scholarly journals First-in-Human Trial of EphA2-Redirected CAR T-Cells in Patients With Recurrent Glioblastoma: A Preliminary Report of Three Cases at the Starting Dose

2021 ◽  
Vol 11 ◽  
Author(s):  
Qingtang Lin ◽  
Teer Ba ◽  
Jinyuan Ho ◽  
Dandan Chen ◽  
Ye Cheng ◽  
...  
Keyword(s):  
T Cells ◽  
Treatment Options ◽  
Recurrent Glioblastoma ◽  
Human Trial ◽  
Car T Cells ◽  
Tumor Associated Antigen ◽  
Patient Reported ◽  
Car T ◽  
Starting Dose ◽  
Positive Recurrent

Glioblastoma is the most common primary brain malignancy with limited treatment options. EphA2 is a tumor-associated-antigen overexpressed in glioblastoma. Pre-clinical studies have demonstrated the promise of EphA2-redirected CAR T-cells against glioblastoma. We conduct the first-in-human trial of EphA2-redirected CAR T-cells in patients with EphA2-positive recurrent glioblastoma and report the results of three patients enrolled as the first cohort receiving the starting dosage (1×106 cells/kg). A single infusion of EphA2-redirected CAR T-cells was administrated intravenously, with the lymphodepletion regimen consisting of fludarabine and Cyclophosphamide. In two patients, there was grade 2 cytokine release syndrome accompanied by pulmonary edema, which resolved completely with dexamethasone medication. Except that, there was no other organ toxicity including neurotoxicity. In both the peripheral blood and cerebral-spinal-fluid, we observed the expansion of CAR T-cells which persisted for more than four weeks. In one patient, there was a transit diminishment of the tumor. Among these three patients, one patient reported SD and two patients reported PD, with overall survival ranging from 86 to 181 days. At the tested dose level (1×106 cells/kg), intravenously infusion of EphA2-rediretected CAR T-cells were preliminary tolerable with transient clinical efficacy. Future study with adjusted dose and infusion frequency of CAR T-cells is warranted.Trial Registration NumbersNCT 03423992

scholarly journals Immunotherapy using IgE or CAR T cells for cancers expressing the tumor antigen SLC3A2

2021 ◽  
Vol 9 (6) ◽  
pp. e002140
Author(s):  
Giulia Pellizzari ◽  
Olivier Martinez ◽  
Silvia Crescioli ◽  
Robert Page ◽  
Ashley Di Meo ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
T Cells ◽  
T Cell ◽  
Type I ◽  
Cell Therapies ◽  
Car T Cells ◽  
Car T Cell ◽  
Tumor Associated Antigen ◽  
Car T

BackgroundCancer immunotherapy with monoclonal antibodies and chimeric antigen receptor (CAR) T cell therapies can benefit from selection of new targets with high levels of tumor specificity and from early assessments of efficacy and safety to derisk potential therapies.MethodsEmploying mass spectrometry, bioinformatics, immuno-mass spectrometry and CRISPR/Cas9 we identified the target of the tumor-specific SF-25 antibody. We engineered IgE and CAR T cell immunotherapies derived from the SF-25 clone and evaluated potential for cancer therapy.ResultsWe identified the target of the SF-25 clone as the tumor-associated antigen SLC3A2, a cell surface protein with key roles in cancer metabolism. We generated IgE monoclonal antibody, and CAR T cell immunotherapies each recognizing SLC3A2. In concordance with preclinical and, more recently, clinical findings with the first-in-class IgE antibody MOv18 (recognizing the tumor-associated antigen Folate Receptor alpha), SF-25 IgE potentiated Fc-mediated effector functions against cancer cells in vitro and restricted human tumor xenograft growth in mice engrafted with human effector cells. The antibody did not trigger basophil activation in cancer patient blood ex vivo, suggesting failure to induce type I hypersensitivity, and supporting safe therapeutic administration. SLC3A2-specific CAR T cells demonstrated cytotoxicity against tumor cells, stimulated interferon-γ and interleukin-2 production in vitro. In vivo SLC3A2-specific CAR T cells significantly increased overall survival and reduced growth of subcutaneous PC3-LN3-luciferase xenografts. No weight loss, manifestations of cytokine release syndrome or graft-versus-host disease, were detected.ConclusionsThese findings identify efficacious and potentially safe tumor-targeting of SLC3A2 with novel immune-activating antibody and genetically modified cell therapies.

