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100 Background: Teclistamab (JNJ-64007957) is a bispecific BCMA x CD3 antibody that induces T cell-mediated cytotoxicity against BCMA-expressing myeloma cells. Initial results from an ongoing study of teclistamab in RRMM (NCT03145181) are presented. Methods: Pts have MM and are RR to standard therapies. Primary objective for part 1 is to identify a recommended phase 2 dose(s). Multiple intravenous (iv) doses ± priming doses were explored. Adverse events (AEs) were graded per CTCAE v4.03 and cytokine release syndrome (CRS) per Lee et al 2014. Response was investigator-assessed using IMWG criteria; minimal residual disease (MRD) in bone marrow was assessed by next generation sequencing. Results: As of 31 Jan 2020, 66 pts had received iv teclistamab (0.3–270 µg/kg). Median age was 64 y (24–82), median prior therapies was 6 (2–14), 97% triple-class exposed, 83% triple-class refractory, and 38% penta-drug refractory. Most common treatment-related AEs (all grade) were CRS (56%), neutropenia (26%), and anemia (23%). CRS events were all grade 1–2 and generally confined to initial doses. 8% of pts had treatment-related neurotoxicity (3% grade ≥3), and 9% had infusion related reaction. Infection-related AEs were reported in 61% of pts (21% grade ≥3). 2 dose-limiting toxicities were reported: grade 4 delirium (resolved after 16 days) and grade 4 thrombocytopenia (resolved after 1 day). 36% of pts had treatment-related grade ≥3 AEs; neutropenia (20%) and anemia (14%) were most frequent. Only 1 grade 5 AE was reported (respiratory failure in the setting of pneumonia deemed unrelated by the investigator). PK results indicate that the half-life of teclistamab supports weekly dosing. On-target pharmacodynamic activity (T cell redistribution and activation along with transient release of cytokines) was observed at doses ≥9.6 µg/kg. Cytokine production was modulated with step-up dosing while T cell activation was maintained. 65 pts were evaluable for response. Activity was observed starting at treatment doses ≥38.4 µg/kg, with 20/52 (38%) pts achieving a response. At the highest dose, 7/9 (78%) pts responded (1 response pending confirmation). Of MRD-evaluable pts who had complete response, 2/2 were MRD negative at 10−6 with treatment ongoing > 12 mo. Conclusions: Teclistamab has manageable safety across all doses explored. A 78% overall response rate was observed at the highest weekly treatment dose in pts with advanced RRMM, supporting further evaluation of teclistamab in expansion cohorts. Clinical trial information: NCT03145181.

