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H3K27M-mutant diffuse midline gliomas (DMGs) express high levels of the disialoganglioside GD2 (ref. 1 ). Chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) eradicated DMGs in preclinical models 1 . Arm A of Phase I trial no. NCT04196413 (ref.  2 ) administered one intravenous (IV) dose of autologous GD2-CART to patients with H3K27M-mutant pontine (DIPG) or spinal DMG (sDMG) at two dose levels (DL1, 1 × 10 6  kg − 1 ; DL2, 3 × 10 6  kg −1 ) following lymphodepleting chemotherapy. Patients with clinical or imaging benefit were eligible for subsequent intracerebroventricular (ICV) intracranial infusions (10–30 × 10 6 GD2-CART). Primary objectives were manufacturing feasibility, tolerability and the identification of maximally tolerated IV dose. Secondary objectives included preliminary assessments of benefit. Thirteen patients enroled, with 11 receiving IV GD2-CART on study ( n  = 3 DL1 (3 DIPG); n  = 8 DL2 (6 DIPG, 2 sDMG)). GD2-CART manufacture was successful for all patients. No dose-limiting toxicities occurred on DL1, but three patients experienced dose-limiting cytokine release syndrome on DL2, establishing DL1 as the maximally tolerated IV dose. Nine patients received ICV infusions, with no dose-limiting toxicities. All patients exhibited tumour inflammation-associated neurotoxicity, safely managed with intensive monitoring and care. Four patients demonstrated major volumetric tumour reductions (52, 54, 91 and 100%), with a further three patients exhibiting smaller reductions. One patient exhibited a complete response ongoing for over 30 months since enrolment. Nine patients demonstrated neurological benefit, as measured by a protocol-directed clinical improvement score. Sequential IV, followed by ICV GD2-CART, induced tumour regressions and neurological improvements in patients with DIPG and those with sDMG. We evaluated the use of chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) for H3K27M + diffuse midline glioma (DMG), finding that intravenous administration of GD2-CART, followed by intracranial infusions, induced tumour regressions and neurological improvements in patients with H3K27M-mutant pontine or spinal DMG.

Outcomes are poor for patients with large B-cell lymphoma who relapse after CD19-directed chimeric antigen receptor (CAR) T-cell therapy (CAR19). CD22 is a nearly universally expressed B-cell surface antigen and the efficacy of a CD22-directed CAR T-cell therapy (CAR22) in large B-cell lymphoma is unknown, which was what we aimed to examine in this study. In this single centre, open-label, dose-escalation phase 1 trial, we intravenously administered CAR22 at two dose levels (1 million and 3 million CAR22-positive T cells per kg of bodyweight) to adult patients (aged ≥18 years) who relapsed after CAR19 or had CD19-negative large B-cell lymphoma. The primary endpoints were manufacturing feasibility, safety measured by the incidence and severity of adverse events and dose-limiting toxicities, and identification of the maximum tolerated dose (ie, the recommended phase 2 dose). This study is registered with ClinicalTrials.gov (NCT04088890) and is active, but closed for enrolment. From Oct 17, 2019, to Oct 19, 2022, a total of 41 patients were assessed for eligibility; however, one patient withdrew. 40 patients underwent leukapheresis and 38 (95%) had CAR T-cell products manufactured successfully. The median age was 65 years (range 25–84), 17 (45%) were women, 32 (84%) had elevated pretreatment lactate dehydrogenase, 11 (29%) had refractory disease to all previous therapies, and patients had received a median of four lines of previous therapy (range 3–8). Of the 38 patients treated, 37 (97%) had relapsed after previous CAR19. The identified maximum tolerated dose was 1 million CAR T cells per kg. Of 29 patients who received the maximum tolerated dose, no patients developed a dose-limiting toxicity or grade 3 or higher cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, or immune effector cell-associated haemophagocytic lymphohistiocytosis-like syndrome. This trial identifies CD22 as an immunotherapeutic target in large B-cell lymphoma and demonstrates the durable clinical activity of CAR22 in patients with disease progression after CAR19 therapy. Although these findings are promising, it is essential to recognise that this is a phase 1 dose-finding study. Further investigations are warranted to establish the long-term efficacy and to delineate the patient subgroups that will derive the most benefit from this therapeutic approach. National Cancer Institute, National Institutes of Health, Stanford Cancer Institute, Leukemia & Lymphoma Society, Parker Institute for Cancer Immunotherapy, Lymph & Co, and the European Hematology Association.

