Evaluation of controlled IL-12 in combination with a PD-1 inhibitor in subjects with recurrent glioblastoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2020-2020 ◽  
Author(s):  
E. Antonio Chiocca ◽  
Rimas Vincas Lukas ◽  
Ganesh Rao ◽  
John A. Barrett ◽  
Jill Y. Buck ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cytotoxic T Cells ◽  
Phase 1 ◽  
Safety Data ◽  
Recurrent Glioblastoma ◽  
Therapeutic Window ◽  
Open Label ◽  
Median Baseline ◽  
Immune Mediated

2020 Background: Ad-RTS-hIL-12 (Ad) is a novel gene therapy candidate conditionally expressing IL-12 under the control of veledimex (V) acting via the proprietary RheoSwitch Therapeutic System (RTS) gene switch with a therapeutic window. Intratumoral Ad + oral V monotherapy (Phase 1 study, NCT02026271 ) resulted in a new sustained intra-tumor influx of activated cytotoxic T cells, consistent with an immune-mediated anti-tumor effect improving median overall survival (mOS) of subjects with recurrent glioblastoma (rGBM). This correlated with an increased circulating CD8+/FoxP3+ T cell ratio (“cytoindex”), an emerging biomarker for mOS. PD-1 expression on infiltrating T cells at biopsy after Ad+V, supports combining controlled IL-12 with a PD-1 inhibitor to further augment T-cell-mediated anti-tumor effects. The rationale is also supported by increased OS (100% combo vs 63% for Ad+V vs 40% for anti-PD-1) in mice bearing GL-261 glioma. Methods: An ongoing open label, dose-escalation Phase 1 trial (NCT03636477) is evaluating safety and tolerability of local, controlled IL-12 with nivolumab (nivo) in adult subjects with rGBM. Ad was administered by single intratumoral injection (2 x 1011 viral particles, Day 0) plus V (10-20 mg) PO QD x 15 with nivo (1-3mg/kg) IV on Days -7, 15, then Q2W. Results: Safety data revealed a similar profile as Ad +V monotherapy. Adverse reactions (ARs) during follow-on nivo dosing were consistent with anti-PD-1 reports. ARs were manageable and reversible with no synergistic toxicities. Nivo alone did not alter peripheral IL-12 levels (median baseline (before anti-PD-1) 0.9 pg/mL; Day 0 1 pg/mL) increasing to 5.5 pg/mL on Day 3. Nivo alone increased peripheral T cells (CD3+CD8+ median baseline 23%; Day 0 26%) and Ad+V elevated peripheral CD3+CD8+ to 31% at Day 14. Nivo alone decreased regulatory T cells (FoxP3 baseline 1.5% vs Day 0 0.8%). Ad+V decreased these to 0.3% (Day 14). Combination therapy improved the cytoindex (baseline 15; Day 0 29; Day 14 80). Conclusions: Controlled IL-12 production using Ad + V with nivo is a rational combination with initial data consistent with immune-mediated anti-tumor effects with a favorable safety profile, warranting continued investigation in rGBM. Clinical trial information: NCT03636477.

Controlled IL-12 in combination with a PD-1 inhibitor subjects with recurrent glioblastoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2510-2510
Author(s):  
E. Antonio Chiocca ◽  
Rimas Vincas Lukas ◽  
Clark C Chen ◽  
Ganesh Rao ◽  
Christina Amidei ◽  
...  
Keyword(s):  
T Cells ◽  
Transcriptional Control ◽  
Phase 1 ◽  
Safety Data ◽  
Intratumoral Injection ◽  
Recurrent Glioblastoma ◽  
Phase 2 ◽  
Open Label ◽  
Rational Combination ◽  
Circulating T Cells

