scholarly journals RBTT-12. A PHASE I STUDY OF EGFRVIII-DIRECTED CAR T CELLS COMBINED WITH PD-1 INHIBITION IN PATIENTS WITH NEWLY, DIAGNOSED, MGMT-UNMETHYLATED GLIOBLASTOMA: TRIAL IN PROGRESS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi221-vi221 ◽  
Author(s):  
Stephen Bagley ◽  
Arati Desai ◽  
Zev Binder ◽  
MacLean Nasrallah ◽  
Wei-Ting Hwang ◽  
...  
Keyword(s):  
T Cells ◽  
Phase I ◽  
Phase I Study ◽  
Phase 1 ◽  
Objective Response ◽  
Tumor Resection ◽  
Adjuvant Radiation ◽  
Newly Diagnosed ◽  
Car T Cells ◽  
Car T

Abstract BACKGROUND This study builds on the results of the University of Pennsylvania sponsored phase I study of a single peripheral infusion of chimeric antigen receptor (CAR) T cells targeting epidermal growth factor receptor variant III (EGFRvIII) in recurrent glioblastoma (GBM) (NCT02209376). A dose of 5x108 CART-EGFRvIII cells was safe, and the cells were able to expand in the host and reach the GBM tumor in the brain. In addition, there was no cross-reactivity of CART-EGFRvIII cells with wild-type EGFR normally expressed by human tissues. Some patients required tumor resection after CAR T cell infusion. In situ evaluation of the tumor microenvironment demonstrated increased and robust expression of inhibitory molecules, such as programmed death-ligand 1 (PD-L1), compared to pre–CART-EGFRvIII tumor specimens. Therefore, we hypothesized that using a combination of CART-EGFRvIII cells and a PD-1 inhibitor would improve the outcome of the treatment. METHODS This single-center study (NCT03726515) has a single-arm, open-label, phase 1 design and will enroll 7 patients with newly diagnosed, O6-methylguanine-methyltransferase (MGMT)-unmethylated, EGFRvIII+ GBM. Following maximal safe tumor resection, patients receive a short course of adjuvant radiation with a total dose of 40 Gy administered in 15 fractions. Peripheral IV infusions of 2x108 CART-EGFRvIII cells and 200mg pembrolizumab begin 2–3 weeks after completing radiation therapy. Thereafter, subjects receive CART-EGFRvIII cells + pembrolizumab in 3-week cycles for up to 3 infusions of CART-EGFRvIII cells and 4 infusions of pembrolizumab. The primary endpoint of the study is the safety and tolerability of administering multiple infusions of CART-EGFRvIII cells in combination with pembrolizumab, as measured by the occurrence of study-related adverse events. Secondary endpoints include overall survival, progression-free survival, and objective response rate. PROGRESS: At 5 June 2019, 2 patients have been enrolled and treated on study.

Abstract 2329: Clinical manufacturing of CAR T cells targeting ICAM-1 for a phase I study against advanced thyroid cancer therapy

2019 ◽  
Author(s):  
Yogindra Vedvyas ◽  
Jaclyn E. McCloskey ◽  
Yanping Yang ◽  
Irene M. Min ◽  
Thomas J. Fahey ◽  
...  
Keyword(s):  
T Cells ◽  
Thyroid Cancer ◽  
Cancer Therapy ◽  
Phase I ◽  
Phase I Study ◽  
Car T Cells ◽  
Car T ◽  
Advanced Thyroid Cancer

Abstract 2329: Clinical manufacturing of CAR T cells targeting ICAM-1 for a phase I study against advanced thyroid cancer therapy

2019 ◽  
Author(s):  
Yogindra Vedvyas ◽  
Jaclyn E. McCloskey ◽  
Yanping Yang ◽  
Irene M. Min ◽  
Thomas J. Fahey ◽  
...  
Keyword(s):  
T Cells ◽  
Thyroid Cancer ◽  
Cancer Therapy ◽  
Phase I ◽  
Phase I Study ◽  
Car T Cells ◽  
Car T ◽  
Advanced Thyroid Cancer

scholarly journals Efficacy, Toxicity and Targets for Adoptive Cellular Therapy in Multiple Myeloma: A Systematic Review

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5649-5649
Author(s):  
Muhammad Usman ◽  
Muhammad Junaid Tariq ◽  
Awais Ijaz ◽  
Muhammad Asad Fraz ◽  
Ali Younas Khan ◽  
...  
Keyword(s):  
T Cells ◽  
Phase I ◽  
Natural Killer ◽  
Cellular Therapy ◽  
Objective Response ◽  
Complete Response ◽  
Adoptive Cellular Therapy ◽  
Car T Cells ◽  
Car T ◽  
Grade 3

