scholarly journals IM-05 * MULTISPECIFIC CAR T CELLS FOR THE TREATMENT OF HIGH GRADE GLIOMA

2015 ◽  
Vol 17 (suppl 3) ◽  
pp. iii16-iii16
Author(s):  
K. Bielamowicz ◽  
K. Fousek ◽  
T. Byrd ◽  
K. Chow ◽  
Z. Yi ◽  
...  
Keyword(s):  
T Cells ◽  
High Grade Glioma ◽  
High Grade ◽  
Car T Cells ◽  
Car T

scholarly journals IMMU-10. ENGINEERED PD-L1 RECEPTORS AUGMENT ANTI-TUMOR ACTIVITY OF HER2 CAR T CELLS IN HIGH GRADE GLIOMA

2017 ◽  
Vol 19 (suppl_4) ◽  
pp. iv29-iv29
Author(s):  
Daniel Landi ◽  
Kristen Fousek ◽  
Malini Mukherjee ◽  
Ankita Shree ◽  
Heba Samaha ◽  
...  
Keyword(s):  
T Cells ◽  
High Grade Glioma ◽  
High Grade ◽  
Car T Cells ◽  
Car T ◽  
Anti Tumor Activity

scholarly journals NIMG-74. MULTIPARAMETER MRI INVESTIGATION OF HIGH-GRADE GLIOMA RESPONSE TO CAR T CELL IMMUNOTHERAPY

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi178-vi178
Author(s):  
Harshan Ravi ◽  
Olya Stringfield ◽  
Gustavo De Leon ◽  
Sandra Johnston ◽  
Russell Rockne ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cells ◽  
T Cell ◽  
High Grade Glioma ◽  
High Grade ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract INTRODUCTION Immunotherapy with engineered CAR T cells is a promising new therapy for glioblastoma, for which predictive and prognostic biomarkers are needed to inform effective intervention. Recently, our group analyzed standard-of-care (SOC) MRI images of long-term and short-term glioblastoma survivors and identified six intratumoral “habitats” of which “Habitat 6” was correlated with survival at diagnosis in high-grade glioma. Based on the MRI characteristics of “Habitat 6”, viz. high enhancement and high edema, we hypothesized that it could be a marker of tumor immune infiltrates. We are studying longitudinal changes in tumor “habitat” composition on MRIs of subjects with recurrent high-grade glioma treated with CAR T cells engineered to target IL13Ra2. METHODS MRI scans of the brain were acquired in 6 subjects at 3.0 T at baseline and various times before and after initiation of CAR T cell therapy. FLAIR, T1W and T1W-CE MRI images were registered to T2W images and six intratumoral “habitats” were computed as per our recently published methodology. The six habitats generated at the end of the tumor segmentation process were: “Habitat 1” (low FLAIR, low enhancement), “Habitat 2” (high FLAIR, low enhancement), “Habitat 3” (low FLAIR, medium enhancement), “Habitat 4” (high FLAIR, medium enhancement), “Habitat 5” (low FLAIR, high enhancement), and “Habitat 6” (high FLAIR, high enhancement). RESULTS Analysis of temporal changes in the six “habitats” shows an initial increase in both “Habitat 4” and “Habitat 6” following CAR T cell therapy initiation. Subjects with higher absolute volumes of “Habitat 6” at the baseline (pre-treatment) showed longer overall survival. Overall survival is a function of absolute “Habitat 6” volume at baseline, its direction of change immediately post-therapy, the duration of any increase in “Habitat 6” post-treatment, and the “Habitat 6” to “Habitat 4” ratio. Additional subjects are being evaluated to further understand these preliminary observations.