2510 Background: Monotherapy with intratumoral Ad-RTS-hIL-12 (Ad), a gene therapeutic conditionally expressing IL-12 under the transcriptional control of oral veledimex (“Controlled IL-12”), was shown in a phase 1 study (NCT02026271) to elicit a new and sustained intra-tumoral infiltration of T cells with co-expression of PD-1. We report updated findings following completion of enrollment (with follow-up ongoing) for a phase 1 substudy (NCT03636477) evaluating safety and tolerability of local, Controlled IL-12 in combination with nivolumab (nivo) in adults with recurrent glioblastoma (rGBM). Methods: Multicenter, open label, dose-escalation phase 1 trial to evaluate safety and tolerability of local, Controlled IL-12 with nivo in adult subjects with rGBM. Ad was administered by single intratumoral injection (2 x 1011 viral particles, Day 0 at time of resection) plus V (10 or 20 mg) PO QD x 15 with nivo (1 or 3 mg/kg) IV on Days -7, 15, then Q2W. Results: 21 subjects were treated (Cohort 1: V 10 mg, nivo 1 mg/kg, n = 3; Cohort 2: V 10 mg, nivo 3 mg/kg, n = 3; and Cohort 3: V 20 mg, nivo 3 mg/kg, n = 3 + 12 expansion). Safety data were similar to Ad+V monotherapy. Adverse reactions during follow-on nivo dosing were consistent with anti-PD-1 labeling, manageable, and generally reversible with no synergistic toxicities. Focusing on the 20mg V cohort (recommended phase 2 dose), serum IL-12 mean ± SEM (screening, 0.4 ± 0.1 pg/mL; Day 0, 0.6 ± 0.1 pg/mL), increased after Ad+V to 8.7 ± 3.3 pg/mL on Day 3. Similarly, serum IFN-g levels did not increase due to nivo alone (screening, 0 ± 0 pg/mL; Day 0, 0 ± 0 pg/mL), increasing after Ad+V to 6.2 ± 2.3 pg/mL on Day 7. Additionally, nivo alone did not significantly increase circulating T cells (CD3+ CD8+%) (paired differences comparison, Day 0 to screening) 3.1%, p =0.13, whereas Ad+V significantly increased peripheral T cells (Day 28 - Day 0) 3.6%, p =0.02. Pseudoprogression followed by a decrease in size (SPD) has been shown as evidenced by serial MRIs in a subgroup of subjects. Preliminary overall survival findings will be presented. Conclusions: Controlled IL-12 with PD-1 inhibition is a rational combination with initial data consistent with immune-mediated effects, a favorable safety profile, and early evidence of anti-tumor effects. An additional phase 2 study combining Controlled IL-12 with cemiplimab-rwlc in adults with rGBM is ongoing. Clinical trial information: NCT03636477 .

scholarly journals CTIM-05. COMBINATION OF CONTROLLED INTERLEUKIN-12 GENE THERAPY WITH IMMUNE CHECKPOINT BLOCKADE IN RECURRENT GLIOBLASTOMA: UPDATED RESULTS OF A MULTI-INSTITUTIONAL, OPEN LABEL PHASE 1 TRIAL

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii33-ii33
Author(s):  
E Antonio Chiocca ◽  
Rimas Lukas ◽  
Clark Chen ◽  
Ganesh Rao ◽  
Christina Amidei ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Gene Therapy ◽  
T Cells ◽  
Immune Checkpoint ◽  
Phase 1 ◽  
Safety Data ◽  
Recurrent Glioblastoma ◽  
Interleukin 12 ◽  
Open Label ◽  
Phase 1 Trial