The two projects described in this thesis sought to tackle two distinct aspects attributed to the general failure of Chimeric Antigen Receptor T cells (CAR Ts) against solid tumors. The first is the possibility of on-target off-tumor toxicity. Epidermal growth factor receptor (EGFR) is a promising target based on its overexpression in a variety of cancers, but its presence on healthy tissue led to severe toxicities through clinical trials of anti-EGFR CAR T cells. Due to murine EGFR (mEGFR) sharing 88% amino acid sequence with human EGFR, we decided to generate a syngeneic mouse model to replicate and help predict toxicities seen clinically. To model potential effects of these CAR T toxicities, we have developed a system using both CAR T cells and tumors derived from syngeneic C57BL/6 mice. Since all cells originate from the same genetic background, we can observe the effects of our anti-mEGFR CAR T cells under an intact immune system. These findings underscore the importance of our model predicting CAR T cell-mediated toxicities. Although still early, this system may be used as an effective model of other potential CAR T-cell toxicities against antigen targets that are comparable between human and mice. The second project sought to resolve the problem of the immunosuppressive tumor microenvironment (TME) perpetrated in pancreatic ductal adenocarcinoma (PDAC). We developed a bicistronic lentiviral vector for a CAR T cell that additionally secretes a bispecfic T-cell engaging Antibody Molecule (TEAM) denoted as CARTEAM. This two-target approach seeks to eliminate the surrounding Cancer Associated Fibroblasts (CAFs) that play a large role in immunosuppression of immune cells in clinical PDAC cases and increases the anti-tumor efficacy. Based on in vitro results, our CARTEAM system may be a clinically relevant immunotherapy for PDAC.

The objective of this research was to develop a novel fixed-film biofilter and investigate the feasibility of this biofilter for the treatment of TCE in a laboratory setup. To select the best microorganism for the remediation of TCE, batch studies using six different microorganisms were conducted to determine biokinetic parameters (the maximum TCE degradation rate, the extent of both TCE degradation and mineralization). For TCE bioremediation, B. cepacia PR1$\\sb{23}$ was chosen because it has relatively high TCE degradation rates, a high growth rate, and the advantage of expressing the TCE-degrading enzyme (TOM) constitutively (without a toxic inducer). To show TCE degradation by the microorganism resulted in complete TCE mineralization (e.g., generation of chloride ions), a novel medium was formulated where the TCE degradation activity of B. cepacia PR1$\\sb{23}$ in a biofilter was determined without removing the fixed biomass in the biofilter. To confirm the presence of B. cepacia PR1$\\sb{23}$ and expression of its TCE-degrading enzyme (TOM), a plate assay with indole was developed. An aerobic, single-pass, fixed-film biofilter with a pure culture of B. cepacia PR1$\\sb{23}$ was designed for the continuous degradation and mineralization of gas-phase trichloroethylene (using sintered glass and activated carbon as supporting materials). At gas-phase TCE concentrations ranging from 0.04 to 2.42 mg/L of air and a volumetric air flow rate of 0.1 L/min, initial maximum TCE degradation rates of 8.6 to 392.3 mg TCE/L of reactor/day were obtained. Using chloride ion generation as the indicator of TCE mineralization, the bioreactor with activated carbon mineralized an average of 6.9 to 10.3 mg TCE/L of reactor/day at 0.242 mg/L TCE concentration with 0.1 L/min of air flow for 38 to 40 days. However, TOM was inactivated at a rate which increased with increasing TCE concentration (e.g., in $\\sim$2 days at 0.242 mg/L and less than 1 day at 2.42 mg/L) although the biofilter could be operated for longer periods at lower TCE concentrations. A mathematical model was developed which includes axial dispersion, convection, film mass transfer, and biodegradation terms coupled with TCE-degrading enzyme deactivation. The numerical simulation of this model was in good agreement in most part with the experimental results; however, the agreement was not as good at early times in the experiment. The proposed model suggests the best microorganism to be considered for TCE degradation would be a microbe with high TCE-degrading enzyme activity and high transformation capacity for TCE.

During the past several months, President Ma Ying-jeou's administration has been pushing for amendments to the Act Governing Food Sanitation to allow U.S. beef imports containing the leanness-enhancing drug in the hopes of resuming talks with the United States on the Trade and Investment Framework Agreement (TIFA).

The government is currently working on economic cooperation agreements with Singapore and New Zealand, in order to facilitate trade liberalization, Ma said.

According to the Public Television Act, the PTS needs to \"set up a board of directors consisting of 17 to 21 people,\" and the Legislature is required to recommend 11 to 15 people as directors and supervisors.

(ProQuest: ... denotes non-USASCII text omitted) Almost a third of Chinese New Year foods inspected by Taipei's Department of Health (DOH) were found to be in violation of government standards, according to official results released yesterday.

KMT Attempt to Defuse Crisis Political commentators claim that the KMT has come up with a strategy to defuse the DPP's momentum, adding that the ruling party's legislative caucus has taken a seemingly concessional attitude toward the opposition over the past few days, in an apparent effort to diminish the justification of the planned demonstration.