scholarly journals Treatment of Aggressive T Cell Lymphoblastic Lymphoma/leukemia Using Anti-CD5 CAR T Cells

2021 ◽  
Author(s):  
Jia Feng ◽  
Haichan Xu ◽  
Andrew Cinquina ◽  
Zehua Wu ◽  
Qi Chen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Response ◽  
Treatment Options ◽  
Lymphoblastic Lymphoma ◽  
Cns Involvement ◽  
Car T Cells ◽  
Car T ◽  
T Cell Malignancies ◽  
Leukemias And Lymphomas

AbstractWhile treatment for B-cell malignancies has been revolutionized through the advent of CAR immunotherapy, similar strategies for T-cell malignancies have been limited. Additionally, T-cell leukemias and lymphomas can commonly metastasize to the CNS, where outcomes are poor and treatment options are associated with severe side effects. Consequently, the development of safer and more effective alternatives for targeting malignant T cells that have invaded the CNS remains clinically important. CD5 CAR has previously been shown to effectively target various T-cell cancers in preclinical studies. As IL-15 strengthens the anti-tumor response, we have modified CD5 CAR to secrete an IL-15/IL-15sushi complex. In a Phase I clinical trial, these CD5-IL15/IL15sushi CAR T cells were tested for safety and efficacy in a patient with refractory T-LBL with CNS infiltration. CD5-IL15/IL15sushi CAR T cells were able to rapidly ablate the CNS lymphoblasts within a few weeks, resulting in the remission of the patient’s lymphoma. Despite the presence of CD5 on normal T cells, the patient only experienced a brief, transient T-cell aplasia. These results suggest that CD5-IL15/IL15sushi CAR T cells may be a safe and useful treatment of T-cell malignancies and may be particularly beneficial for patients with CNS involvement.Graphical Abstract

CTIM-29. CLINICAL EVALUATION OF CHLOROTOXIN-DIRECTED CAR T CELLS FOR PATIENTS WITH RECURRENT GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi57-vi57
Author(s):  
Christine Brown ◽  
M Suzette Blanchard ◽  
Maryam Aftabizadeh ◽  
Jonathan Hibbard ◽  
Ramsinh Dodia ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Scorpion Venom ◽  
Clinical Findings ◽  
Recurrent Glioblastoma ◽  
Disease Response ◽  
Car T Cells ◽  
Best Response ◽  
Car T

Abstract Chlorotoxin (CLTX), a peptide component of scorpion venom, exhibits selective and broad binding to glioblastoma (GBM) and other tumors with minimal activity against non-malignant cells. We have developed a novel CAR that utilizes CLTX as the tumor targeting domain. Preclinical studies established that CLTX-CAR T cells target GBM through recognition of a receptor complex incorporating membrane-bound matrix metalloprotease-2 (MMP-2). Here, we report initial clinical findings for our phase I trial evaluating safety and bioactivity of CLTX-CAR T cells in patients with MMP2+ recurrent GBM (NCT04214392). Weekly infusions of CLTX-CAR T cells are delivered locoregionally, either directly into the tumor cavity (ICT; Arm 1), or in combination with intracerebroventricular (ICV) delivery (dual ICT/ICV; Arm 2). At this interim analysis, four participants have received at least three cycles of CLTX-CAR T cells ICT (Arm 1; 3-8 cycles) at dose level 1 (DL1; 4M, 20M, 20M CAR T cells per cycle). None of the participants experienced dose limiting toxicity (DLT) during the DLT evaluation period of 28-days, although one participant experienced a serious adverse event of grade 3 cerebral edema, possibly attributed to CAR T cells. Overall, Arm 1-DL1 was well-tolerated, and the next patient cohort will be treated on Arm 2-DL1 (dual ICT/ICV; 8M, 40M, 40M CAR T cells per cycle), as per protocol design. Disease response was assessed by RANO, overall survival, and time to progression; three of four participants achieved a best response of stable disease. Liquid biopsy detected persistent CAR T cells in the tumor cavity throughout treatment, suggesting that the therapeutic cells are not immunogenic. Ongoing studies are evaluating biomarkers of response and resistance, including CAR T cell activation and inflammatory cytokines. This clinical study provides first-in-human evidence for the safety and feasibility of CLTX-CAR T cells as a new class of toxin-based CARs for treatment of GBM.