Abstract A published clinical trial of veledimex (V)-regulatable interleukin-12 (IL-12) gene therapy (“Controlled IL-12”) under the control of a transcriptional switch (RheoSwitch Therapeutic Systemâ, RTSâ) as monotherapy in recurrent glioblastoma (rGBM) showed sustained infiltration of activated T cells within the tumor months after treatment (Sci Transl Med. 2019;11(505)). These T cells demonstrated up-regulation of immune checkpoint signaling, providing a rationale for combination therapy with the PD-1 inhibitor, nivolumab (nivo). We report interim findings following completion of enrollment (with follow-up ongoing) for a multi-institutional, open label, dose-escalation phase 1 trial (NCT03636477) evaluating safety and tolerability of loco-regional Controlled IL-12 in combination with nivo in adults with rGBM. Replication-incompetent adenovirus coding for RTS-IL-12 (Ad) was administered during surgery by free-hand injection into the tumor and periphery (2 x 1011 viral particles, Day 0) accompanied by V (10 or 20 mg) PO QD x 15 (Days 0 to 14) in combination with nivo (1 or 3 mg/kg) IV on Days -7, 15, then Q2W. Twenty-one subjects were treated (Cohort 1: V 10 mg, nivo 1 mg/kg, n=3; Cohort 2: V 10 mg, nivo 3 mg/kg, n=3; and Cohort 3: V 20 mg, nivo 3 mg/kg, n=3 & 12 in expansion). Safety data were comparable to Ad+V monotherapy. Adverse reactions (ARs) during follow-on nivo dosing were consistent with nivo labeling. ARs were manageable and generally reversible with no synergistic toxicities. Updated overall survival findings will be presented. Baseline and post-treatment histochemical staining and multiplex immunofluorescence analyses for a subgroup of subjects will be discussed. The safety of this combination immunotherapy has been established, leading to a currently accruing phase 2 clinical trial of loco-regional Controlled IL-12 gene therapy in combination with the PD-1 inhibitor cemiplimab-rwlc (NCT 04006119).

Phase I/II dose escalation and expansion study of FLX475 alone and in combination with pembrolizumab in advanced cancer.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. TPS24-TPS24
Author(s):  
William Ho ◽  
Nicole Nasrah ◽  
Dan Johnson
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
Dose Escalation ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Single Agent ◽  
Safety Data ◽  
Receptor Occupancy ◽  
Open Label ◽  
Ligand Expression

TPS24 Background: Regulatory T cells (Treg) can dampen anti-tumor immune responses in the tumor microenvironment (TME). The predominant chemokine receptor on human Treg is CCR4, the receptor for the chemokines CCL17 and CCL22, which are produced by tumor cells, tumor-associated macrophages and dendritic cells, as well as by effector T cells (Teff) in the setting of an inflammatory anti-tumor response. Preclinical studies with orally-available CCR4 antagonists have demonstrated potent inhibition of Treg migration into tumors, an increase in the intratumoral Teff/Treg ratio, and anti-tumor efficacy as a single agent and in combination with checkpoint inhibitors. In a first-in-human trial conducted in healthy volunteers, the oral CCR4 antagonist FLX475 was demonstrated to be well tolerated with outstanding PK properties. A robust PD assay measuring receptor occupancy on circulating Treg demonstrated the ability to safely achieve exposure levels predicted to maximally inhibit Treg recruitment into tumors via CCR4 signaling. These human PK, PD, and safety data have enabled a streamlined design of a Phase 1/2 study of FLX475 in cancer patients both as monotherapy and in combination with checkpoint inhibitor. Methods: This clinical trial is a Phase 1/2, open-label, dose-escalation and cohort expansion study to determine the safety and preliminary anti-tumor activity of FLX475 as monotherapy and in combination with pembrolizumab. The study is being conducted in 2 parts, a dose-escalation phase (Part 1) and a cohort expansion phase (Part 2). In Part 1 (Phase 1) of the study, at least 3 to 6 eligible subjects will be enrolled in sequential cohorts treated with successively higher doses of FLX475 as monotherapy or in combination with pembrolizumab (Part 1b). In Part 2 (Phase 2) of the study, expansion cohorts of both checkpoint-naïve and checkpoint-experienced patients with tumor types predicted to be enriched for Treg and/or CCR4 ligand expression (i.e. “charged tumors”) -- including both EBV+ and HPV+ tumors and NSCLC, HNSCC, and TNBC -- will be enrolled using a Simon 2-stage design. As of November 6, 2018, Cohort 1 has been completed without DLT. Clinical trial information: NCT03674567.

scholarly journals Window-of-opportunity clinical trial of pembrolizumab in patients with recurrent glioblastoma reveals predominance of immune-suppressive macrophages

2019 ◽  
Vol 22 (4) ◽  
pp. 539-549 ◽  
Author(s):  
John de Groot ◽  
Marta Penas-Prado ◽  
Kristin Alfaro-Munoz ◽  
Kathy Hunter ◽  
Be Lian Pei ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
Therapeutic Window ◽  
Window Of Opportunity ◽  
Open Label ◽  
Activation Markers ◽  
Immune Effector ◽  
Immune Effector Function

