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P-BCMA-ALLO1 is an allogeneic CAR-T that targets B-cell Maturation Antigen (BCMA) and is currently being investigated for the treatment of RRMM. P-BCMA-ALLO1 cells are manufactured from healthy donor T-cells using non-viral transposon-based integration (piggyBac® DNA Delivery System) that introduces a human anti-BCMA V H-based CAR and an iCas9 safety switch. The piggyBac® DNA delivery system produces a highly enriched T stem cell memory product. The Cas-CLOVER™ Site-Specific Gene Editing System eliminates endogenous T cell receptor (TCR) expression via knockout of the TCR beta chain 1 gene to prevent graft-vs-host disease (GvHD), and the beta-2 microglobulin gene to reduce Major Histocompatibility Complex (MHC) class I expression to eliminate host-vs-graft responses. P-BCMA-ALLO1 demonstrated compelling activity in MM xenografts, providing rationale for this first-in-human phase I study.

Costello: Poseida Therapeutics: Research Funding; Janssen: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Cohen:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Patents/Intellectual property licensed, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda,: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Patel:Bristol Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Precision Biosciences: Research Funding; Oncopeptides: Consultancy; Poseida: Research Funding; Nektar: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Cellectis: Research Funding. Berdeja:Lilly: Research Funding; BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Research Funding; Bioclinica: Consultancy; Glenmark: Research Funding; Acetylon: Research Funding; Vivolux: Research Funding; Abbvie: Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; CURIS: Research Funding; Janssen: Consultancy, Research Funding; Legend: Consultancy; Bluebird: Research Funding; Karyopharm: Consultancy; Kesios: Research Funding; Teva: Research Funding; Servier: Consultancy; Amgen: Consultancy, Research Funding; Cellularity: Research Funding; Celgene: Consultancy, Research Funding; Poseida: Research Funding; Prothena: Consultancy; Kite Pharma: Consultancy; EMD Sorono: Research Funding; Genentech, Inc.: Research Funding; Constellation: Research Funding. Shah:BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding; GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy. Ganguly:Kadmon: Other: Ad Board; KITE Pharma: Speakers Bureau; Settle Genetics: Speakers Bureau. Abedi:BMS, Gilead Sciences: Research Funding; AbbVie, BMS, Gilead Sciences, Seattle Genetics, Takeda: Speakers Bureau. Yalamanchili:Poseida Therapeutics: Current Employment, Current equity holder in private company. Gregory:Kesios: Research Funding; Sanofi: Research Funding; Janssen: Research Funding; Celularity: Research Funding; Teva: Research Funding; Vivolux: Research Funding; Lilly: Research Funding; Constellation: Research Funding; BMS: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Poseida: Research Funding; CRISP Therapeutics: Research Funding; CURIS: Research Funding; Acetylon: Research Funding; Incyte Corporation: Consultancy; Bluebird: Research Funding; Amgen: Research Funding; AbbVie: Research Funding; Takeda: Research Funding; Genentech: Research Funding; Glenmark: Research Funding; EMD Sorono: Research Funding.

P-BCMA-101 is an autologous chimeric antigen receptor-T cell (CAR-T) therapeutic targeting BCMA and comprised of a high percentage of desirable stem cell memory T cells. P-BCMA-101 is manufactured using a novel transposon-based system called piggyBac and is designed to increase efficacy while minimizing toxicity.

P-BCMA-101 and P-BCMA-ALLO1, autologous and allogeneic BCMA targeting CAR-T cell therapies respectively, are manufactured using a novel transposon-based system called piggyBac (PB). They comprise a high percentage of desirable stem cell memory T-cells associated with efficacy and safety. Single agent P-BCMA-101 data was previously reported showing marked efficacy and minimal toxicity (PRIME study), and exploratory combination cohorts have also been evaluated. P-BCMA-ALLO1 is expected to be first assessed in patients by the time of this presentation. Here we report results for P-BCMA-101 exploratory cohorts and P-BCMA-ALLO1.

