics of mice without causing overt adverse effects. RVG modification enables CAR-T cells to cross the BBB, and stimulation with glioma cells induces 70R CAR-T cells to expand in a resting state. The modification of RVG29 has a positive impact on CAR-T therapy for brain tumors and may have potential in CAR-T therapy for glioma.
Generation of CAR T cells for adoptive therapy in the context of glioblastoma standard of care. [2021]Adoptive T cell immunotherapy offers a promising strategy for specifically targeting and eliminating malignant gliomas. T cells can be engineered ex vivo to express chimeric antigen receptors specific for glioma antigens (CAR T cells). The expansion and function of adoptively transferred CAR T cells can be potentiated by the lymphodepletive and tumoricidal effects of standard of care chemotherapy and radiotherapy. We describe a method for generating CAR T cells targeting EGFRvIII, a glioma-specific antigen, and evaluating their efficacy when combined with a murine model of glioblastoma standard of care. T cells are engineered by transduction with a retroviral vector containing the anti-EGFRvIII CAR gene. Tumor-bearing animals are subjected to host conditioning by a course of temozolomide and whole brain irradiation at dose regimens designed to model clinical standard of care. CAR T cells are then delivered intravenously to primed hosts. This method can be used to evaluate the antitumor efficacy of CAR T cells in the context of standard of care.
Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy. [2023]A patient with recurrent multifocal glioblastoma received chimeric antigen receptor (CAR)-engineered T cells targeting the tumor-associated antigen interleukin-13 receptor alpha 2 (IL13Rα2). Multiple infusions of CAR T cells were administered over 220 days through two intracranial delivery routes - infusions into the resected tumor cavity followed by infusions into the ventricular system. Intracranial infusions of IL13Rα2-targeted CAR T cells were not associated with any toxic effects of grade 3 or higher. After CAR T-cell treatment, regression of all intracranial and spinal tumors was observed, along with corresponding increases in levels of cytokines and immune cells in the cerebrospinal fluid. This clinical response continued for 7.5 months after the initiation of CAR T-cell therapy. (Funded by Gateway for Cancer Research and others; ClinicalTrials.gov number, NCT02208362 .).