CAR T-Cell Therapy for Brain Cancer
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: City of Hope Medical Center
Must not be taking: Bevacizumab
Disqualifiers: Uncontrolled seizures, Active infection, HIV, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This phase I trial studies the side effects and best dose of chimeric antigen receptor (CAR) T cells with a chlorotoxin tumor-targeting domain in treating patients with MPP2+ glioblastoma that has come back (recurrent) or that is growing, spreading, or getting worse (progressive). Vaccines made from a gene-modified virus may help the body build an effective immune response to kill tumor cells.
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, it does mention that participants should not have uncontrolled illnesses or active infections requiring antibiotics, which might imply some restrictions. It's best to discuss your current medications with the trial team to get a clear answer.
What data supports the effectiveness of this treatment for brain cancer?
Research shows that CLTX-CAR T cells, which use a component from scorpion venom to target brain cancer cells, have been effective in mice, causing tumor regression without harming normal cells. This suggests potential for treating glioblastoma in humans.
12345Is CAR T-cell therapy generally safe for humans?
CAR T-cell therapy, including versions targeting brain cancer, has shown significant promise in treating certain cancers, but it can cause serious side effects. Common risks include cytokine release syndrome (a severe immune reaction) and neurotoxicity (nerve damage), which can be life-threatening. While management of these side effects has improved, they remain a concern, especially as the therapy is used for more types of cancer.
678910How is the CAR T-Cell Therapy for Brain Cancer different from other treatments?
This treatment uses a unique approach by engineering T cells with a chlorotoxin (a component of scorpion venom) to specifically target and destroy glioblastoma cells, which is different from other treatments that may not effectively target the diverse tumor cells in brain cancer.
1271112Eligibility Criteria
This trial is for adults with a specific brain cancer called MMP2+ recurrent or progressive glioblastoma. They must have a certain level of physical function, normal liver and kidney tests, not be pregnant, and agree to use birth control. People can't join if they have uncontrolled seizures, HIV/hepatitis infections, are pregnant/breastfeeding, recently had certain therapies like bevacizumab, or any condition that makes it unsafe to participate.Inclusion Criteria
Women of childbearing potential (WOCBP): negative urine or serum pregnancy test (to be performed within 14 days prior to leukapheresis unless otherwise stated)
I have no allergies or adverse reactions to leukapheresis, steroids, or tocilizumab.
I was diagnosed with a high-grade brain tumor.
+19 more
Exclusion Criteria
I have another active cancer besides the one being studied.
I have not received bevacizumab therapy in the last 3 months.
I have a serious illness that is not under control.
+9 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive chlorotoxin (EQ)-CD28-CD3zeta-CD19t-expressing CAR T-lymphocytes via dual or single delivery for 3 weekly cycles over 28 days
4 weeks
3 visits (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment
12 months
Visits at 30 days, 3, 6, 9, and 12 months
Long-term follow-up
Participants are monitored yearly for up to 15 years to assess long-term outcomes and safety
Up to 15 years
Participant Groups
The study is testing CAR T cells modified with chlorotoxin to target tumor cells in patients with aggressive brain tumors. It aims to find the safest dose and see how well these engineered immune cells work against glioblastoma when delivered either directly into the tumor site or into cerebrospinal fluid.
2Treatment groups
Experimental Treatment
Group I: Treatment (CAR T cell therapy) IIExperimental Treatment1 Intervention
Arm 2 participants will undergo resection/biopsy of their tumor and placement of a Rickham catheter at the site of the resection/biopsy and the lateral ventricle. Patients receive chlorotoxin (EQ)-CD28-CD3zeta-CD19t-expressing CAR T-lymphocytes NCI SYs via dual delivery starting on day 0 for 3 weekly cycles over 28 days. Each treatment cycle begins with two CAR T cell infusions (intracranial intratumoral or intracavitary \[ICT\]) and also into the lateral ventricle (intracranial intraventricular \[ICV\]) and lasts for 1 week. Beginning 1 week after cycle 3, patients may continue with CAR T treatment per principal investigator and patient discretion. Treatment continues in the absence of disease progression or unacceptable toxicity.
