Trial Summary
What is the purpose of this trial?This phase I trial studies the side effects and best dose of HER2-CAR T cells in treating patients with cancer that has spread to the brain or leptomeninges and has come back (recurrent). HER2-CAR T cells delivered into the ventricles of the brain may recognize and kill tumor cells.
Do I need to stop my current medications for the trial?
Yes, you will need to stop treatment with chemotherapy or endocrine therapy during the first 3 cycles of the HER2-CAR T cell study. Additionally, there are specific washout periods required for certain medications before starting the trial.
What data supports the idea that CAR T-Cell Therapy for Brain Metastasis is an effective treatment?
The available research shows that CAR T-Cell Therapy, specifically HER2-CAR T cells, is effective in treating brain metastasis from breast cancer. In studies using mouse models, HER2-CAR T cells with a specific design showed improved targeting of tumors and reduced exhaustion of T cells, which means they stayed active longer. When delivered directly into the brain, these cells demonstrated strong anti-tumor activity. Additionally, in pediatric patients with central nervous system tumors, the treatment was well tolerated. This suggests that CAR T-Cell Therapy could be a promising option compared to other treatments that may not effectively target brain metastases.
12345What safety data is available for HER2 CAR T-cell therapy?
HER2 CAR T-cell therapy has been associated with serious toxicities such as cytokine release syndrome and neurotoxicity, including severe neurologic adverse events like encephalopathy and cerebral edema. Intracranial delivery in pediatric CNS tumors was well tolerated in a small study. Strategies to improve safety are being explored, but the unpredictability of these toxicities remains a concern.
26789Is the treatment HER2-CAR T Cells a promising treatment for brain metastasis?
Yes, HER2-CAR T Cells are a promising treatment for brain metastasis. They have shown strong ability to target and kill cancer cells in the brain, especially when delivered directly to the brain area. This treatment has been effective in reducing tumor growth and improving outcomes in experimental models.
1251011Eligibility Criteria
This trial is for patients with recurrent brain or leptomeningeal metastases from HER2+ cancer, post-radiation therapy. They must have acceptable organ function, no severe heart issues, controlled seizures, not be on high-dose steroids or oxygen support, and agree to contraception if applicable. Excluded are those with active infections, other cancers, HIV, uncontrolled illnesses or requiring dialysis.Inclusion Criteria
My brain cancer has returned after radiation treatment.
I have brain metastases and choose not to have radiation or chemotherapy.
I am able to care for myself but may not be able to do active work.
+32 more
Exclusion Criteria
I have another active cancer besides the one being studied.
I am not willing to pause my chemotherapy or hormone therapy for the first 3 cycles of the HER2-CAR T cell study.
You have tested positive for HIV within the past 4 weeks.
+13 more
Participant Groups
The study tests the safety and optimal dosage of HER2-CAR T cells injected into the brain's ventricles to target and destroy tumor cells in patients whose cancer has spread to the brain/leptomeninges and returned after treatment.
1Treatment groups
Experimental Treatment
Group I: Treatment (HER2-CAR T cells)Experimental Treatment1 Intervention
Patients receive HER2-CAR T cells via intraventricular administration over 5 minutes once weekly for 3 doses in the absence of disease progression or unacceptable toxicity. If patients continue to meet all eligibility criteria, they may receive additional cycles of HER2-CAR T cells at principal investigator's discretion.
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
California Institute for Regenerative Medicine (CIRM)Collaborator
References
Regional Delivery of Chimeric Antigen Receptor-Engineered T Cells Effectively Targets HER2+ Breast Cancer Metastasis to the Brain. [2020]Purpose: Metastasis to the brain from breast cancer remains a significant clinical challenge, and may be targeted with CAR-based immunotherapy. CAR design optimization for solid tumors is crucial due to the absence of truly restricted antigen expression and potential safety concerns with "on-target off-tumor" activity. Here, we have optimized HER2-CAR T cells for the treatment of breast to brain metastases, and determined optimal second-generation CAR design and route of administration for xenograft mouse models of breast metastatic brain tumors, including multifocal and leptomeningeal disease.Experimental Design: HER2-CAR constructs containing either CD28 or 4-1BB intracellular costimulatory signaling domains were compared for functional activity in vitro by measuring cytokine production, T-cell proliferation, and tumor killing capacity. We also evaluated HER2-CAR T cells delivered by intravenous, local intratumoral, or regional intraventricular routes of administration using in vivo human xenograft models of breast cancer that have metastasized to the brain.Results: Here, we have shown that HER2-CARs containing the 4-1BB costimulatory domain confer improved tumor targeting with reduced T-cell exhaustion phenotype and enhanced proliferative capacity compared with HER2-CARs containing the CD28 costimulatory domain. Local intracranial delivery of HER2-CARs showed potent in vivo antitumor activity in orthotopic xenograft models. Importantly, we demonstrated robust antitumor efficacy following regional intraventricular delivery of HER2-CAR T cells for the treatment of multifocal brain metastases and leptomeningeal disease.Conclusions: Our study shows the importance of CAR design in defining an optimized CAR T cell, and highlights intraventricular delivery of HER2-CAR T cells for treating multifocal brain metastases. Clin Cancer Res; 24(1); 95-105. ©2017 AACR.