Introduction: Mosunetuzumab is a full-length bispecific CD20/CD3 antibody that redirects endogenous T-cells to kill malignant B-cells by concomitantly binding to CD3 on T-cells and CD20 on B-cells. We report results of an ongoing multicenter Phase 1/1b study (NCT02500407) evaluating mosunetuzumab in relapsed/refractory (R/R) B-cell NHL patients (pts). Methods: Pts received mosunetuzumab intravenously (IV) as follows: Group A, mosunetuzumab administered on day (D) 1 of each 21-day cycle (C); and Group B, ascending doses of mosunetuzumab administered on D1, D8, and D15 of C1, then at a fixed dose on D1 of every 21-day cycle thereafter, up to a maximum of 17 cycles. Single-pt dose escalation converting to a 3+3 design was used in Group A; standard 3+3 escalation was used in Group B. Additional pts were enrolled to further characterize clinical activity at cleared dose levels. Primary outcome measures are maximum tolerated dose (MTD) based on dose-limiting toxicities (DLTs), tolerability, pharmacokinetics (PK), and best objective response. Results: As of 13 April 2018, 98 pts were enrolled to receive mosunetuzumab (diffuse large B-cell lymphoma [DLBCL]/transformed [tr] follicular lymphoma [FL] n=55, FL n=29, mantle cell lymphoma n=3; other NHL n=11; Table 1). The median duration of treatment was 81 days (range 8-162 days) in Group A and 68 days (range 1-306 days) in Group B. 26 pts remain on treatment and 18 completed treatment, of whom 10 remain in follow-up. 54 pts (55%) discontinued treatment due to disease progression (n=43, 44%), withdrawal of consent (n=5, 5%), adverse events (AEs) (n=2, 2%), use of another anticancer agent (n=2, 2%), physician decision (n=1, 1%) or death (n=1, 1%; hemophagocytic lymphohistiocytosis). Doses up to 2.8mg were assessed in Group A (n=33) and up to 1.0/2.0/13.5mg in Group B (the C1D1/C1D8/C1D15 dose; subsequent doses = C1D15 dose; n=65). DLTs were reported in 6 pts: neutropenia (n=2, both grade 4), cytokine release syndrome (CRS; n=1, grade 2), increased liver transaminases (grade 4) and hepatic encephalopathy (grade 3) (n=1), hypotension (n=1, grade 3) and anemia (n=1, grade 3). The MTD has not yet been reached in either group. Safety was similar in both groups even with higher dose levels tested in Group B (Table 2). The majority of treatment-emergent AEs occurred during Cycle 1. CRS was the most frequently reported drug-related AE; occurred in 21/98 (21%) pts and mostly occurred with the first dose. All cases of CRS were grade 1-2 per Lee et al. (Blood 2014) grading criteria. Grade ≥3 AEs occurred in 51/98 (52%) pts, of which 22/98 (22%) were considered treatment-related. Grade ≥3 treatment-emergent neutropenia was observed in 13/98 (13%) pts. One case of febrile neutropenia was reported (assessed as unrelated to study drug); no neutropenia-related infections were reported. Only one treatment-related grade ≥3 neurotoxicity was reported (grade 3 hepatic encephalopathy). One fatality from hemophagocytic lymphohistiocytosis in a pt with suspected chronic active Epstein-Barr virus infection was attributed to study treatment and one pt died of hepatic failure 26 days after the first dose; considered possibly related to treatment. Mosunetuzumab displayed a half-life of 6-11 days. Pharmacodynamic activity was evident from peripheral CD8+ and CD4+ T-cell activation following mosunetuzumab administration. Mosunetuzumab exhibited anti-tumor activity at doses ≥1.2mg (Figure 1). Among pts receiving doses ≥1.2mg, 66 patients (18 FL, 39 DLBCL/trFL and 9 other histologies) had at least 3-month follow-up and were considered efficacy-evaluable. Objective responses were observed in 27/66 (41%) evaluable pts, including 11/18 (61%) FL pts and 13/39 (33%) DLBCL/ trFL. 18 pts (27%) had a complete response (CR), including 50% (9/18) of FL pts and 21% (8/39) of DLBCL/trFL pts. Responses were observed in pts considered refractory to anti-CD20 therapy and in pts who had relapsed following CD19-directed CAR-T therapy. CRs appear durable, with all pts achieving a CR remaining in remission (median follow-up 372 days, range 95- 690 days). Conclusions: Mosunetuzumab is clinically active in R/R B-cell NHL. The safety profile, with MTD not yet reached and with most AEs being low-grade and manageable, appears favorable compared to current standard anti-lymphoma therapies including T-cell directed agents. Mosunetuzumab monotherapy shows promising and durable efficacy in FL and in DLBCL. Disclosures Sehn: Morphosys: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Merck: Consultancy, Honoraria. Assouline:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding; Pfizer: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau. Flinn:Agios: Research Funding; Seattle Genetics: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; BeiGene: Research Funding; Trillium: Research Funding; Gilead: Research Funding; ArQule: Research Funding; Verastem: Consultancy, Research Funding; Curis: Research Funding; Forma: Research Funding; Merck: Research Funding; Kite: Research Funding; Calithera: Research Funding; Takeda: Research Funding; Constellation: Research Funding; TG Therapeutics: Research Funding; Verastem: Research Funding; Pharmacyclics: Research Funding; Portola: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Novartis: Research Funding; Janssen: Research Funding; Infinity: Research Funding. Isufi:Genentech: Consultancy; Novartis: Consultancy. Kim:Kyowa-Kirin: Research Funding; Celltrion: Honoraria, Research Funding; J&J: Research Funding; Celgene: Research Funding; Eisai: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Mundipharma: Research Funding; Novartis: Research Funding; Takeda: Research Funding; Merck: Research Funding. Matasar:Seattle Genetics: Honoraria. Nastoupil:Karus: Research Funding; TG Therappeutics: Research Funding; Merck: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Juno: Honoraria; Gilead: Honoraria; Genentech: Honoraria, Research Funding; Spectrum: Honoraria; Janssen: Research Funding. Hernandez:Genentech: Employment. Li:Genentech: Employment, Equity Ownership. Kulkarni:Genentech: Employment. McCall:Genentech: Employment. McClellan:Genentech: Employment. Yin:Genentech: Employment, Equity Ownership. Gupta:Genentech: Employment, Equity Ownership. Chu:Genentech: Employment, Equity Ownership. Bartlett:Millennium: Research Funding; ImaginAB: Research Funding; Astra Zeneca: Research Funding; Immune Design: Research Funding; Forty Seven: Research Funding; Celgene: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck & Co: Research Funding; Janssen: Research Funding; Genentech: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Research Funding; Novartis: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding.