scholarly journals IMMU-16. INTRA-TUMOURAL IL-12 DELIVERY ENABLES CAR T-CELL IMMUNOTHERAPY FOR HIGH-GRADE GLIOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii363-iii363
Author(s):  
Giulia Agliardi ◽  
Anna Rita Liuzzi ◽  
Alastair Hotblack ◽  
Donatella De Feo ◽  
Nicolás Núñez ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
High Grade Glioma ◽  
High Grade ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract Treatment with T-cells redirected to tumour specificity with a chimeric antigen receptor (CAR) may be well suited to treat intracranial tumours due to the ability of T-cells to access the central nervous system and migrate to infiltrative sites of disease. In adult glioblastoma, a case report of local and distant eradication of intracranial and spinal tumour deposits following intraventricular infusion of IL13Ra2-CAR T-cells indicates the potential of this approach. However, in contrast to the sustained complete remissions observed in haematological malignancies, in the majority of patients with glioblastoma CAR T-cell therapy has not resulted in clinical benefit. Tumour heterogeneity and the highly immune inhibitory tumour microenvironment (TME) are likely key barriers to achieving durable anti-tumour immunity. Here use intra-tumoural administration of IL-12 to enable CAR T-cell immunity. We employed CAR-T cells targeting the tumour-specific epidermal growth factor variant III (EGFRvIII). In an immunocompetent orthotopic mouse model of high-grade glioma, we show that CAR-T cells alone failed to control fully established tumour, but when combined with a single, locally delivered dose of IL-12, durable antitumor responses were achieved. IL-12 not only boosted cytotoxicity of CAR T-cells, but also reshaped the TME driving increased infiltration of proinflammatory CD4+ T-cells, decreased numbers of regulatory T-cells (Tregs) and activation of the myeloid compartment. Critically, immunotherapy enabling benefits of IL-12 were achieved with minimal systemic effects. Our findings show that local delivery of IL-12 is an effective adjuvant for CAR-T cell therapy for high-grade glioma. Assessment of application in high-risk childhood brain tumours is ongoing.

scholarly journals A Phase I Study of CD19-Targeted 19(T2)28z1xx CAR T Cells in Adult Patients with Relapsed or Refractory B-Cell Malignancies

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 43-44
Author(s):  
Jae H. Park ◽  
Isabelle Riviere ◽  
Devanjan S. Sikder ◽  
Vladimir P. Bermudez ◽  
Brigitte Senechal ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Dose Escalation ◽  
Research Funding ◽  
High Grade ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Background: Autologous CAR T cell therapy targeting the B-cell specific surface antigen CD19 has demonstrated favorable clinical responses in relapsed or refractory (R/B) B-cell lymphomas (BCL). However, despite 40-60% initial complete response (CR) rates, only a subset of patients experience durable remissions, and there is a need to further improve the efficacy of CAR therapies by preventing relapse and attaining a deeper CR. We hypothesized that the redundancy of CD28 and CD3V signaling in a CAR design incorporating all 3 CD3Vimmunoreceptor tyrosine-based activation motifs (ITAMs) might foster counterproductive T cell differentiation and exhaustion, and therefore created a new CD19 CAR construct with calibrated CAR activation potential by mutating 2 of the 3 ITAMs, termed 1XX. In systemic ALL mouse models, 19-28z1XX CAR induced effective tumor eradication at low CAR T cell doses with improved survival compared to conventional 19-28z CAR. Further preclinical studies demonstrated that the enhanced therapeutic benefit resulted from the reduced strength of activation mediated by the 19-28z1XX CAR, achieving a favorable balance of effector and memory functions, thereby enhancing persistence of functional CAR T cells and promoting effective elimination of CD19+ leukemia at lower T cell doses than needed with 19-28z CAR T cells (Feucht J et al. Nat Med 2019). To further improve the persistence of functional CAR T cells, we screened different humanized CD19-directed scFv in the context of a 19-28z1XX CAR design and proved high specificity and functionality of 19-28z1XX CARs containing a novel humanized scFv T2 - termed 19(T2)28z1XX. Study Design and Methods: This study is a single center Phase I clinical trial of 19(T2)28z1XX in patients with R/R B-cell malignancies at Memorial Sloan Kettering Cancer Center (NCT04464200). Key disease eligibility criteria include R/R diffuse large B cell lymphoma (DLBCL), high grade BCL, primary mediastinal BCL, indolent BCL and chronic lymphocytic leukemia (CLL). Patients with prior CD19 CAR therapies are eligible as long as expression of CD19 is confirmed. Key exclusion criteria include ongoing immunosuppression such as systemic GvHD therapy and active CNS disease. The study uses a 3+3 dose-escalation design to identify the maximum tolerated dose for BCL. There are 5 planned flat-dose levels. Patients will receive conditioning chemotherapy consisting of 3 days of fludarabine and cyclophosphamide followed by a single infusion of 19(T2)28z1XX CAR T cells. In the dose-escalation phase, patients with DLBCL, high grade BCL, and primary mediastinal BCL are eligible to participate. Once the recommended phase 2 dose (RP2D) is determined, the study will open to dose expansion phase with two cohorts. Cohort 1 includes DLBCL, high grade BCL and primary mediastinal BCL (i.e. same eligibility criteria as the dose-escalation phase). Cohort 2 will include patients with indolent BCL, CLL, and Richter's transformation. The dose-expansion part of the trial is designed to further characterize the safety, efficacy, and pharmacokinetics of 19(T2)28z1XX CAR in multiple indications. The primary objective of the trial is to evaluate safety and tolerability and determine the recommended Phase 2 dose of 19(T2)28z1XX. Key secondary objectives include evaluation of 19(T2)28z1XX's efficacy and cellular kinetics. Exploratory objectives include assessment of B cell aplasia, and analysis of serum cytokines. The trial has begun enrollment in August 2020. The investigators are hopeful this study will lead to development of improved CD19 CAR T cell therapy with enhanced efficacy and favorable toxicity profiles with lower infused T cell dose. Disclosures Park: AstraZeneca: Consultancy; Servier: Consultancy, Research Funding; Autolus: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy; Minverva: Consultancy; Artiva: Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics: Research Funding; Kite: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Genentech/Roche: Research Funding; Juno Therapeutics: Research Funding; GSK: Consultancy; Intellia: Consultancy; Allogene: Consultancy. Riviere:Fate Therapeutics Inc.: Consultancy, Other: Ownership interest , Research Funding; FloDesign Sonics: Consultancy, Other: Ownership interest; Juno Therapeutics: Other: Ownership interest, Research Funding; Takeda: Research Funding; Atara: Research Funding. Palomba:Genentech: Research Funding; Juno Therapeutics, a Bristol-Meyers Squibb Company: Honoraria, Research Funding; Regeneron: Research Funding; Novartis: Honoraria; Merck: Honoraria; Celgene: Honoraria; Pharmacyclics: Honoraria. Brentjens:BMS: Research Funding; Gracell Therapeutics: Consultancy; Juno Therapeutics (a Bristol Myers Squibb company): Patents & Royalties. Sadelain:Atara: Patents & Royalties, Research Funding; Fate Therapeutics: Patents & Royalties, Research Funding; Minerva: Other: Biotechnologies , Patents & Royalties; Mnemo: Patents & Royalties; Takeda: Patents & Royalties, Research Funding. OffLabel Disclosure: Cyclophosphamide and fludarabine will be used as conditioning therapy prior to 19(T2)28z1XX CAR T cell administration.