First-in-human trial of bispecific CAR-T cells

2020 ◽  
Vol 19 (12) ◽  
pp. 838-838
Author(s):  
Sarah Crunkhorn
Keyword(s):  
T Cells ◽  
Human Trial ◽  
Car T Cells ◽  
Car T

Abstract B079: The efficacy of CD133 BiTEs and CAR-T cells in preclinical model of recurrent glioblastoma

2016 ◽  
Author(s):  
Parvez Vora ◽  
Chirayu Chokshi ◽  
Maleeha Qazi ◽  
Chitra Venugopal ◽  
Sujeivan Mahendram ◽  
...  
Keyword(s):  
T Cells ◽  
Recurrent Glioblastoma ◽  
Preclinical Model ◽  
Car T Cells ◽  
Car T

scholarly journals Multiplexed Engineered, Off-the-Shelf T Cells Carrying Three Tumor-Associated Antigen-Targeting Modalities: CAR + Pan-Tumor Targeting TCR + CD16 Fc Receptor

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 32-32
Author(s):  
Cokey Nguyen ◽  
Eigen Peralta ◽  
Chia-Wei Chang ◽  
Wen-I Yeh ◽  
Yijia Pan ◽  
...  
Keyword(s):  
T Cells ◽  
Monoclonal Antibodies ◽  
T Cell ◽  
Tumor Heterogeneity ◽  
Tumor Antigens ◽  
Fc Receptor ◽  
Car T Cells ◽  
Tumor Associated Antigen ◽  
Car T

Autologous chimeric antigen receptor (CAR)-T cell therapy has shown great promise in various hematologic malignancies. However, the complexities associated with immune cell evasion are prevalent causes of disease relapse in many cancers. With the advent of pluripotent stem cell (iPSC)-derived CAR-T cells, many factors that hamper therapeutic efficacy of CAR-T cells can be addressed through multiplexed engineering at the clonal level. This includes enhanced potency, increased capacity for multi-antigen targeting, and the consistency of a clonally derived engineered cellular product for off-the-shelf patient administration. In particular, strategies to mitigate antigen escape and address tumor heterogeneity may help promote durable responses. To combine the potent targeted therapy of the CAR with universal targeting of secondary and tertiary antigens, we expressed an MR1 clonal T cell receptor (TCR) and a high-affinity, non-cleavable CD16 Fc receptor (hnCD16) in our iPSC-derived CAR19 T cells (CAR19-iT cells) directed to leukemia and lymphoma and CAR-MICA/B T cells directed to solid tumors. The MR1-TCR allows highly specific recognition of tumor associated antigen presented by the MR1 protein. The non-polymorphic MHC class I-related protein MR1 is widely expressed with minimal variability among patients and enables the unique prospect to be a universal cancer immunotherapy by using the cognate MR1-TCR. The hnCD16 Fc receptor has been shown to improve antibody-dependent cellular cytotoxicity (ADCC) leveraging the broad range of available therapeutic monoclonal antibodies to target clinically validated tumor antigens. A preliminary assessment demonstrated that MR1-TCR overexpressed in T cells allowed for enhanced recognition of multiple hematological and solid tumor cell lines. Notably, prominent target specific killing was seen in A549 lung carcinoma cells (>75% reduction in total viable cells) with the directed cytotoxicity specifically inhibited by an MR1 blocking antibody. Next, in vitro functional testing was performed on the engineered CAR19-iT cells in co-culture assays where we measured killing of tumor cells via MR1-TCR engagement and via hnCD16 mediated ADCC. Specifically, we show that CAR19-iT cells expressing hnCD16 can be efficiently directed to lyse CD20+ Raji cells in the presence of rituximab or HER2+ SKOV3 cells in the presence of Herceptin, demonstrating the potential to target both hematological malignancies and solid tumors with one target modality in combination with various monoclonal antibodies. Moreover, CAR19-iT cells expressing either MR1-TCR or hnCD16 show the ability to control growth of CD19 KO lymphoma cells in the co-culture assays, further highlighting the unique ability to elicit multiple ways to target antigen escape. Further in vitro and in vivo combinatorial targeting studies focused on antigen escape and tumor heterogeneity are ongoing and will be discussed. In summary, the advances presented here demonstrate that both the MR1-TCR and hnCD16 modalities synergize with CAR-iT cells as an off-the-shelf therapeutic that can provide durable responses and enable broad applicability for targeting of additional tumor antigens where single-agent therapeutics fail to provide clinical benefit for patients. Disclosures Nguyen: Fate Therapeutics, Inc.: Current Employment. Peralta:Fate Therapeutics, Inc.: Current Employment. Lu:Fate Therapeutics, Inc.: Current Employment. Sung:Fate Therapeutics, Inc.: Current Employment. Lee:Fate Therapeutics, Inc.: Current Employment.