Abstract Background We sought to ascertain the immune effector function of pembrolizumab within the glioblastoma (GBM) microenvironment during the therapeutic window. Methods In an open-label, single-center, single-arm phase II “window-of-opportunity” trial in 15 patients with recurrent (operable) GBM receiving up to 2 pembrolizumab doses before surgery and every 3 weeks afterward until disease progression or unacceptable toxicities occurred, immune responses were evaluated within the tumor. Results No treatment-related deaths occurred. Overall median follow-up time was 50 months. Of 14 patients monitored, 10 had progressive disease, 3 had a partial response, and 1 had stable disease. Median progression-free survival (PFS) was 4.5 months (95% CI: 2.27, 6.83), and the 6-month PFS rate was 40%. Median overall survival (OS) was 20 months, with an estimated 1-year OS rate of 63%. GBM patients’ recurrent tumors contained few T cells that demonstrated a paucity of immune activation markers, but the tumor microenvironment was markedly enriched for CD68+ macrophages. Conclusions Immune analyses indicated that pembrolizumab anti–programmed cell death 1 (PD-1) monotherapy alone can’t induce effector immunologic response in most GBM patients, probably owing to a scarcity of T cells within the tumor microenvironment and a CD68+ macrophage preponderance.

Phase I/II dose-escalation and expansion study of FLX475 alone and in combination with pembrolizumab in advanced cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3163-TPS3163
Author(s):  
John D. Powderly ◽  
Bartosz Chmielowski ◽  
Julie R. Brahmer ◽  
Sarina Anne Piha-Paul ◽  
Samantha Elizabeth Bowyer ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
Dose Escalation ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Single Agent ◽  
Safety Data ◽  
Receptor Occupancy ◽  
Phase 2 ◽  
Open Label

TPS3163 Background: Regulatory T cells (Treg) can dampen anti-tumor immune responses in the tumor microenvironment (TME). The predominant chemokine receptor on human Treg is CCR4, the receptor for the chemokines CCL17 and CCL22, which are produced by tumor cells, tumor-associated macrophages and dendritic cells, as well as by effector T cells (Teff) in the setting of an inflammatory anti-tumor response. Preclinical studies with orally-available CCR4 antagonists have demonstrated potent inhibition of Treg migration into tumors, an increase in the intratumoral Teff/Treg ratio, and anti-tumor efficacy as a single agent and in combination with checkpoint inhibitors. In a first-in-human trial conducted in healthy volunteers, the oral CCR4 antagonist FLX475 was demonstrated to be well tolerated with outstanding PK properties. A robust PD assay measuring receptor occupancy on circulating Treg demonstrated the ability to safely achieve exposure levels predicted to maximally inhibit Treg recruitment into tumors via CCR4 signaling. These human PK, PD, and safety data have enabled a streamlined design of a Phase 1/2 study of FLX475 in cancer patients both as monotherapy and in combination with checkpoint inhibitor. Methods: This clinical trial is a Phase 1/2, open-label, dose-escalation and cohort expansion study to determine the safety and preliminary anti-tumor activity of FLX475 as monotherapy and in combination with pembrolizumab. The study is being conducted in 2 parts, a dose-escalation phase (Part 1) and a cohort expansion phase (Part 2). In Part 1 (Phase 1) of the study, at least 3 to 6 eligible subjects are being enrolled in sequential cohorts treated with successively higher doses of FLX475 as monotherapy (Part 1a) or in combination with pembrolizumab (Part 1b). In Part 2 (Phase 2) of the study, expansion cohorts of both checkpoint-naïve and checkpoint-experienced patients with tumor types predicted to be enriched for Treg and/or CCR4 ligand expression (i.e. “charged tumors”) -- including both EBV+ and HPV+ tumors and NSCLC, HNSCC, and TNBC -- will be enrolled using a Simon 2-stage design. As of February 4, 2020, Phase 1 dose escalation has been completed and a recommended Phase 2 dose chosen for both FLX475 monotherapy and combination therapy with pembrolizumab. Enrollment into Phase 2 expansion cohorts has been initiated. Clinical trial information: NCT03674567 .