Introduction and Hypothesis: Steroid soaking may decrease mesh-triggered inflammatory reaction in tissue. We aimed to investigate the tissue reaction to a steroid-soaked mesh material and an unsoaked mesh material in the rat model. Methods: Neutral and steroid-soaked type I macroporous polypropylene (PP) monofilament and polyvinylidene fluoride (PVF) mesh materials were implanted on the rectus abdominis muscle of 20 mature Wistar albino rats. Animals were divided into four groups: PP mesh with steroid (PP-S), PP mesh without steroid, PVF mesh with steroid (PVF-S), and PVF mesh without steroid. The rats were killed after 12 weeks, and histologic, immunohistochemical and electron microscopic examinations were performed. For immunohistochemical analysis, polyclonal rabbit anti-mouse CD3, rabbit anti-mouse CD68, rabbit anti-mouse CD15, and rabbit anti-mouse CD34 antibodies were used for the detection of lymphocytes, macrophages, polymorphonuclear leukocyte foreign body giant cells, and fibromyocyte stem cells, respectively. Samples were stained with hematoxylin and eosin for the histologic evaluation of inflammation and with Masson’s trichrome stain for the evaluation of collagen deposition. Pore size and mesh ultrastructure were evaluated by electron microscopy. Results: Expression of CD3 was lower in the PVF, PVF-S and PP-S groups, and expression of CD34 was higher in the PVF-S and PP-S groups than in the PP groups (p < 0.05). Collagen deposition was lower in the PVF, PVF-S and PP-S groups (p < 0.05). Histologically, the intensity of inflammation was lower in the PVF-S and PP-S groups than in the PP mesh group (p < 0.05). There were no significant differences among the groups in terms of pore size and mesh ultrastructure on electron microscopic examination (p > 0.05). Conclusions: PVF mesh induces less inflammation than PP mesh, and in both mesh types steroid soaking further decreases inflammation without changing the pore size. © 2016, The International Urogynecological Association.

Background Accumulating evidence suggests that the balance between pathogenic effector T cells (Teffs) and regulatory T cells (Tregs) may be important for controlling atherosclerotic disease. We hypothesized that a combination therapy with anti‐ CD 3 antibody ( CD 3‐Ab) and IL ‐2/anti‐ IL ‐2 monoclonal antibody complex ( IL ‐2 complex) aimed at increasing the ratio of Tregs to Teffs would effectively inhibit atherosclerosis in mice. Methods and Results We treated apolipoprotein E‐deficient mice fed a high‐cholesterol diet with vehicle, CD 3‐Ab, IL ‐2 complex, or their combination. Mice receiving the combination therapy had markedly reduced atherosclerotic lesions than mice treated with CD 3‐Ab or IL ‐2 complex alone. In addition, a striking increase in the Treg/Teff ratio of lymphoid organs and atherosclerotic lesions, along with plaque stabilization characterized by decreased macrophage content and increased collagen content was observed. The combination treatment also markedly reduced splenic Ly6C high inflammatory monocytes and might induce a favorable macrophage phenotype change in atherosclerotic lesions. Conclusions Our results indicate that in addition to suppressing Teff responses, enhancing Treg‐mediated immune responses is more efficacious in preventing atherosclerosis, suggesting a novel therapeutic approach for atherosclerosis.