Abstract Introduction Advancement in multiple myeloma (MM) has led to the development of adoptive cell transfer (ACT), an immunotherapeutic modality that utilizes body's own effector cells (T cells or Natural killer cells) to kill cancer cells. These include chimeric antigen receptor T cells (CAR-T cells), genetically modified T cell receptors (TCRs), activated Natural Killer (NK) cells and native T cells armed with bispecific antibodies. Potential antigen targets for TCRs in MM include B cell maturation antigen (BCMA), CD19, CD138, NKG2D, Ig kappa, LeY and SLMF7/CS-1, MAGE A3 and NY-ESO-1. The purpose of this review is to summarize various types of cellular therapies which are being tested in early phase clinical trials for treatment of MM. Methods We performed a comprehensive literature search (PubMed, EMBASE, AdisInsight and Clinicaltrials.gov) between January 2008 to December 2017, to identify early phase (I and I/II) trials of cellular therapy for the treatment of MM. We included studies involving cellular therapy, irrespective of the geo-location, age, sex or specific eligibility criteria. Results With initial search yielded 2537 phase I and phase I/II studies. After initial screening by two reviewers and categorization by mechanism of action, 37 clinical trials (CTs) that involved ACT were included. Out of the 37 trials, 18 are active or completed (Table 1) and 19 are recruiting subjects (Table 2). Most explored mechanism of action (21 CTs) in these trials is CAR T-cell therapy directed against B cell maturation antigen (BCMA). Anti-BCMA CART has shown promising efficacy of up to 100% objective response (OR) in a phase I trial (NCT03090659, n=22). In a phase I/II trial by Fan et al. (n=19), 6 (32%) patients showed complete response (CR), 12 (63%) developed near complete response (nCR), 1 (5%) achieved partial response (PR). In phase I trial by Ali et al. (2016, n=12), anti-BCMA CART cells led to stringent complete response (sCR) in 1 (8%) patient, very good partial response (VGPR) in 2 (16%), PR in 1 (8%) and stable disease (SD) in 8 (66%). Grade 3-4 cytokine release syndrome (CRS) was reported in 3 (25%) patients receiving high dose of CAR T cells (9 x 106 / kg in 2 patients and 3 x 106 /kg in 1 patient). Cohen et al., 2017 (n= 24) reported the objective response rate (ORR) defined as ≥PR in 11 (47%) patients. In 75% of patients with grade 3-4 CRS, tocilizumab/siltuximab was used to manage CRS. According to Garfall et al. (2018, n=10), administration of anti-CD19 CART after autologus stem cell transplant (auto-SCT) improved progression free survival (PFS) in 2 (20%) patients compared to PFS due to auto-SCT done earlier in same patients (from 181 to 479 days and 127 to 249 days). Leivas et al. (2016, n=5) showed that infusion of expanded and activated natural killer cells (NKAE) with lenalidomide have shown better response (PR=1, SD=1, SD to PD=1) than NKAE with bortezomib (SD=1, PD=1). In 10 (83%) patients, VGPR or better response was achieved after infusion of allogenic cord blood derived NK cells along with auto-SCT (Shah et al., 2017). Rapoport et al. (2017, n=25) infused CAR T-cells against cancer testes antigens (NY-ESO-1, LAGE-1a) and demonstrated the OR in 19 (76%) patients (1 sCR, 12 VGPR, 6PR) at day 100. Al-Kadhimi et al. (2011, n=9) administered activated autologous T cells armed with bispecific antibodies against CD3 and CD20 (aATC) prior to auto-SCT. Two patients achieved VGPR, two patients achieved CR while five patients developed PR. Fowler et al. (2016, n=20) used type 1 polarized, rapamycin resistant T (T1-Rapa) cells after auto-SCT in high risk myeloma patients. Out of 19 evaluable patients, 5 had ongoing CR (at 733, 787, 847, 926, 1186 days) while 14 patients had disease progression (from 64 to 917 days). No adverse effects or dose limiting toxicity was observed in any of the patients. Conclusion Adoptive cellular therapy has shown excellent clinical activity against myeloma cells in relapsed refractory patients. The adverse events like CRS and infusion reactions are concerning but manageable. The results of trials involving T cells targeting BCMA are very encouraging. Disclosures No relevant conflicts of interest to declare.