scholarly journals 589. Oral Tablet Vaccination Induces Heightened Cross-Reactive CD8 T Cell Responses to SARS-COV-2 in Humans

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S397-S397
Author(s):  
Susan Johnson ◽  
Clarissa Martinez ◽  
Mario Cortese ◽  
Josefina Martinez ◽  
Shaily Garg ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Phase 1 ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Vaccine Platform ◽  
Open Label ◽  
Oral Tablet ◽  
Cell Responses

Abstract Background Covid-19 has accelerated global demand for easily distributed vaccines. Furthermore, as variant SARS-CoV-2 strains that circumvent antibody responses emerge, cross-protective vaccines provide substantial public health benefits. Vaxart is developing a shelf stable oral tablet vaccine that incorporates both the spike (S) and the more conserved nucleocapsid (N) proteins. Vaxart’s vaccine platform uses a non-replicating adenovirus and a TLR3 agonist as an adjuvant. Methods In an open-label phase 1 clinical study, 35 healthy subjects received either a single low (1x1010 IU; n=15) or high (5x1010 IU; n=15) dose of the vaccine candidate VXA-CoV2-1 with a small cohort receiving 2 low doses. PBMCs were taken at pre- and 7 days post-vaccination and restimulated with S and N peptides from SARS-CoV-2 or the 4 human endemic coronaviruses (HCoV). Cells were stained for CD4/CD8/CD107a (surface) and IFNγ/TNFα (intracellular). Subjects that received an intramuscular (i.m.) mRNA vaccine had PBMCs taken at the same timepoints and were compared in the same assay. Results The study’s results indicate that the VXA-CoV2-1 tablet was well tolerated. The majority of subjects had an increase in S-specific anti-viral CD8+ T cell responses. 19/26 (73%) subjects had a measurable CD8+ T cell response on day 8 above baseline, on average 1.5-4.6%. In a comparator experiment with the 2 SARS-CoV-2 i.m. mRNA vaccines, VXA-CoV2-1 outperformed other vaccine candidates with a >3.5-fold increase in S specific antiviral CD8 T cell responses. T cell responses specific to the 4 endemic HCoV were increased by 0.6% in subjects given VXA-CoV2-1. Conclusion Here we describe a room temperature stable tablet that induces SARS-CoV-2 S specific CD8 T cells of high magnitude after one dose in humans. Overall, the level of antiviral SARS-CoV-2 specific T cells, particularly IFNg-producing CD8s, induced following oral immunization with VXA-CoV2-1 are of higher magnitude than the mRNA vaccines currently in use against COVID-19. T cell responses against 4 endemic HCoV were also induced. Because T cells may be important in protecting against death and severe infection, these results suggest that VXA-CoV2-1 could be cross-protective against a wide array of emerging pandemic coronaviruses. Disclosures Susan Johnson, PhD, Vaxart (Employee) Clarissa Martinez, MPH, Vaxart (Employee) Mario Cortese, PhD, Vaxart (Employee) Josefina Martinez, n/a, Vaxart (Employee) Shaily Garg, BS, Vaxart (Employee) Nadine Peinovich, MPH, Vaxart (Employee) Emery Dora, n/a, Vaxart (Employee) Sean Tucker, PhD, Vaxart (Employee)

scholarly journals A phase 1, open-label, multicenter study to assess the safety, tolerability, and immunogenicity of mRNA-4157 alone in subjects with resected solid tumors and in combination with pembrolizumab in subjects with unresectable solid tumors (Keynote-603).