Group II: Treatment (CAR T cell therapy) IExperimental Treatment1 Intervention
Arm 1 participants will undergo resection/biopsy of their tumor and placement of a Rickham catheter at the site of the resection/biopsy. Patients receive chlorotoxin (EQ)-CD28-CD3zeta-CD19t-expressing CAR T-lymphocytes NCI SYs via single delivery starting on day 0 for 3 weekly cycles over 28 days. Each treatment cycle begins with one CAR T cell infusion delivered intracranial intratumoral or intracavitary \[ICT\] and lasts for 1 week. Beginning 1 week after cycle 3, patients may continue with CAR T cell treatment per principal investigator and patient discretion. Treatment continues in the absence of disease progression or unacceptable toxicity.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
City of Hope Medical CenterDuarte, CA
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Who Is Running the Clinical Trial?
City of Hope Medical CenterLead Sponsor
National Cancer Institute (NCI)Collaborator
References
Chlorotoxin-directed CAR T cells for specific and effective targeting of glioblastoma. [2022]Although chimeric antigen receptor (CAR) T cells have demonstrated signs of antitumor activity against glioblastoma (GBM), tumor heterogeneity remains a critical challenge. To achieve broader and more effective GBM targeting, we developed a peptide-bearing CAR exploiting the GBM-binding potential of chlorotoxin (CLTX). We find that CLTX peptide binds a great proportion of tumors and constituent tumor cells. CAR T cells using CLTX as the targeting domain (CLTX-CAR T cells) mediate potent anti-GBM activity and efficiently target tumors lacking expression of other GBM-associated antigens. Treatment with CLTX-CAR T cells resulted in tumor regression in orthotopic xenograft GBM tumor models. CLTX-CAR T cells do not exhibit observable off-target effector activity against normal cells or after adoptive transfer into mice. Effective targeting by CLTX-CAR T cells requires cell surface expression of matrix metalloproteinase-2. Our results pioneer a peptide toxin in CAR design, expanding the repertoire of tumor-selective CAR T cells with the potential to reduce antigen escape.
Looking to Scorpion Venom for GBM Treatment. [2021]Chlorotoxin, a small peptide component of scorpion venom, may help pinpoint glioblastoma cells for destruction when engineered into a chimeric antigen receptor T-cell therapy. The concept has shown efficacy in mice, without off-target toxicity, and will soon be assessed in patients.
Immunotoxins and recombinant toxins in the treatment of solid carcinomas. [2023]Cancer remains the second most common cause of death in our society, and advanced disease is often refractory to surgical, chemotherapeutic, and radiologic interventions. One novel approach to cancer treatment involves targeting a cytotoxic agent to a cancer cell. Immunotoxins have been developed that contain a potent toxin (either Pseudomonas exotoxin, ricin toxin, or diphtheria toxin) coupled to a targeting moiety that directs the molecule to cells expressing a certain antigen. Chemically coupled immunotoxins have been developed over the past 12 years. These bind to and kill cells expressing many tumor-associated antigens. Initial clinical results were disappointing, but recent results have been more promising. Furthermore, newer immunotoxins have been developed that will soon be in clinical trials. Some of these are recombinant toxins that have been developed using techniques of genetic engineering. Transforming growth factor-alpha, acidic fibroblast growth factor, insulin-like growth factor-1, interleukin-2, interleukin-4, interleukin-6, the binding portions of monoclonal antibodies, and CD4 have been used to direct toxins to cancer cells or cells infected with the human immunodeficiency virus type 1. Efforts are under way to circumvent problems such as immunogenicity that may limit the clinical usefulness of immunotoxins.
