No abstract

The gastrointestinal tract represents one of the largest body surfaces that is exposed to the outside world. It is the only mucosal surface that is required to simultaneously recognize and defend against pathogens, while allowing nutrients containing foreign antigens to be tolerated and absorbed. It differentiates between these foreign substances through a complex system of pattern recognition receptors expressed on the surface of the intestinal epithelial cells as well as the underlying immune cells. These immune cells actively sample and evaluate microbes and other particles that pass through the lumen of the gut. This local sensing system is part of a broader distributed signaling system that is connected to the rest of the body through the enteric nervous system, the immune system, and the metabolic system. While local tissue homeostasis is maintained by commensal bacteria that colonize the gut, colonization itself may not be required for the activation of distributed signaling networks that can result in modulation of peripheral inflammation. Herein, we describe the ability of a gut-restricted strain of commensal bacteria to drive systemic anti-inflammatory effects in a manner that does not rely upon its ability to colonize the gastrointestinal tract or alter the mucosal microbiome. Orally administered EDP1867, a gamma-irradiated strain of Veillonella parvula, rapidly transits through the murine gut without colonization or alteration of the background microbiome flora. In murine models of inflammatory disease including delayed-type hypersensitivity (DTH), atopic dermatitis, psoriasis, and experimental autoimmune encephalomyelitis (EAE), treatment with EDP1867 resulted in significant reduction in inflammation and immunopathology. Ex vivo cytokine analyses revealed that EDP1867 treatment diminished production of pro-inflammatory cytokines involved in inflammatory cascades. Furthermore, blockade of lymphocyte migration to the gut-associated lymphoid tissues impaired the ability of EDP1867 to resolve peripheral inflammation, supporting the hypothesis that circulating immune cells are responsible for promulgating the signals from the gut to peripheral tissues. Finally, we show that adoptively transferred T cells from EDP1867-treated mice inhibit inflammation induced in recipient mice. These results demonstrate that an orally-delivered, non-viable strain of commensal bacteria can mediate potent anti-inflammatory effects in peripheral tissues through transient occupancy of the gastrointestinal tract, and support the development of non-living bacterial strains for therapeutic applications.

mutation and the degree of differentiation or node invasion (p¼0.46 and p¼0.24 respectively). Conclusion:The prognostic impact of RAS mutation was demonstrated in our patients. Treatment for metastatic cancers remains challenging in Tunisia despite recent advances. Thanks to the identification of RAS status, unjustified expenses of anti-EGFR targeted therapy could be avoided.Legal entity responsible for the study: The authors.

CD38 targeting antibodies are at different phases of clinical development, with daratumumab already approved as monotherapy and in combination with standards of care in multiple myeloma (MM). Anti-CD38 monoclonal antibodies (mAbs) induce tumor cell depletion in part by Fc-dependent effector mechanisms such as antibody dependent cellular cytotoxicity (ADCC), antibody dependent cellular phagocytosis (ADCP), and complement dependent cytotoxicity (CDC). However, not all MM patients achieve minimal residual disease (MRD)-negativity and similar clinical response. In addition, some patients on daratumumab develop resistance due to reduced cell surface CD38 and high levels of complement inhibitors (CD55 and CD59). We have leveraged Fc multimerization technology (Ortiz et al Sci Transl Med. 2016; 8: 365) to generate an optimized platform (SIF; selective immunomodulator of Fc receptors) that utilizes the valency effect of Fc multimerization to enhance binding to the Fcγ receptors and complement. We combined the Fab-region of CD38 targeting mAb to SIF platform to generate an anti-CD38 SIFbody to enhance immune and complement mediated cytotoxicity against tumor cells. In several human tumor cell line-based cytotoxic assays using primary human effector cells (NK cells and macrophages) and complement, the anti-CD38 SIFbody demonstrates up to 10-fold increase in efficacy and ≥16-fold increase in potency compared to daratumumab and the surrogate therapeutic anti-CD38 mAb (TAK-079). In isolated whole human blood incubated with tumor cells, the anti-CD38 SIFbody demonstrated 40-100 fold increase in potency and 2-3 fold increase in efficacy. In bone marrow cells isolated from MM patients with >80% plasma cells anti-CD38 SIFbody showed better potency and a 3-5 fold increased efficacy (with 100% plasma cell elimination) than daratumumab, suggesting the SIFbody may be more suitable molecule for achieving greater MRD-negativity rates in MM patients. Daratumumab fails to induce CDC against tumor cell lines with low CD38 and high CD55 and CD59, however the SIFbody achieves 100% efficacy in such settings, suggesting this molecule may be effective in patients who are developing resistance to treatment. In single dose pharmacodynamic and tolerability studies in cynomolgus monkeys SIFbody demonstrated up to 5-fold increase in B cell depletion from peripheral blood compared to TAK-079 across all dose ranges (0.3, 1, & 3 mg/kg) tested without any adverse events. Therefore, by leveraging our Fc multimerization technology we have generated a differentiated potential best-in-class anti-CD38 therapeutic. Citation Format: Amit Choudhury, Daniel F. Ortiz, Shannon Argueta, Kevin Garofalo, Jonathan C. Lansing, Utsav Jetley, Danice Wilkins, Carlos Bosques, Edward Cochran, Naveen Bhatnagar, Jay Duffner, Abhinav Gupta, Stan Lee, Karunya Srinivasan, Viraj Parge, Radouane Zouaoui, Jason Wang, Anthony M. Manning. Discovery of a potential best-in-class anti-CD38 therapeutic utilizing Fc multimerization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 561.