2019 ◽  
Vol 5 (suppl) ◽  
pp. 93-93
Author(s):  
Howard A. Burris III ◽  
Manish R. Patel ◽  
Daniel C. Cho ◽  
Jeffrey Melson Clarke ◽  
Martin Gutierrez ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Solid Tumors ◽  
Phase 1 ◽  
Open Label ◽  
Dose Escalation Study ◽  
Phase 2 Clinical Trial ◽  
Clinical Responses ◽  
Grade 3 ◽  
Personalized Approach

93 Background: T-cell targeting of mutation-derived epitopes (neoantigens) has been demonstrated to drive anti-tumor responses. Immunizing patients against such neoantigens in combination with a checkpoint inhibitor (CPI) may elicit greater anti-tumor responses than CPI alone. Mutations are rarely shared between patients, thus requiring a personalized approach to vaccine design. Methods: This is an interim report of a phase I dose escalation study of mRNA-4157 given as monotherapy in patients with resected solid tumors and in combination with pembrolizumab in patients with unresectable solid tumors. mRNA-4157 is a lipid encapsulated personalized vaccine encoding multiple neoantigens selected using a proprietary algorithm designed to induce neoantigen specific T cells and associated anti-tumor responses. Patients received up to 9 cycles (Q3W) of mRNA-4157 by IM injection (0.04 – 1 mg). In combination arm, pembrolizumab (200 mg) was administered for two cycles prior to combination with mRNA-4157 for up to 9 cycles and may continue on pembrolizumab monotherapy for up to 2 years. Results: As of 10-May-2019, 33 patients received mRNA-4157 alone or in combination. No DLTs or related SAEs or AEs ≥ grade 3 were reported. Of the 13 patients treated with monotherapy (3 melanoma, 8 NSCLC, 2 MSI-high CRC), 11 patients remain disease free on study, median follow-up of 10 months. Of the 20 patients treated in combination (1 TMB-high metastatic cutaneous squamous cell, 4 bladder, 2 HNSCC, 1 melanoma, 7 NSCLC, 2 SCLC, 3 MSI-high (CRC, prostate, endometrial), 13 had received prior CPI, 5 PRs (2 in patients previously treated with PD-1/L1 inhibitors), 6 SD, and 8 PD were reported. Neoantigen specific CD8+ T-cell responses have been detected. Conclusions: mRNA-4157 is safe and well tolerated at all dose levels tested. Clinical responses have been observed in combination with pembrolizumab and neoantigen-specific T cells have been induced, supporting the advancement of mRNA-4157 to phase 2. Clinical trial information: NCT 03739931.

scholarly journals Immune-Mediated Cytotoxicity in Inflammatory Bowel Disease

1990 ◽  
Vol 4 (7) ◽  
pp. 278-284 ◽  
Author(s):  
Stephan R Targan ◽  
Richard L Deem ◽  
Fergus Shanahan
Keyword(s):  
T Cells ◽  
Crohn’S Disease ◽  
T Cell ◽  
Crohn's Disease ◽  
Epithelial Cells ◽  
Cytotoxic T Cells ◽  
Target Cells ◽  
Immune Mediated ◽  
Inflammatory Bowel

Thirty years of research on the role of immune-mediated cytotoxic activity in the tissue injury of inflammatory bowel disease (IBD) has yielded only inconclusive data on the relevance of cytotoxic mechanisms. Two hypotheses have been advanced. One is that the destruction of target cells is mediated by direct recognition of target antigens by cytotoxic cells which in turn triggers lysis. Another hypothesis is that lysis occurs via an indirect bystander mechanism in which cells do not recognize a specific antigen on the target, but upon nonspecific activation release cytokines which are capable of lysing the target. The authors have investigated both hypotheses and studied the role of cytotoxic T cells and cytotoxic rectors released from activated T cells in the destruction of epithelial cells. Elevated levels of cytotoxic T cells were found in peripheral blood lymphocytes of patients with IBD, particularly Crohn's disease. The cytotoxic T cells were contained within the Leu 7+, CD8+ T cell subset and were detected using anti-CD3-triggered lysis. Increased cytotoxic T cell activity was also present within inflamed mucosa of patients with both Crohn's disease and ulcerative colitis. The specific targets of this activity have yet to be determined. Activation of mucosal T cells by antibodies to the T cell receptor (anti-CD3) in organ culture of normal fetal jejunum induces an enteropathy characterized by villous atrophy and crypt cell hyperplasia. This same change is seen near aphthous ulcers in patients with Crohn's disease. Soluble cytokines produced by T cells might be responsible for the mucosa! damage observed in these two models of mucosal injury. The goal of this study was to establish in vitro if cytotoxic cytokines can be released by triggering isolated colonic T cells, and what cytokine interactions are required for killing of colonic epithelial cells. These results demonstrate that human lamina propria lymphocyte T cells, triggered by addition of anti-CD3 and target cells, produce tumour necrosis factor-alpha and interferon-gamma, both of which are required for optimal killing of HT-29. Simultaneous release of these cytokines in the vicinity of epithelial cells during immune responses could play an important role in mucosal damage in IBD. The development of animal models and long term cultures of epithelial cells will allow many advances in research of the role of immune-mediated cytotoxicity in IBD.