Phase I study of immunotherapy for advanced ROR1+ malignancies with autologous ROR1-specific chimeric antigen receptor-modified (CAR)-T cells.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. TPS79-TPS79 ◽  
Author(s):  
Jennifer M Specht ◽  
Sylvia Lee ◽  
Cameron Turtle ◽  
Carolina Berger ◽  
Josh Veatch ◽  
...  
Keyword(s):  
T Cells ◽  
Phase I ◽  
Phase I Study ◽  
Lentiviral Vector ◽  
Tumor Regression ◽  
Ex Vivo ◽  
Orphan Receptor ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T

TPS79 Background: CAR-T cells have demonstrated marked tumor regression in patients (pts) with hematologic malignancies. ROR1, a tyrosine kinase orphan receptor, is expressed in triple negative breast cancers (TNBC) and non-small cell lung cancers (NSCLC) and is a novel candidate for CAR-T cell therapy. ROR1-specific CAR-T cells are engineered with lentiviral vector encoding ROR1 scFv/4-1BB/CD3ζ and a truncated EGFR molecule to permit elimination of ROR1 CAR-T cells in case of toxicity. Methods: NCT02706362 is a phase I study evaluating the safety and anti-tumor activity of adoptively transferred autologous ROR1 CAR-T cells in pts with advanced ROR1+ TNBC and NSCLC. Eligibility criteria include: metastatic TNBC or NSCLC; measurable disease; prior standard therapy with no maximum on number of prior regimens; tumor ROR1 expression > 20% by IHC; KPS > 70%; age ≥18; negative pregnancy test for women of childbearing potential; informed consent; adequate organ function. Exclusions are: active autoimmune disease or uncontrolled infection, HIV seropositive status, contraindication to cyclophosphamide, anticipated survival < 3 months, and/or untreated CNS metastases. After screening, leukapheresis is performed, CD8+ and CD4+ T cells are selected, then transduced with the ROR1+ CAR lentivirus and expanded. Lymphodepletion with cyclophosphamide and fludarabine is followed 36-96 hours later by infusion of ROR1 CAR-T cells in escalating doses (3.3 x 105/kg - 1 x 107/kg cells with defined CD8+ and CD4+ composition). Pts are treated in cohorts of 2 to determine cell dose associated with an estimated toxicity rate of < 25%. Primary aim is to determine the maximum tolerated dose (MTD) and safety of ex vivo expanded ROR1 CAR-T cells. Secondary aims include persistence and phenotype of transferred T cells, trafficking of T cells to tumor site, in vivo function, and preliminary antitumor activity of ROR1 CAR-T cells by RECIST 1.1. Dose escalation is determined by CRM algorithm with minimum of 21-day interval following infusion between pts. Preliminary estimates of efficacy will be obtained among all pts and those treated at estimated MTD. Six of 30 pts have been enrolled with no DLTs observed. Clinical trial information: NCT02706392.

Phase I study of CRISPR-engineered CAR-T cells with PD-1 inactivation in treating mesothelin-positive solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3038-3038
Author(s):  
Zhenguang Wang ◽  
Meixia Chen ◽  
Yan Zhang ◽  
Yang Liu ◽  
Qingming Yang ◽  
...  
Keyword(s):  
T Cells ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Surface Expression ◽  
Dose Escalation Study ◽  
Car T Cells ◽  
Car T ◽  
The Mean

3038 Background: Our previous phase I study with MPTK-CAR-T (mesothelin-directed 28ζ CAR-T cells with PD-1 and TCR disruption by CRISPR-Cas9 system) demonstrated feasibility and safety of CRISPR-mediated PD-1 inactivation in CAR-T cells, and suggested the natural TCR is beneficial for the proliferation of CAR-T cells in solid tumors. Based on these observations, we initiated a pilot dose escalation study to investigate mesothelin-directed CAR-T cells with only PD-1 disruption by CRISPR (termed as GC008t) in patients with mesothelin-positive advanced solid tumors (NCT03747965). Methods: On the data cut-off date (Jan 20, 2020), nine patients (6 pancreatic cancers, 2 ovarian cancers, 1 colorectal cancer) were treated (5 received ≥12 numbers of therapy), three in cohort 1 (0.1-0.2×107/kg), four in cohort 2 (0.5-1.0×107/kg), two in cohort 3 (2.5-5×107/kg). Eight of the 9 patients received lymphodepletion regimen of cyclophosphamide and nab-paclitaxel with or without gemcitabine. Four of the 9 patients received repeat infusions of GC008t per protocol. Results: Comparable proliferation capacity was observed in vitro between the MPTK-CAR-T and the GC008t products. The mean PD-1 surface expression in cell products was 0.5% (range, 0.2%-0.9%). GC008t infusions were well tolerated with no observed on-target/off-tumor toxicity, autoimmune activity. Only two patients in cohort 3 developed grade 1 CRS with fever and rash. Circulating GC008t expanded with a peak at day 7-14 and became undetectable by qPCR beyond 1 month. The mean peak levels of circulating CAR-T cells between GC008t and MPTK-CAR-T at similar dose level were not statistically significant. Failure of GC008t engraftment after repeat infusion was observed in 2 out of 4 patients. The best response of the 7 evaluable patients was stable disease in 4 and partial response in 2 patients (dosed ≥ 1×107/kg) with PFS of 80 and 160 days. Conclusions: Phase I trial of GC008t further establishes that genetic inactivation of PD-1 in CAR-T cells by CRISPR is feasible and safe. The expansion and persistence of CAR-T cells with PD-1 disruption is not improved significantly even in the setting of natural TCR and lymphodepletion. Future endeavors are needed to improve the clinical efficacy of CAR-T therapy in the treatment of solid tumor. Clinical trial information: NCT03747965 .