Expansion of HER2-CAR T cells after lymphodepletion and clinical responses in patients with advanced sarcoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 10508-10508 ◽  
Author(s):  
Meenakshi Hegde ◽  
Christopher C. DeRenzo ◽  
Huimin Zhang ◽  
Melinda Mata ◽  
Claudia Gerken ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Phase 1 ◽  
Treatment Options ◽  
Single Agent ◽  
Absolute Lymphocyte Count ◽  
Car T Cells ◽  
Car T ◽  
Post Infusion ◽  
Advanced Sarcoma

10508 Background: Outcome for patients with advanced sarcoma is extremely poor and treatment options are limited. Encouragingly, in our phase 1 dose-escalation trial (Ahmed et al, JCO 2015), systemic administration of up to 1x108/m2 autologous HER2-CAR T cells in patient with HER2+ sarcoma was safe. While T cells did not expand, 4/19 evaluable patients are alive 37-61 months post infusion without evidence of disease. The goal of this study was to evaluate if lympohodepleting chemotherapy can safely induce the expansion of HER2-CAR T cells. Methods: In a phase 1 clinical study, NCT00902044, we administered 1x108/m2 autologous HER2-CAR (with a CD28.zeta signaling domain) T cells to patients with refractory/metastatic HER2+ sarcoma after lymphodepletion. Results: Six patients with refractory/metastatic HER2+ sarcoma (4 osteosarcoma, 1 rhabdomyosarcoma, 1 synovial sarcoma) with a median age of 16 (range: 4 to 55) received up to 3 infusions of 1x108 cells/m2 CAR T cells after lymphodepletion with either fludarabine (Flu; n = 3) or Flu and cyclophosphamide (Flu/Cy; n = 3). Flu and Flu/Cy induced lymphopenia with an absolute lymphocyte count (ALC) of < 100/ml at the day of the T-cell infusion. Only Flu/Cy induced neutropenia (absolute neutrophil count [ANC] < 500/ml) for up to 14 days. 4/6 patients developed grade 1-2 cytokine release syndrome (CRS) within 24 hours of CAR T-cell infusion that resolved completely with supportive care within 3 days of onset. T cells expanded in 5/6 patients (median 89-fold (range: 41 to 2,893) with a median peak expansion on day 7 (range: 5 to 28). CAR T cells could be detected by qPCR in 6/6 patients at 6 weeks post infusion. One patient with rhabdomyosarcoma metastatic to the bone marrow had a complete responses (CR), 2 had stable disease (SD), and 3 had progressive disease (PD). Two patients are alive with a median overall survival of 14.2 months. Conclusions: Infusion of autologous HER2-CAR T cells after lymphodepletion is safe, and can be associated with objective clinical benefit in patients with advanced HER2+ sarcoma. These findings warrant further evaluation in a phase 2b study as a single agent or in combination with other approaches. Clinical trial information: NCT00902044.