scholarly journals IMMU-48. RATIONAL DEVELOPMENT AND CHARACTERIZATION OF MULTIVALENT TARGETING TANDEM AND PARALLEL CAR T CELLS FOR GLIOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi129-vi129
Author(s):  
Yibo Yin ◽  
Radhika Thokala ◽  
Logan Zhang ◽  
Devneet Kainth ◽  
Leila Haddad ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Cells ◽  
Interleukin 2 ◽  
Growth Factor Receptor ◽  
High Grade Glioma ◽  
Primary Brain Tumor ◽  
Single Chain ◽  
Car T Cells ◽  
Significant Difference ◽  
Car T

Abstract High grade glioma is the most common malignant primary brain tumor. Despite the best available therapy, the median survival is limited. Chimeric antigen receptor (CAR)-T cells effectively attack target positive tumor cells, demonstrating a promising possible treatment. Based on our previous clinical and pre-clinical studies, we utilized epidermal growth factor receptor variant III (EGFRvIII) and interleukin 13 receptor subunit alpha 2 (IL13Rα2) targeting single-chain variable fragments (scFvs) to generate bi-specific tandem CAR T cells and bi-specific parallel CAR T cells to decrease the potential of antigen escape and tumor recurrence. 5, 10, 15 or 20 flexible amino acids were utilized to link scFvs in tandem CARs. Ribosomal “skipping” 2A peptides were utilized to generate parallel CAR T cells. Flow-based IL13Rα2 staining on glioma stem cells (GSCs) showed 7 out 11 cases positive (64%) heterogeneous intratumoral expression. Tandem CAR T cells and parallel CAR T cells upregulated CD69 expression (P< 0.0001), generated IFNγ, interleukin 2 and TNFα (P< 0.0001), as well as exhibiting cytotoxic activity (P< 0.0001) when compared against un-transduced T cells, in co-culture with either single- or double-target positive GSCs. There was no significant difference between different lengths of linker in tandem CAR T cells. Parallel CAR T cells generated a larger cytokine response (P< 0.0001) and more effectively killed target positive cells (P< 0.05) than tandem CAR T cells. In summary, glioma associated target expression is heterogeneous in GSCs. Multivalent tandem CAR T cells and parallel CAR T cells effectively respond to target expressing tumor cells. The function of tandem CAR T cells is not relative with the length of linker. Parallel CAR T cells are a more promising strategy in generating gene modified multivalent targeting T cells.