Orvacabtagene autoleucel (orva-cel), a B-cell maturation antigen (BCMA)-directed CAR T cell therapy for patients (pts) with relapsed/refractory multiple myeloma (RRMM): update of the phase 1/2 EVOLVE study (NCT03430011).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 8504-8504 ◽  
Author(s):  
Sham Mailankody ◽  
Andrzej J. Jakubowiak ◽  
Myo Htut ◽  
Luciano J. Costa ◽  
Kelvin Lee ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Median Time ◽  
Phase 1 ◽  
Objective Response ◽  
Bridging Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Grade 3

8504 Background: Orva-cel is an investigational, BCMA-directed CAR T cell product with a fully human binder. Over 100 pts have been treated in the EVOLVE phase 1 study. Pts treated at 50 and 150 × 106 CAR+ T cells were previously reported (Mailankody ASH 2018 #957). We now report results of the higher dose levels (DLs) in 51 pts who received orva-cel manufactured using the process intended to support commercial use. Methods: Pts with RRMM who had ≥3 prior regimens, a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 monoclonal antibody (mAb), received orva-cel at 300, 450, and 600 × 106 CAR+ T cells after lymphodepletion with fludarabine/cyclophosphamide. Results: Median pt age was 61 (range, 33–77) y; median time from diagnosis was 7.0 (range, 1.7–23.6) y, with a median of 6 (range, 3–18) prior regimens. Overall, 92% of pts were penta-exposed (2 IMiDs, 2 PIs, and an mAb); 61% of pts received bridging therapy (77% were refractory to bridging therapy). Two pts had dose-limiting toxicities: grade 3 neurological event (NE) for >7 d at 300 × 106 CAR+ T cells and grade 4 neutropenia for >28 d at 450 × 106 CAR+ T cells. Key efficacy and safety outcomes are shown in the Table. Cytokine release syndrome (CRS)/NEs were managed with tocilizumab and/or steroids (78%), anakinra (14%), and/or vasopressors (6%). Grade ≥3 anemia, neutropenia, and thrombocytopenia at 29 d occurred in 21%, 55%, and 44% of pts (median time to resolution to grade ≤2 of any cytopenia, ≤2.1 mo). Grade ≥3 infections occurred in 14%. After a median follow-up (F/U) of 5.9 mo, median progression-free survival was not reached. Conclusions: Orva-cel at 300, 450, and 600 × 106 CAR+ T cells demonstrated manageable safety (CRS grade ≥3: 2%; NE grade ≥3: 4%) and compelling efficacy in heavily pretreated pts with RRMM, with a 91% objective response rate (ORR) and 39% complete response (CR)/stringent CR (sCR) rate. Updated results will be presented, including minimal residual disease, durability of response, and recommended phase 2 dose. Clinical trial information: NCT03430011 . [Table: see text]

Zuma-6: Phase 1-2 multicenter study evaluating safety and efficacy of axicabtagene ciloleucel (axi-cel; KTE-C19) in combination with atezolizumab in patients with refractory diffuse large b-cell lymphoma (DLBCL).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS7572-TPS7572 ◽  
Author(s):  
Frederick Lundry Locke ◽  
Jason R. Westin ◽  
David Bernard Miklos ◽  
Alex Francisco Herrera ◽  
Caron Alyce Jacobson ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Clinical Outcomes ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Objective Response ◽  
B Cell Lymphoma ◽  
Safety And Efficacy ◽  
Car T Cells ◽  
Car T