Locoregional Delivery of CAR-T Cells Is Feasible in Pediatric CNS Tumors. [2022]Intracranial delivery of HER2-targeting CAR-T cells was well tolerated in 3 patients with CNS tumors.
Regression of experimental medulloblastoma following transfer of HER2-specific T cells. [2014]Medulloblastoma is a common malignant brain tumor of childhood. Human epidermal growth factor receptor 2 (HER2) is expressed by 40% of medulloblastomas and is a risk factor for poor outcome with current aggressive multimodal therapy. In contrast to breast cancer, HER2 is expressed only at low levels in medulloblastomas, rendering monoclonal antibodies ineffective. We determined if T cells grafted with a HER2-specific chimeric antigen receptor (CAR; HER2-specific T cells) recognized and killed HER2-positive medulloblastomas. Ex vivo, stimulation of HER2-specific T cells with HER2-positive medulloblastomas resulted in T-cell proliferation and secretion of IFN-gamma and interleukin 2 (IL-2) in a HER2-dependent manner. HER2-specific T cells killed autologous HER2-positive primary medulloblastoma cells and medulloblastoma cell lines in cytotoxicity assays, whereas HER2-negative tumor cells were not killed. No functional difference was observed between HER2-specific T cells generated from medulloblastoma patients and healthy donors. In vivo, the adoptive transfer of HER2-specific T cells resulted in sustained regression of established medulloblastomas in an orthotopic, xenogenic severe combined immunodeficiency model. In contrast, delivery of nontransduced T cells did not change the tumor growth pattern. Adoptive transfer of HER2-specific T cells may represent a promising immunotherapeutic approach for medulloblastoma.
Immunotherapy for osteosarcoma: genetic modification of T cells overcomes low levels of tumor antigen expression. [2021]Human epidermal growth factor receptor 2 (HER2) is expressed by the majority of human osteosarcomas and is a risk factor for poor outcome. Unlike breast cancer, osteosarcoma cells express HER2 at too low, a level for patients to benefit from HER2 monoclonal antibodies. We reasoned that this limitation might be overcome by genetically modifying T cells with HER2-specific chimeric antigen receptors (CARs), because even a low frequency of receptor engagement could be sufficient to induce effector cell killing of the tumor. HER2-specific T cells were generated by retroviral transduction with a HER2-specific CAR containing a CD28.zeta signaling domain. HER2-specific T cells recognized HER2-positive osteosarcoma cells as judged by their ability to proliferate, produce immunostimulatory T helper 1 cytokines, and kill HER2-positive osteosarcoma cell lines in vitro. The adoptive transfer of HER2-specific T cells caused regression of established osteosarcoma xenografts in locoregional as well as metastatic mouse models. In contrast, delivery of nontransduced (NT) T cells did not change the tumor growth pattern. Genetic modification of T cells with CARs specific for target antigens, expressed at too low a level to be effectively recognized by monoclonal antibodies, may allow immunotherapy to be more broadly applicable for human cancer therapy.
HER2-specific T cells target primary glioblastoma stem cells and induce regression of autologous experimental tumors. [2022]Glioblastoma multiforme (GBM) is the most aggressive human primary brain tumor and is currently incurable. Immunotherapies have the potential to target GBM stem cells, which are resistant to conventional therapies. Human epidermal growth factor receptor 2 (HER2) is a validated immunotherapy target, and we determined if HER2-specific T cells can be generated from GBM patients that will target autologous HER2-positive GBMs and their CD133-positive stem cell compartment.