Purpose: To assess the frequency and the functional characteristics of one major component of immune tolerance, the CD4+FoxP3+ regulatory T cells (Tregs) in a mouse model of abdominal irradiation. Methods and Materials: Mice were exposed to a single abdominal dose of γ-radiation (10 Gy). We evaluated small intestine Treg infiltration by Foxp3 immunostaining and the functional suppressive activity of Tregs isolated from mesenteric lymph nodes. Results: Foxp3 immunostaining showed that radiation induced a long-term infiltration of the intestine by Tregs (levels 5.5 times greater than in controls). Co-culture of Tregs from mesenteric lymph nodes with CD4+ effector cells showed that the Tregs had lost their suppressive function. This loss was associated with a significant decrease in the levels of Foxp3, TGF-β, and CTLA-4 mRNA, all required for optimal Treg function. At Day 90 after irradiation, Tregs regained their suppressive activity as forkhead box P3 (Foxp3), transforming growth factor beta (TGF-β), and cytotoxic T-lymphocyte antigen 4 (CTLA-4) expression returned to normal. Analysis of the secretory function of mesenteric lymph node Tregs, activated in vitro with anti-CD3/anti-CD28 Abs, showed that this dysfunction was independent of a defect in interleukin-10 secretion. Conclusion: Radiation caused a long-term accumulation of function-impaired Foxp3+CD4+ Tregs in the intestine. Our study provides new insights into how radiation affects the immune tolerance in peripheral tissues. © 2011 Elsevier Inc.

The aim of this report was to present a case of epitheliotropic cutaneous lymphoma (mycosis fungoides) in a coati. The animal was presented for evaluation of a non-pruritic nodule. Although the diagnosis of cutaneous histiocytoma was made histologically, plaques and erosions appeared in new areas of the skin along with rapid deterioration of body condition that led to euthanasia in less than one month following initial presentation. Epitheliotropic cutaneous lymphoma was confirmed with plaque biopsies. Cross-reactivity of a polyclonal antihuman CD3 antibody to coati T lymphocytes was also observed. Apart from skin lesions, only pleuritis was post-mortem diagnosed most likely because of immunosuppression secondarily to malignant neoplasia.

Recent studies have shown that probiotics are beneficial in T-cell-mediated inflammatory diseases. The molecular mechanism by which probiotics work remains elusive, but accumulating evidence indicates that probiotics can modulate immune cell responses. Since T cells express receptors for bacterial products or components, we examined whether different strains of lactobacilli directly regulate the functions of human T cells. CD4 + T cells were isolated from blood and intestinal lamina propria (LP) of normal individuals and patients with inflammatory bowel disease (IBD). Mononuclear cells were also isolated from Peyer's patches. Cells were activated with anti-CD3/CD2/CD28 in the presence or absence of Lactobacillus paracasei subsp. paracasei B21060, L. paracasei subsp. paracasei F19, or L. casei subsp. casei DG. Cell proliferation and death, Foxp3, intracellular pH, and cytokine production were evaluated by flow cytometry. We showed that L. paracasei subsp. paracasei B21060 but neither L. paracasei subsp. paracasei F19 nor L. casei subsp. casei DG inhibited blood CD4 + T-cell growth. This effect was associated with no change in cell survival, expression of Foxp3, or production of gamma interferon, interleukin-4 (IL-4), IL-5, and IL-10. L. paracasei subsp. paracasei B21060-mediated blockade of CD4 + T-cell proliferation required a viable bacterium and was associated with decreased MCT-1 expression and low intracellular pH. L. paracasei subsp. paracasei B21060 also inhibited the growth of Peyer's patch mononuclear cells, normal lymphocytes, and IBD CD4 + LP lymphocytes without affecting cytokine production. The data show that L. paracasei subsp. paracasei B21060 blocks T-cell growth, thus suggesting a mechanism by which these probiotics could interfere with T-cell-driven immune responses.