Derman: Sanofi: Membership on an entity's Board of Directors or advisory committees. Deol: Kite, a Gilead Company: Consultancy. Ali: BMS: Research Funding; Aduro: Research Funding; Poseida: Research Funding; Aduro: Consultancy; Amgen: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy; BMS: Consultancy; Janssen: Consultancy. Dholaria: Pfizer: Research Funding; MEI: Research Funding; Poseida: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Angiocrine: Research Funding; Jazz: Speakers Bureau; Celgene: Speakers Bureau. Berdeja: Bioclinica: Consultancy; BMS: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Lilly: Research Funding; Abbvie: Research Funding; EMD Sorono: Research Funding; Takeda: Consultancy, Research Funding; Prothena: Consultancy; Servier: Consultancy; Janssen: Consultancy, Research Funding; Karyopharm: Consultancy; Vivolux: Research Funding; Cellularity: Research Funding; Novartis: Research Funding; Poseida: Research Funding; CURIS: Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; Acetylon: Research Funding; Amgen: Consultancy, Research Funding; Teva: Research Funding; Legend: Consultancy; Kite Pharma: Consultancy; Bluebird: Research Funding; Constellation: Research Funding; Glenmark: Research Funding; Genentech: Research Funding; Kesios: Research Funding. Cohen: GlaxoSmithKline: Consultancy, Research Funding; AstraZeneca: Consultancy; Genentech/Roche: Consultancy; BMS/Celgene: Consultancy; Novartis: Research Funding; Oncopeptides: Consultancy; Takeda: Consultancy; Janssen: Consultancy. Patel: Oncopeptides: Consultancy; BMS Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pfizer: Consultancy. Siegel: Karyopharm: Honoraria; Amgen Inc.: Honoraria; Takeda: Honoraria; Bristol Myers Squibb: Honoraria, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau; Celularity: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau. Nath: Actinium: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. McArthur: Poseida: Current Employment, Current equity holder in publicly-traded company. McCaigue: Poseida: Current Employment, Current equity holder in publicly-traded company. Martin: Poseida: Current Employment, Current equity holder in publicly-traded company. Ghoddusi: Poseida: Current Employment, Current equity holder in publicly-traded company. Namini: Poseida: Current Employment, Current equity holder in publicly-traded company. Ostertag: Poseida: Current Employment, Current equity holder in publicly-traded company. Spear: Poseida: Current Employment, Current equity holder in publicly-traded company. Belani: Poseida Therapeutics: Current Employment, Current equity holder in publicly-traded company; Amgen: Current equity holder in publicly-traded company. Shah: Indapta Therapeutics: Consultancy; CareDx: Consultancy; BMS/Celgene: Research Funding; Amgen: Consultancy; Janssen: Research Funding; Bluebird Bio: Research Funding; Precision Biosciences: Research Funding; Karyopharm: Consultancy; Nektar: Research Funding; Oncopeptides: Consultancy; Poseida: Research Funding; Sanofi: Consultancy; CSL Behring: Consultancy; Kite: Consultancy; GSK: Consultancy; Sutro Biopharma: Research Funding; Teneobio: Research Funding.

The efficacy of lactulose as an antiendotoxin was studied and the effect of lactulose or colistin on faecal flora was investigated in a hapten-induced rat model of colitis. Enteral administration of lactulose to rats with colitis was associated with a significant reduction in the systemic concentration of endotoxin (median (range) 5.4 (0–19.9) versus23.7 (0–145.0) pg/ml in colitic rats treated with water; 4.6 (0–10.8) pg/ml in healthy animals). Enteral administration of colistin significantly reduced the faecal count of aerobic Gram-negative bacilli (median (range) 2.84 (1.40–8.43) versus8.26 (4.50–10.40) log10colony-forming units per g faeces after treatment with water) but not the faecal load of endotoxin. Patients with inflammatory bowel disease may benefit from enteral treatment with lactulose to prevent systemic endotoxaemia and/or with colistin to modify enteric bacteria.

In 30 patients undergoing elective repair of abdominal aortic aneurysm the intramucosal pH (pHi) of the sigmoid colon was measured. Blood for endotoxin assay was taken at intervals before, during and after surgery. Daily measurements were made of liver transaminase activity and of arterial partial pressure of oxygen (PaO2). The mean(s.e.m.) peak systemic endotoxin concentration in those who developed intramucosal acidosis (pHibelow 7·00) was 90(14) pg/ml, compared with 42(5) pg/ml in those who did not (P< 0·01). In the 14 patients whose pHifell below 7·00, the mean(s.e.m.) postoperative rise in aspartate transaminase activity was 346(74) per cent, compared with 181(20) per cent in those whose pHiremained above this level (P< 0·05). The mean(s.e.m.) postoperative ratio of PaO2, to the fraction of inspired oxygen was 177(11) mmHg in those with intramucosal acidosis, compared with 260(24) mmHg in those whose pHiremained above 7·00 (P< 0·01). These results demonstrate a relationship between bowel ischaemia, endotoxaemia and organ impairment following elective aneurysm repair.

Effects of the nonsteroidal anti-inflammatory drug, diclofenac, on stimulated monocyte superoxide production were assessed directly in vitro and following treatment of patients with rheumatoid arthritis ex vivo. Diclofenac inhibited superoxide generation provoked by serum treated zymosan (STZ) and fluoride anion (F) but not by phorbol myristate acetate (PMA) in vitro. Following patient therapy, inhibition of superoxide production occurred when STZ and PMA, but not F were used as stimuli. No changes were seen in control subjects. The contrasting profiles of inhibition seen in vitro and ex vivo suggest an indirect effect on superoxide production during clinical use of the agent. These data are consistent with the hypothesis that anti-inflammatory drugs may act in rheumatoid arthritis by inhibiting phagocyte super-oxide anion production.