Driving better and safer HER2-specific CARs for cancer therapy. [2019]Given the clinical efficacy of chimeric antigen receptor (CAR)-based therapy in hematological malignancies, CAR T-cell therapy for a number of solid tumors has been actively investigated. Human epidermal growth factor receptor 2 (HER2) is a well-established therapeutic target in breast, as well as other types of cancer. However, HER2 CAR T cells pose a risk of lethal toxicity including cytokine release syndrome from "on-target, off-tumor" recognition of HER2. In this review, we summarize the development of conventional HER2 CAR technology, the alternative selection of CAR hosts, the novel HER2 CAR designs, clinical studies and toxicity. Furthermore, we also discuss the main strategies for improving the safety of HER2 CAR-based cancer therapies.
Clinical Predictors of Neurotoxicity After Chimeric Antigen Receptor T-Cell Therapy. [2021]Chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory hematologic malignant neoplasm causes severe neurologic adverse events ranging from encephalopathy and aphasia to cerebral edema and death. The cause of neurotoxicity is incompletely understood, and its unpredictability is a reason for prolonged hospitalization after CAR T-cell infusion.
Characterization of chimeric antigen receptor modified T cells expressing scFv-IL-13Rα2 after radiolabeling with 89Zirconium oxine for PET imaging. [2023]Chimeric antigen receptor (CAR) T cell therapy is an exciting cell-based cancer immunotherapy. Unfortunately, CAR-T cell therapy is associated with serious toxicities such as cytokine release syndrome (CRS) and neurotoxicity. The mechanism of these serious adverse events (SAEs) and how homing, distribution and retention of CAR-T cells contribute to toxicities is not fully understood. Enabling in vitro methods to allow meaningful, sensitive in vivo biodistribution studies is needed to better understand CAR-T cell disposition and its relationship to both effectiveness and safety of these products.
Toxicity and management in CAR T-cell therapy. [2023]T cells can be genetically modified to target tumors through the expression of a chimeric antigen receptor (CAR). Most notably, CAR T cells have demonstrated clinical efficacy in hematologic malignancies with more modest responses when targeting solid tumors. However, CAR T cells also have the capacity to elicit expected and unexpected toxicities including: cytokine release syndrome, neurologic toxicity, "on target/off tumor" recognition, and anaphylaxis. Theoretical toxicities including clonal expansion secondary to insertional oncogenesis, graft versus host disease, and off-target antigen recognition have not been clinically evident. Abrogating toxicity has become a critical step in the successful application of this emerging technology. To this end, we review the reported and theoretical toxicities of CAR T cells and their management.
Combination of tucatinib and neural stem cells secreting anti-HER2 antibody prolongs survival of mice with metastatic brain cancer. [2022]Brain metastases are a leading cause of death in patients with breast cancer. The lack of clinical trials and the presence of the blood-brain barrier limit therapeutic options. Furthermore, overexpression of the human epidermal growth factor receptor 2 (HER2) increases the incidence of breast cancer brain metastases (BCBM). HER2-targeting agents, such as the monoclonal antibodies trastuzumab and pertuzumab, improved outcomes in patients with breast cancer and extracranial metastases. However, continued BCBM progression in breast cancer patients highlighted the need for novel and effective targeted therapies against intracranial metastases. In this study, we engineered the highly migratory and brain tumor tropic human neural stem cells (NSCs) LM008 to continuously secrete high amounts of functional, stable, full-length antibodies against HER2 (anti-HER2Ab) without compromising the stemness of LM008 cells. The secreted anti-HER2Ab impaired tumor cell proliferation in vitro in HER2+ BCBM cells by inhibiting the PI3K-Akt signaling pathway and resulted in a significant benefit when injected in intracranial xenograft models. In addition, dual HER2 blockade using anti-HER2Ab LM008 NSCs and the tyrosine kinase inhibitor tucatinib significantly improved the survival of mice in a clinically relevant model of multiple HER2+ BCBM. These findings provide compelling evidence for the use of HER2Ab-secreting LM008 NSCs in combination with tucatinib as a promising therapeutic regimen for patients with HER2+ BCBM.
CAR-T cells for pediatric brain tumors: Present and future. [2021]Chimeric Antigen Receptor T (CAR-T) cells are currently approved for B cell malignancies only, in children and adults. Despite a lack of robust evidence to approve such cellular immunotherapy for pediatric solid tumors, there is a growing interest for this approach in the treatment of pediatric brain tumors. Following the identification of tumor antigens as targets, the first clinical trials demonstrated some degree of clinical and biological responses to CAR-T cells for such tumor types. Additionaly, several preclinical studies have recently identified new attractive targets and antigen combination strategies, along with a superior tumor trafficking following locoregional administration. We review here the preclinical and clinical knowledge at the basis of the current clinical development of CAR-T cells for pediatric brain tumors.