Neuropilin-1 drives tumor-specific uptake of chlorotoxin. [2020]Label="BACKGROUND">Chlorotoxin (Cltx) isolated from scorpion venom is an established tumor targeting and antiangiogenic peptide. Radiolabeled Cltx therapeutic (131I-TM601) yielded promising results in human glioma clinical studies, and the imaging agent tozuleristide, is under investigation in CNS cancer studies. Several binding targets have previously been proposed for Cltx but none effectively explain its pleiotropic effects; its true target remains ambiguous and is the focus of this study.
Recombinant immunotoxins: protein engineering for cancer therapy. [2023]Recombinant immunotoxins for cancer therapy are composed of the variable regions of 'cancer-specific' antibodies fused to truncated toxins that are usually derived from bacteria or plants. Protein engineering has been used to modify these molecules so that the toxin moiety by itself does not bind to normal human cells, but retains all other cytotoxic functions. The antibody moiety directs the toxin selectively to cancer cells, which are killed; cells that do not carry that particular cancer antigen are not recognized and are therefore spared. Many recombinant immunotoxins show a high degree of cytotoxic activity and specificity towards cancer cells cultured in vitro and have been shown to cause the regression of human tumor xenografts grown in mice. Clinical trials that are in progress will show whether these promising pre-clinical results can be translated into successful cancer therapy.
Novel Use of Extracorporeal Blood Purification for Treatment of Severe, Refractory Neurotoxicity After Chimeric Antigen Receptor T-Cell Therapy-A Case Report. [2021]Chimeric antigen receptor T-cell therapies (CAR-T) are transforming the treatment of B-cell leukemias and lymphomas. Cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome represent common, potentially life-threatening toxicities from chimeric antigen receptor T-cell therapy treatment.
[Next generation engineered T cells for cell therapy: from lymphoma to solid tumors]. [2019]FDA approval and French ATU for chimeric antigen receptor (CAR) T cells represent an advanced step in the challenge of immunotherapy to cure cancer. The field of adoptive cell therapy emerged with the discovery that tumor-infiltrating-lymphocytes (TIL) can be used to treat melanoma patients. CAR T cells are engineered by gene transfer to express both receptors that target tumor-associated molecules and killing T cell functions. We report here how several decades of technology combining the specific recognition of an antibody with T cell function have led to the potent activity of CD19-targeting CAR KYMRIAH™ and YESCARTA™ i.e, high remission rates in patients with chemorefractory lymphoma. However, potentially fatal toxicity including cytokine release syndrome and neurotoxicity need next generation developments. Affinity fine-tuning, combinational CARs and guidelines for toxicity management are enhancing the safety of more powerful CAR T. Such CARs are emerging for solid tumor targeting. Synthetic biology approaches leading to personalized cell therapy marks the beginning of a new area.
Evaluation and management of chimeric antigen receptor (CAR) T-cell-associated neurotoxicity. [2021]Adoptive cell therapies are a group of cancer immunotherapies that involve the infusion of engineered immune cells targeting specific tumor antigens, with chimeric antigen receptor (CAR) T cells at the vanguard of this revolution in cancer therapy. Several CAR T-cell products have been approved for the treatment of leukemia and lymphoma and many more are currently undergoing evaluation in clinical trials for the treatment of other liquid and solid malignancies. Despite their remarkable effectiveness, as with other immunotherapies, CAR T cells are frequently associated with systemic and neurologic toxicity. There has been a major effort by many institutions to develop specific protocols to guide the management of treatment-associated toxicities (eg, cytokine release syndrome [CRS]). However, neurotoxic effects of CAR T-cell therapies are more difficult to evaluate and treat, not easily lending themselves to an algorithmic approach to diagnosis and management. Given the steadily expanding use of CAR T-cell therapies for various malignancies, it is of critical importance for neuro-oncologists to be familiar with the clinical presentation and management principles of CAR T-cell-associated neurotoxicity. Here, we present key principles for the evaluation and management of patients affected by CAR T-cell-associated neurotoxicity based on the most recent evidence.
