BackgroundHydroxyethyl starches have been withdrawn from the European market. In Sweden, dextran was the main colloid until 2000, when starches overtook the market. After the recent 6S-trial, it was suggested that dextran could be reinstituted, but concerns for greater coagulopathy, bleeding and anaphylaxis still remain. An experimental study from our department indicated that isovolemic substitution of dextran-70 did not derange the von Willebrand function more than albumin 5%, considering the fact that dextran is hyperoncotic in comparison to albumin 5% and, therefore, induces a greater plasma volume expansion and thereby a greater dilutional coagulopathy.MethodsEighteen patients undergoing major gynaecological surgery were assigned to receive either 5% albumin or 6% dextran-70 with 9 patients in each group. Standard coagulation tests, including prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen and platelet count, viscoelastic coagulation test thromboelastometry (ROTEM) and the Multiplate platelet aggregation test were used to test for coagulation defects at different time points perioperatively. Blood loss, blood loss replacement data and haemodynamic parameters were retrieved from anaesthetic and postoperative charts. A local departmental fluid and transfusion/infusion protocol assured haemoglobin > 90 g/l and mean arterial pressure > 65 mmHg with Ringer’s acetate in addition to the colloid use.ResultsThere were no differences in demographic data between the groups. The tissue factor-activated (EXTEM) clot-structure parameter ROTEM A10 was decreased significantly in the dextran group as compared to the albumin group after the infusion of 500 ml of either colloid solution. The PT and aPTT were significantly prolonged, and the platelet count decreased postoperatively in the dextran group, whereas albumin only deranged fibrinogen levels as compared to preoperative levels. There were no differences in Multiplate platelet aggregometry, amount of haemorrhage or transfusion of blood components between the groups.ConclusionsStandard plasma-based coagulation tests, platelet count and whole blood viscoelastic clot structure are affected by 6% dextran-70 to a greater extent than by 5% albumin, but platelet aggregation is not. Future studies should use more advanced haemodynamic monitoring to assess isovolemic plasma volume expansion with dextran and whether this affects haemostasis to a lesser degree.
BackgroundEffective cancer treatment requires durable elimination of malignant cells. Cytotoxic chemotherapeutic agents used to treat cancer often show initial anti-tumor efficacy, but fail to produce long-term durable responses in patients. The elicitation of durable responses and improved survival in response to cytotoxic agents may be associated with the induction of innate and adaptive immune response to the cancer. For example, tumor cells undergoing apoptosis following exposure to some cytotoxic agents emit immunostimulatory damage-associated molecular patterns (DAMPs), this form of cell death is termed immunogenic cell death (ICD). ICD can promote the recruitment and activation of both the innate and adaptive immune system, providing an additional mechanism to drive an anti-tumor response.MethodsVedotin-based antibody drug conjugates (ADCs) drive cytotoxicity in tumor cells by engaging tumor antigens on the cell surface, internalizing with the cell surface antigen, and delivering monomethyl auristatin E (MMAE) payload. Following intracellular delivery, MMAE induces mitotic arrest, as well as an endoplasmic reticulum (ER) stress response resulting from microtubule disruption. Following tumor cell treatment, indicators of the ER stress response are observed with vedotin-based ADCs including induction of phospho-JNK and CHOP, This mechanism of MMAE induced ER stress results in emission of hallmark ICD DAMPs including cell-surface calreticulin, extracellular release of HMGB1 and ATP. In this presentation we highlight the ability of MMAE to induce the hallmarks of ICD in multiple cancers across different tissue origins using distinct valine-citrulline-MMAE (vedotin)-based ADCs.ResultsThe culmination of these ICD hallmarks resulted in innate immune cell activation in vitro and in vivo in mouse xenograft models. Tumor bearing mice treated with vedotin-based ADCs resulted in the promotion of immune cell recruitment and activation in tumors. Analysis of immune activation by vedotin-based ADCs included production of innate cytokines and upregulation of HLA/MHC-Class I/II expression, which supports a role in activating both the innate and adaptive immune response. To further our understanding of the potent and broad ability of vedotin ADCs to induce ICD, we have also begun to examine the ICD potential of different classes of ADC payloads including other microtubule inhibitors (auristatins and maytansines), and DNA damaging agents (DNA alkylators or topoisomerase inhibitors). Initial data indicate differences in ICD induction by these agents.ConclusionsThese results help build the rationale for vedotin-based ADCs as preferred partners for immune checkpoint blockade agents.Ethics ApprovalStudies with human samples were performed according to institutional ethics standards. Animal studies were approved by and conducted in accordance with Seattle Genetics Institutional Care and Use Committee protocol #SGE-029.
Carcinoembryonic antigen cell adhesion molecule 5, CEACAM5, is a glycosylphosphatidylinositol-anchored glycoprotein highly expressed on the cell surface of several epithelial tumors. CEACAM5 is expressed in virtually all colorectal cancer, ~90% of which to high levels while normal tissue expression is limited. The high prevalence of CEACAM5 expression in colorectal tumor cells prompted us to develop an investigational anti-CEACAM5 antibody-drug conjugate (ADC) for the potential treatment of CRC patients. We developed a novel ADC, by conjugating an anti-CEACAM5 antibody with a drug linker to a topoisomerase I inhibitor payload. The anti-CEACAM5 antibody was chosen based on its high selectivity for CEACAM5 and its potential to direct cytotoxic payloads to tumor. The topoisomerase I payload was optimized for potency, reduced PGP efflux and enhanced bystander activity. The novel anti-CEACAM5 topoisomerase I inhibitor ADC binds to CEACAM5 at nanomolar (nM) concentrations and kills CEACAM5-positive colon tumor cells with varying levels of CEACAM5 at sub-nM concentrations with no or very low cytotoxicity towards CEACAM5-negative cells. Mechanistically, the potent anti-tumor activity of the ADC is both mediated by direct internalization, processing, and release of the cytotoxic payload within the CEACAM5-expressing tumor cells, and by a bystander effect mediated by diffusion of the payload to the neighboring CEACAM5-negative tumor cells. The novel anti-CEACAM5 topoisomerase I inhibitor ADC is well tolerated in rats after repeated administration of 30 and 50 mg/kg/day, Q1W x 4. In vivo efficacy of this ADC at 1, 3 and 10 mg/kg (single administration) was evaluated in four CRC patient-derived xenografts (PDXs) models. The conjugate elicits potent and specific and dose dependent antitumor activity with complete regression (CR) at 10 mg/kg in the 4 models. This robust anti-tumor activity was further confirmed in a Single Mouse Trial of 16 CRC PDX models, consisting in the use of one animal per PDX model per treatment arm and for which the evaluation of efficacy was based on the criteria RECIST (Response Evaluation Criteria In Solid Tumors) used in clinic. In these criteria, the overall response rate includes complete response (CR) and partial response (PR) and the a disease control rate includes CR, PR and stable disease (SD). The ADC induces a disease control rate of 95% and an overall response rate of 50% following a single dose of 10 mg/kg. The outstanding anti-tumor activity across CRC PDX models and its favorable safety profile in rats support further evaluation of this investigational novel topoisomerase I ADC in CRC patients. Citation Format: Yves Baudat, Haley Neff-LaFord, Celine Nicolazzi, Dave Meyer, Johann Petur Sigurjonsson, Ryan Lyski, Valeria Fantin, Marie-Priscille Brun, Marielle Chiron, Stephanie Decary. A novel topoisomerase I inhibitor antibody-drug conjugate targeting CEACAM5 has potent anti-tumor activity in colorectal cancer models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4890.
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