scholarly journals Updated Analysis of a Phase 1, Open-Label Study of LCAR-B38M, a Chimeric Antigen Receptor T Cell Therapy Directed Against B-Cell Maturation Antigen, in Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 955-955 ◽  
Author(s):  
Wan-Hong Zhao ◽  
Jie Liu ◽  
Bai-Yan Wang ◽  
Yin-Xia Chen ◽  
Xing-Mei Cao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Median Duration ◽  
Phase 1 ◽  
Open Label ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Grade 3

Abstract LCAR-B38M is a bispecific chimeric antigen receptor T cell (CAR T) therapy directed against B-cell maturation antigen (BCMA). The bi-epitope BCMA binding moieties confer high avidity binding and distinguish LCAR-B38M from other BCMA CAR constructs. Preliminary results of LCAR-B38M in patients (pts) with relapsed/refractory (R/R) multiple myeloma (MM) showed encouraging efficacy and manageable safety (Fan et al.JCO 2017;35:18_suppl LBA3001). Here we present updated safety and efficacy results of the trial. LEGEND-2 (NCT03090659) is an ongoing phase 1, single-arm, open-label multicenter study evaluating LCAR-B38M in pts (18-80 years) with R/R MM. Lymphodepletion was performed using 3 doses of cyclophosphamide 300 mg/m2 on days -5, -4, and -3. Five days after lymphodepletion, LCAR-B38M CAR T cells (median CAR+ cell dose = 0.5x106 cells/kg, [range, 0.07-2x106]) were given in 3 infusions (20, 30, and 50% of total dose). The primary objective is to evaluate the safety of LCAR-B38M CAR T cells; the secondary objective is to evaluate the anti-myeloma response of the treatment. Adverse events (AEs) were graded using the Common Terminology Criteria for AE, v.4.03, and cytokine release syndrome (CRS) was assessed according to Lee et al. (Blood 2014;124:188-95). Response was evaluated using International Myeloma Working Group criteria. This analysis presents data from a single institution. As of June 25, 2018, 57 pts have been infused with LCAR-B38M CAR T cells. The median age was 54 years (range, 27-72), median number of prior therapies was 3 (range, 1-9), and 74% of pts had stage III disease by Durie-Salmon staging. The median duration of follow-up for all pts was 12 months (range, 0.7-25). AEs were reported by all pts; most common were pyrexia (91%), CRS (90%), thrombocytopenia (49%), and leukopenia (47%). Grade ≥3 AEs were reported by 65% of pts; most common were leukopenia (30%), thrombocytopenia (23%), and increased aspartate aminotransferase (21%). CRS was mostly grade 1 (47%) and 2 (35%); 4 pts (7%) had grade 3 cases. Liver function abnormalities were the most common signs of end organ injury among pts with CRS. The median time to onset of CRS was 9 days (range, 1-19). All but 1 CRS events resolved, with a median duration of 9 days (range, 3-57). No clear relationship was demonstrated between dose and CRS; there may be some effect at higher doses, but conclusions are limited by the small number of pts in the grade 3 CRS group (n=4; Figure 1A). Neurotoxicity was observed in 1 pt who had grade 1 aphasia, agitation, and seizure-like activity. The overall response rate (partial response [PR] or better) was 88% (95% confidence interval [CI], 76-95). Complete response (CR) was achieved by 42 pts (74%; 95% CI, 60-85), very good partial response was achieved by 2 pts (4%; 95% CI, 0.4-12), and PR was achieved by 6 pts (11%; 95% CI, 4-22; Figure 1B). Among pts with CR, 39/42 were minimal residual disease (MRD) negative by 8-color flow cytometry. The median time to initial response was 1 month (range, 0.4-4). No clear relationship between LCAR-B38M CAR T cell dose and response was observed (Figure 1C). BCMA expression did not correlate with clinical response. The median duration of response (DOR) was 16 months (95% CI, 12-not reached [NR]). The median DOR for pts who achieved a CR was 22 months (95% CI, 14-NR). At data cutoff, 18 pts (36%) who achieved PR or better progressed. The median progression-free survival (PFS) for all treated pts was 15 months (95% CI, 11-NR); median PFS for pts who achieved CR was 24 months (95% CI, 15-NR). The median overall survival was not reached. Overall, 17 pts died during the study and follow-up period; causes of death were progressive disease (PD; n=14), suicide after PD (n=1), esophagitis (n=1), and pulmonary embolism and acute coronary syndrome (n=1). Peak levels of LCAR-B38M (≥1x104 copies/µg genomic DNA) were observed in a majority of pts with blood samples for analysis (n=32). LCAR-B38M CAR T cells were not detectable in peripheral blood in 71% of pts at 4 months; 5 pts showed CAR T cell persistence up to 10 months. This ongoing first-in-human study has provided initial proof-of-concept that bispecific LCAR-B38M CAR T cells may be a highly effective therapy for R/R MM. LCAR-B38M CAR T cell therapy displayed a manageable safety profile consistent with its known mechanism of action and demonstrated deep and durable responses in pts with R/R MM. A phase 1/2 study of LCAR-B38M in R/R MM has been initiated in the US (NCT03548207). Disclosures Zhuang: Nanjing Legend Biotech: Employment. Fan:Nanjing Legend Biotech: Employment.