Neurologic Toxicities of Cancer Immunotherapies: a Review. [2020]This review provides clinical characterization and approach to management of neurotoxicities associated with checkpoint inhibitor therapy and chimeric antigen receptor T cell (CAR T cell) therapy.
Building safety into CAR-T therapy. [2023]Chimeric antigen receptor T cell (CAR-T) therapy is an innovative immunotherapeutic approach that utilizes genetically modified T-cells to eliminate cancer cells using the specificity of a monoclonal antibody (mAb) coupled to the potent cytotoxicity of the T-lymphocyte. CAR-T therapy has yielded significant improvements in relapsed/refractory B-cell malignancies. Given these successes, CAR-T has quickly spread to other hematologic malignancies and is being increasingly explored in solid tumors. From early clinical applications to present day, CAR-T cell therapy has been accompanied by significant toxicities, namely cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and on-target off-tumor (OTOT) effects. While medical management has improved for CRS and ICANS, the ongoing threat of refractory symptoms and unanticipated idiosyncratic toxicities highlights the need for more powerful safety measures. This is particularly poignant as CAR T-cell therapy continues to expand into the solid tumor space, where the risk of unpredictable toxicities remains high. We will review CAR-T as an immunotherapeutic approach including emergence of unique toxicities throughout development. We will discuss known and novel strategies to mitigate these toxicities; additional safety challenges in the treatment of solid tumors, and how the inducible Caspase 9 "safety switch" provides an ideal platform for continued exploration.
CAR T Cell Therapy in Primary Brain Tumors: Current Investigations and the Future. [2022]Chimeric antigen receptor T cells (CAR T cells) are engineered cells expressing a chimeric antigen receptor (CAR) against a specific tumor antigen (TA) that allows for the identification and elimination of cancer cells. The remarkable clinical effect seen with CAR T cell therapies against hematological malignancies have attracted interest in developing such therapies for solid tumors, including brain tumors. Glioblastoma (GBM) is the most common primary brain tumor in adults and is associated with poor prognosis due to its highly aggressive nature. Pediatric brain cancers are similarly aggressive and thus are a major cause of pediatric cancer-related death. CAR T cell therapy represents a promising avenue for therapy against these malignancies. Several specific TAs, such as EGFR/EGFRvIII, IL13Rα2, B7-H3, and HER2, have been targeted in preclinical studies and clinical trials. Unfortunately, CAR T cells against brain tumors have showed limited efficacy due to TA heterogeneity, difficulty trafficking from blood to tumor sites, and the immunosuppressive tumor microenvironment. Here, we review current CAR T cell approaches in treating cancers, with particular focus on brain cancers. We also describe a novel technique of focused ultrasound controlling the activation of engineered CAR T cells to achieve the safer cell therapies. Finally, we summarize the development of combinational strategies to improve the efficacy and overcome historical limitations of CAR T cell therapy.
Advances in Chimeric Antigen Receptor (CAR) T-Cell Therapies for the Treatment of Primary Brain Tumors. [2022]Immunotherapy has revolutionized the care of cancer patients. A diverse set of strategies to overcome cancer immunosuppression and enhance the tumor-directed immune response are in clinical use, but have not achieved transformative benefits for brain tumor patients. Adoptive cell therapies, which employ a patient's own immune cells to generate directed anti-tumor activity, are emerging technologies that hold promise to improve the treatment of primary brain tumors in children and adults. Here, we review recent advances in chimeric antigen receptor (CAR) T-cell therapies for the treatment of aggressive primary brain tumors, including glioblastoma and diffuse midline glioma, H3 K27M-mutant. We highlight current approaches, discuss encouraging investigational data, and describe key challenges in the development and implementation of these types of therapies in the neuro-oncology setting.