• Systemic endotoxemia consistently occurs in jaundiced patients undergoing surgery. Kupffer cell dysfunction is implicated in the development of endotoxemia and its postoperative complications. A novel in situ single-pass hepatic perfusion technique using a fluorescein isothiocyanate-labeled latex probe was developed for measuring Kupffer cell clearance capacity and was applied in an animal model of biliary obstruction. Control rats and rats jaundiced for 1, 2, 3, and 4 weeks' duration were studied. Kupffer cell clearance capacity, plasma bilirubin, endotoxin, and anti-core glycolipid concentrations were measured. Maximal hyperbilirubinemia preceded reduced Kupffer cell clearance capacity. Rats jaundiced for greater than 2 weeks had a significantly decreased Kupffer cell clearance capacity but significantly higher endotoxin and anticore glycolipid concentrations. Anticore glycolipid concentrations correlated strongly with systemic endotoxemia and both were inversely correlated with duration of jaundice. Impairment of Kupffer cell clearance capacity may contribute to endotoxemia associated with cholestasis.(Arch Surg. 1993;128:200-205)

Background It has been suggested that bowel permeability is altered following abdominal aortic aneurysm surgery. The effect of ischaemia-reperfusion injury to the lower limb on the morphological structure, neutrophil infiltration and permeability of the bowel was investigated.
Methods Histological assessment of the bowel was undertaken in five groups of Wistar rats: control, 3 h of bilateral hind limb ischaemia and 3 h of bilateral hind limb ischaemia followed by 1, 2 or 3 h of reperfusion. Using an everted gut sac model and 14C-labelled polyethylene glycol, the effect of ischaemia-reperfusion on small bowel permeability was studied.
Results The small bowel showed a significant decrease in mucosal thickness, villus height and crypt depth in animals subjected to ischaemia followed by 2-hr reperfusion (mean(s.e.m.) 420(15), 217(9) and 163(6) mum respectively) compared with controls (481(11), 245(6) and 195(6) mum) (P&lt;0·05). Neutrophil count within the lamina propria was similar in the different groups. A significant increase in mean(s.e.m.) 14C-labelled polyethylene glycol translocation was detected in animals subjected to ischaemia-reperfusion compared with controls (760(40) versus 560(27) c.p.m. per ml per h) (P&lt;0·05).
Conclusion These data suggest that reperfusion of acutely ischaemic extremities produces structural and functional changes in the small intestine, although these changes are not associated with increased neutrophil infiltration within the bowel wall.

BACKGROUND: Endotoxaemia is implicated in the pathophysiology of obstructive jaundice. The EndoCab enzyme linked immunosorbent assay (ELISA) is a novel assay which measures endogenous antibody (IgG) to the inner core region of circulating endotoxins (ACGA). AIMS: To investigate the significance of endotoxaemia in biliary obstruction using the EndoCab assay and assess the specificity of the humoral response to endotoxin compared with an exogenous antigenic challenge (tetanus toxoid, TT). METHODS: Three groups of adult male Wistar rats were studied: no operation, sham operation, and bile duct ligation for 21 days (BDL). In the second study, rats rats received prior immunisation with TT. RESULTS: In the preliminary experiment, plasma ACGA was significantly increased in the BDL group (306.6 (18.3)% versus 119.9 (6.7)% and 105.2 (4.6)% in the sham and no operation groups, respectively; p &lt; 0.001). Although the mean endotoxin concentration in the BDL group was greater than that in the control groups this was not significant. There was a strong positive correlation between ACGA and endotoxin concentrations (p = 0.0021). In the second study mean ACGA after 21 days of BDL was significantly elevated (267.1 (31.2)% versus 101.6 (21.2)% at baseline, p &lt; 0.0001). ACGA was unaffected in the other two groups. TT antibody concentrations fell in all three groups; only in the BDL group was the fall significant (97.6 (5.3)% versus 78.8 (4.2)% at baseline, p &lt; 0.05). CONCLUSIONS: The specific rise in ACGA supports the hypothesis that endotoxin has an integral role in the pathophysiology of obstructive jaundice. The production of anticore glycolipid antibodies specifically reflects systemic endotoxaemia in this model. The EndoCab assay provides a novel, sensitive, and specific method for endotoxin detection.

This study compared mortality rates, endotoxaemia, systemic tumour necrosis factor (TNF) and interleukin (IL)-6 concentrations after continuous and intermittent hepatic ischaemia. Two groups of rats were subjected to continuous or intermittent left hepatic inflow occlusion for a total period of 120 min in each group. Intermittent ischaemia was associated with significantly lower mortality rates than continuous ischaemia (four of 20 versus15 of 20; P= 0±0015). In a separate study, again following 120 min continuous or intermittent ischaemia, systemic blood was sampled at 0 min, 1 h, 3 h and 5 h after final clamp release for measurement of endotoxin, TNF and IL-6 concentrations. Endotoxin concentrations were significantly lower at 1 h, as were TNF and IL-6 concentrations at 3 and 5 h, after final clamp release in the group having intermittent ischaemia (P<0±05). Intermittent ischaemia is associated therefore with significantly reduced mortality rates and lower systemic endotoxin, TNF and IL-6 concentrations when compared with continuous ischaemia.