Background: Systemic immunity can be regulated via transient interactions of non-colonizing bacteria and immune cells in the small intestinal mucosa. The potential to harness these interactions for IO treatment was first described by Sivan in 2015. EDP1503 is a non-colonizing preparation of a single strain of Bifidobacterium animalis lactis that, when administered orally, in preclinical models, invokes an anti-tumor immune response by activation of innate and adaptive immune mechanisms. The pleiotropic effects of EDP1503 are initiated in the small intestine and mediated by interactions with multiple pattern-recognition receptors inducing a proinflammatory signature in human PBMCs, activating CD8 and NK cell IFNγ production and cytolytic activity. Preclinically, EDP1503 inhibits tumor growth as a monotherapy and in combination with anti-PD-1/L1. Single agent PD-1/L1 therapies have showed limited clinical benefit in previously treated triple-negative breast cancer (TNBC) patients. Here, we report the safety, tolerability, and efficacy of EDP1503 in combination with pembrolizumab in patients with TNBC (NCT03775850). Methods: EDP1503-101 is an open label Phase 1/2 study of EDP1503 in combination with pembrolizumab. TNBC subjects who had received ≥ 1 treatment regimen for metastatic disease were enrolled. Prior anti-PD-1/L1 treatment was permitted. Subjects initially receive 14 days of EDP1503 monotherapy orally twice a day (b.i.d) and then EDP1503 b.i.d. in combination with pembrolizumab 200 mg iv every 3 weeks. The initial 3 subjects received 2 capsules of EDP1503 b.i.d. All other subjects received 4 capsules b.i.d. Safety and tolerability were assessed using CTCAE v5.0. Evidence of anti-tumor activity was based on investigator-assessed objective response (OR), by RECIST v1.1 and iRECIST, and disease control rate defined as OR and/or stable disease (SD) after 4 cycles of therapy. Paired biopsies at baseline and day 14 were used to establish PD-L1 status and investigate pharmacodynamic biomarker changes. Results: As of 1 October 2020, 15 TNBC subjects had been treated (median age of 52, median of 2 prior lines of therapy and ECOG of 0-1). Additional subjects are being recruited, up to a maximum of 30. EDP1503 was well-tolerated as monotherapy and in combination with pembrolizumab. 53% of subjects experienced treatment-related adverse events (TRAEs). Most common TRAEs were GI-related: abdominal distension (20%), decreased appetite (20%), diarrhea (13%), flatulence (13%). No Grade 4-5 TRAEs were observed. 1 Grade 3 TRAE (diarrhea) leading to treatment discontinuation was reported. In 12 subjects receiving the 4 capsules b.i.d dose, 2 partial responses (PR) and 1 SD were observed, giving an objective response rate (ORR) of 18% and a disease control rate (DCR) of 27% in evaluable patients (n=11). Both responders had tumor burden reductions of >65% by RECIST. One responder had 4 prior lines of therapy for metastatic disease, including a PD-L1 inhibitor combination, has a PD-L1 combined positive score (CPS) of 30 and has been on study treatment for 192 days with a 66% reduction in target lesions. The only residual lesion is 6 mm which is PET-negative. The other responder had 2 prior lines of therapy for metastatic disease, was checkpoint inhibitor naive, has a PD-L1 CPS of 2 and remained on study treatment for 275 days with a 73% reduction in target lesions before discontinuing due to treatment-related AEs. The patient with SD had also previously relapsed on a PD-L1 inhibitor and was on study treatment for 226 days before progressing. Conclusions: EDP1503 administered with pembrolizumab is safe and well-tolerated with no Grade 4-5 TRAEs or SAEs. Clinical benefit was observed in a subset of TNBC patients treated with the combination of EDP1503 and pembrolizumab. This study is continuing to recruit TNBC patients at the high dose of EDP1503. Citation Format: Loise Francisco-Anderson, Shamira Shariffudin, Humphrey Gardner, Peter Sandy, Michael Goldberg, Shubhra Kashyap, Mary Abdou, Maria Sizova, Valeria Kravitz, Holly Ponichtera, Mark Carlson, Shannon Argueta, Chris Davitt, Pooja Parameswaran, Michael Chisamore, Mark Bodmer, Duncan McHale. A phase I/II clinical trial of EDP1503 with pembrolizumab for triple-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-27.