TPS7572 Background: Approximately 1/3 of patients with DLBCL, the most common type of B-cell lymphoma, will become refractory to standard combination chemotherapy and have uniformly poor clinical outcomes (Crump, ASCO 2016). Axi-cel (autologous anti-CD19 chimeric antigen receptor [CAR] T cell therapy) has shown promising response rates in patients with refractory DLBCL compared with standard approaches, although some patients do not respond or progress after an initial response (Locke, Mol Ther 2016). Expression of PD-L1 on DLBCL cells and activation-dependent expression of PD-1 on CAR T cells after infusion led to the hypothesis that PD-1 pathway blockade may augment the activity of axi-cel and result in improved clinical outcomes. This study will evaluate safety and efficacy of axi-cel when given with atezolizumab (anti–PD-L1 antibody), delivered sequentially, in patients with refractory DLBCL. Methods: Phase 1 will enroll ~3-9 patients to estimate the incidence of dose-limiting toxicities. Phase 2 will enroll ~22 patients to evaluate safety and efficacy, with a primary endpoint of complete response (CR) rate (Cheson 2007). Secondary endpoints include key efficacy outcomes such as objective response rate (CR+partial response [PR]), duration of response, progression-free and overall survival, and safety and biomarker outcomes. Eligible adult patients will have received prior adequate therapy (including anti-CD20 monoclonal antibody and an anthracycline-based regimen) and have an ECOG PS of 0-1 and adequate bone marrow and organ function. Patients with a history of Richter transformation, transformed follicular lymphoma, CNS disease, or active infection are not eligible. Patients will receive fludarabine 30 mg/m2/d and cyclophosphamide 500 mg/m2/d × 3 d, followed by a single infusion of axi-cel (target dose, 2 × 106anti-CD19 CAR T cells/kg) followed by atezolizumab 1200 mg given every 21 d for 4 doses (phase 1, first dose to occur 21, 14, and 1 d after axi-cel infusion in cohorts 1, 2, and 3, respectively). The study opened to accrual in September 2016. Clinical trial information: NCT02926833.

scholarly journals IMMU-03. UPDATES ON BRAINCHILD-01, -02, AND -03: PHASE 1 LOCOREGIONAL CAR T CELL TRIALS TARGETING HER2, EGFR, AND B7-H3 FOR CHILDREN WITH RECURRENT CNS TUMORS AND DIPG

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii360-iii360
Author(s):  
Nicholas Vitanza ◽  
Juliane Gust ◽  
Ashley Wilson ◽  
Wenjun Huang ◽  
Francisco Perez ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Phase 1 ◽  
Signs And Symptoms ◽  
Preliminary Evidence ◽  
Cns Tumors ◽  
Disease Response ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Abstract We report preliminary results of three Phase 1 trials of repetitively dosed locoregional CAR T cells for children with recurrent/refractory CNS tumors, targeting HER2 (BrainChild-01), EGFR (BrainChild-02), and B7-H3 (BrainChild-03). Cells are delivered into the tumor cavity (Arm A) or ventricular system (Arm B and BrainChild-03’s DIPG-specific Arm C). Primary endpoints are feasibility and safety. Successful CAR T cell manufacture occurred in 2/2 subjects (BrainChild-01) and 2/3 (BrainChild-02). All subjects tolerated intra-patient dose escalation from 1x107 to 2.5x107 cells/dose without DLTs. Two subjects were evaluable on BrainChild-01 (S-001: glioblastoma, Arm A, survival 173 days post-first infusion, received 6 infusions; S-002: ependymoma, Arm B, survival 111 days, 9 infusions). One subject was evaluable on BrainChild-02 (glioblastoma, Arm A, withdrew from trial at 49 days, 5 infusions). One enrolled patient on BrainChild-03 has not begun treatment. None of the subjects developed new neurologic toxicities, although transient worsening of baseline tumor-related signs and symptoms were seen. Secondary endpoints are efficacy and disease response. No objective radiographic responses have been observed. Both BrainChild-01 subjects had transient systemic CRP elevations following infusions (S-001: peak of 3.9 post Course 1 Week 1; S-002: peak of 2.3 post Course 2 Week 1), possibly indicating an inflammatory response. Both subjects had post-infusion CSF cytokine elevations (CXCL10, GCSF, GM-CSF, IFNa2, IFNg, IL-10, IL12-p40, IL12-p70, IL-15, IL-1a, IL-3, IL-6, IL-7, TNFa, VEGF) without concurrent systemic changes. In summary, we provide preliminary evidence of safety and feasibility of intracranial delivery of CAR T cells for pediatric CNS tumors.

Sign in / Sign up

Export Citation Format

Share Document