scholarly journals ACTR-57. A PHASE 1/2 STUDY TO EVALUATE THE SAFETY AND EFFICACY OF BLOOD-BRAIN BARRIER (BBB) OPENING WITH A NINE-EMITTER IMPLANTABLE ULTRASOUND DEVICE IN RECURRENT GLIOBLASTOMA PATIENTS PRIOR TO CARBOPLATIN

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi26-vi27
Author(s):  
Ahmed Idbaih ◽  
François Ducray ◽  
John DeGroot ◽  
Roger Stupp ◽  
Jacques Guyotat ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Dose Escalation ◽  
Phase 1 ◽  
Safety Data ◽  
Recurrent Glioblastoma ◽  
Brain Barrier ◽  
Open Label ◽  
Safety And Efficacy ◽  
Ultrasound Device ◽  
Blood Brain

Abstract The blood-brain barrier (BBB) limits penetration of systemically administered therapies to brain tumors and peritumoral tissue and may be responsible for the failure of numerous drugs in recent clinical trials for glioblastoma (GBM). Low intensity pulsed ultrasound (LIPU), with concomitant intravenous microbubble injection (DEFINITY®), can temporarily disrupt the BBB for 6–24 hours and allow for enhanced delivery of drugs to the brain. In previous clinical studies, a 1-cm ultrasound (US) device, SonoCloud-1, was implanted in a burr hole of recurrent GBM patients (n=27) and used to disrupt the BBB prior to carboplatin infusion at AUC5. This ongoing pilot phase 1/2 study (NCT03744026) aims to evaluate the safety and efficacy of transient opening of the BBB by LIPU in rGBM with the SonoCloud-9, a larger nine-emitter implantable device, designed to cover the tumor and surrounding infiltrative regions. The ultrasound device is implanted in a 6 cm x 6 cm bone flap window after tumor debulking surgery. Patients receive a 270-second sonication every month with concomitant microbubble injection to disrupt the BBB followed by carboplatin infusion at AUC4-6. Magnetic resonance imaging (MRI) is performed to verify safety and extent of BBB disruption. This study began enrollment in early 2019 and is an international, open-label, single arm, multi-site, dose-escalation and expansion trial to evaluate the safety of escalating sonication volume (“dose”) with concurrent carboplatin. The number of activated emitters in the implant (3, 6, 9) is increased using a 3 + 3 dose escalation design. Safety data of the escalation phase of the study will be presented.

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