scholarly journals A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma

2017 ◽  
Vol 9 (399) ◽  
pp. eaaa0984 ◽  
Author(s):  
Donald M. O’Rourke ◽  
MacLean P. Nasrallah ◽  
Arati Desai ◽  
Jan J. Melenhorst ◽  
Keith Mansfield ◽  
...  
Keyword(s):  
T Cells ◽  
Single Dose ◽  
Recurrent Glioblastoma ◽  
Adaptive Resistance ◽  
Car T Cells ◽  
Car T ◽  
Antigen Loss

scholarly journals Preclinical assessment of the efficacy and specificity of GD2-B7H3 SynNotch CAR-T in metastatic neuroblastoma

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Babak Moghimi ◽  
Sakunthala Muthugounder ◽  
Samy Jambon ◽  
Rachelle Tibbetts ◽  
Long Hung ◽  
...  
Keyword(s):  
T Cells ◽  
High Specificity ◽  
Dependent Manner ◽  
Preclinical Models ◽  
Car T Cells ◽  
Clinical Toxicity ◽  
Tumor Associated Antigen ◽  
Car T ◽  
Metabolic Fitness

AbstractThe ability to utilize preclinical models to predict the clinical toxicity of chimeric antigen receptor (CAR) T cells in solid tumors is tenuous, thereby necessitating the development and evaluation of gated systems. Here we found that murine GD2 CAR-T cells, specific for the tumor-associated antigen GD2, induce fatal neurotoxicity in a costimulatory domain-dependent manner. Meanwhile, human B7H3 CAR-T cells exhibit efficacy in preclinical models of neuroblastoma. Seeking a better CAR, we generated a SynNotch gated CAR-T, GD2-B7H3, recognizing GD2 as the gate and B7H3 as the target. GD2-B7H3 CAR-T cells control the growth of neuroblastoma in vitro and in metastatic xenograft mouse models, with high specificity and efficacy. These improvements come partly from the better metabolic fitness of GD2-B7H3 CAR-T cells, as evidenced by their naïve T-like post-cytotoxicity oxidative metabolism and lower exhaustion profile.

scholarly journals CAR T Cell-Based Immunotherapy for the Treatment of Glioblastoma

2021 ◽  
Vol 15 ◽  
Author(s):  
Luke Maggs ◽  
Giulia Cattaneo ◽  
Ali Emre Dal ◽  
Ali Sanjari Moghaddam ◽  
Soldano Ferrone
Keyword(s):  
T Cells ◽  
T Cell ◽  
Solid Tumors ◽  
Treatment Options ◽  
Acquired Resistance ◽  
Current Treatment ◽  
Central Nervous System Toxicity ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumor in adults. Current treatment options typically consist of surgery followed by chemotherapy or more frequently radiotherapy, however, median patient survival remains at just over 1 year. Therefore, the need for novel curative therapies for GBM is vital. Characterization of GBM cells has contributed to identify several molecules as targets for immunotherapy-based treatments such as EGFR/EGFRvIII, IL13Rα2, B7-H3, and CSPG4. Cytotoxic T lymphocytes collected from a patient can be genetically modified to express a chimeric antigen receptor (CAR) specific for an identified tumor antigen (TA). These CAR T cells can then be re-administered to the patient to identify and eliminate cancer cells. The impressive clinical responses to TA-specific CAR T cell-based therapies in patients with hematological malignancies have generated a lot of interest in the application of this strategy with solid tumors including GBM. Several clinical trials are evaluating TA-specific CAR T cells to treat GBM. Unfortunately, the efficacy of CAR T cells against solid tumors has been limited due to several factors. These include the immunosuppressive tumor microenvironment, inadequate trafficking and infiltration of CAR T cells and their lack of persistence and activity. In particular, GBM has specific limitations to overcome including acquired resistance to therapy, limited diffusion across the blood brain barrier and risks of central nervous system toxicity. Here we review current CAR T cell-based approaches for the treatment of GBM and summarize the mechanisms being explored in pre-clinical, as well as clinical studies to improve their anti-tumor activity.

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