scholarly journals Gene-edited healthy donor CAR T cells show superior anti-tumour activity compared to CAR T cells derived from patients with lymphoma in an in vivo model of high-grade lymphoma

Leukemia ◽  
2021 ◽  
Author(s):  
Charlotte Elizabeth Graham ◽  
Agnieszka Jozwik ◽  
Ruby Quartey-Papafio ◽  
Nikolaos Ioannou ◽  
Ana M. Metelo ◽  
...  
Keyword(s):  
T Cells ◽  
Healthy Donor ◽  
In Vivo Model ◽  
High Grade ◽  
Car T Cells ◽  
Anti Tumour Activity ◽  
Car T ◽  
Tumour Activity

scholarly journals 431 First-in-human phase I clinical trial evaluating intraperitoneal administration of MOv19-BBz CAR T cells in patients with alpha folate receptor-expressing recurrent high grade serous ovarian cancer

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A461-A461
Author(s):  
Payal Shah ◽  
Richard Shlanksy-Goldberg ◽  
Lainie Martin ◽  
Gregory Nadolski ◽  
Elizabeth Hexner ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trial ◽  
T Cells ◽  
Folate Receptor ◽  
Intraperitoneal Administration ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Car T Cells ◽  
Car T ◽  
Signaling Domains

BackgroundMost women with epithelial ovarian cancer develop uniformly incurable disease recurrence. Chimeric antigen receptor (CAR) T cells pair the MHC-independent tumor-recognition capabilities of monoclonal antibodies with the cytotoxicity of effector T cells. The success of CAR T cell therapy in solid tumors has been hindered by (1) difficulty identifying highly expressed, tumor-specific, cell surface target antigens; (2) limited trafficking and infiltration; and (3) suboptimal cytotoxic activity. Alpha folate receptor (FRα) is a transmembrane protein involved in cellular folate transport; expression has been reported in 80% of ovarian cancer, with limited physiologic expression on epithelial cells including bronchial, renal, and intestinal tissue. We hypothesize that intraperitoneal administration of alpha folate receptor (FRα) directed CAR T cells with dual 4-1BB and TCRzeta signaling domains will circumvent the above challenges and be safe, feasible, and elicit anti-tumor responses.MethodsWe initiated a first-in-human phase I clinical trial to evaluate the feasibility, safety and preliminary efficacy of intraperitoneal administration of FRα directed CAR T cells with and without antecedent lymphodepleting chemotherapy (LDC) in women with recurrent high grade serous ovarian cancer. The lentivirally-transduced CAR is composed of a MOv19 anti-FRα-specific single chain variable fragment fused to 4-1BB and TCRzeta signaling domains. Eligible patients have persistent or recurrent high grade serous epithelial ovarian, fallopian tube, or primary peritoneal carcinoma that is not platinum refractory and expresses ≥2+ FRα staining in ≥70% of tumor cells. Subjects must have an ECOG performance status 0–1, measurable disease, adequate hematologic and organ function, and must have progressed on at least two prior chemotherapy regimens for advanced disease. Patients undergo biopsy pre-infusion and Day +14 after infusion. After same-day placement of an intraperitoneal catheter by Interventional Radiology, CAR T cells are administered via a single infusion on three dose cohorts: Cohort 1 (starting cohort), 1–3x107/m2 cells without LDC; Cohort 2, 1–3x107/m2 CAR T cells after LDC; Cohort 3, 1–3x108/m2 cells after LDC. Catheter is removed after infusion. A 3+3 dose escalation design to determine maximum tolerated dose (MTD) yields approximately 9 to 18 subjects. The primary objective is safety and feasibility, and secondary objectives are anti-tumor response (endpoints: overall response rate based on RECIST v 1.1 and irRECIST when feasible, progression-free survival and overall survival). Correlative endpoints include CAR T cell engraftment and persistence in peripheral blood and body fluids examined via quantitative PCR of CAR T DNA, and bioactivity of CAR T cells. Enrollment is ongoing.Trial RegistrationThis trial is registered at ClinicalTrials.gov (NCT03585764).Ethics ApprovalThis study was approved by the Institutional Review Board at the University of Pennsylvania (IRB 830111). All subjects provided written informed consent prior to any study-related procedures.

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