Aims/Hypothesis Insulin resistance has been proposed as a risk factor for type 1 diabetes. We investigated whether adiponectin, an insulin sensitiser, can serve as an additional predictive marker for type 1 diabetes in first-degree relatives of known patients. Methods Adiponectin was followed in 211 persistently islet antibody-positive (Ab+) first-degree relatives of type 1 diabetic patients and in 211 age- and sex-matched persistently antibody-negative relatives, and correlated with antibody status, random proinsulin:C-peptide ratio and HLA-DQ genotype. During follow-up, 37 Ab+ relatives developed type 1 diabetes. Results In the group of 422 relatives, baseline adiponectin correlated inversely with age and BMI and was lower in male than in female participants, especially after 15 years of age (pConclusions/Interpretation Adiponectin levels do not contribute to the prediction of type 1 diabetes in Ab+ relatives.

Aims/Hypothesis Insulin resistance has been proposed as a risk factor for type 1 diabetes. We investigated whether adiponectin, an insulin sensitiser, can serve as an additional predictive marker for type 1 diabetes in first-degree relatives of known patients. Methods Adiponectin was followed in 211 persistently islet antibody-positive (Ab+) first-degree relatives of type 1 diabetic patients and in 211 age- and sex-matched persistently antibody-negative relatives, and correlated with antibody status, random proinsulin:C-peptide ratio and HLA-DQ genotype. During follow-up, 37 Ab+ relatives developed type 1 diabetes. Results In the group of 422 relatives, baseline adiponectin correlated inversely with age and BMI and was lower in male than in female participants, especially after 15 years of age (pConclusions/Interpretation Adiponectin levels do not contribute to the prediction of type 1 diabetes in Ab+ relatives.

First of all we would like to thank Dr. von Herrath, who has long-standing experience in transgenic models in which autoimmunity is triggered by viral agents, and who has also been a close collaborator, for the very stimulating comments on our editorial article. It was indeed the aim of our opinion paper to generate debate. We are pleased that the editor has given us the opportunity to express our views in this reply. Concerning the mouse models, our purpose was to highlight the preclinical importance of the spontaneous overtly diabetic, but not prediabetic, NOD female model. We agree that this is not, for obvious reasons, an easy model to handle and that some time is needed to get the best results from it. This does not mean at all, however, that CD3 antibodies did not show a high efficacy in other experimental models. We fully acknowledge K. Herold's work in the streptozotocin-induced diabetes model in normal mice [1]. We ourselves provided evidence in support of the efficacy of CD3 antibody treatment in the cyclophosphamide-induced diabetes model in NOD mice [2, 3] and, in collaboration with Dr. von Herrath, the LCMV-induced diabetes model in LCMV GP-RIP transgenic mice [4]. The problem is, however, that in addition to CD3 antibodies, an exceedingly high number of other strategies were effective in disease prevention and/or treatment in these other models that were not active at all in overtly diabetic NOD mice, and which, interestingly enough, have not made it to the clinic so far. Concerning the clinical data, the points raised by Drs. Bresson and von Herrath are well taken. We would nevertheless like to express some words of caution about drawing conclusions too fast from the combination of data from trials which were conducted in different ways. In our view, it is neither surprising nor contradictory that the results in the trial conducted by K. Herold did not show a long-term effect in CD3 antibody-treated responder patients, as we observed in our trial. We believe that differences in the design of the study (the European trial was a placebo-controlled phase II study), the patient populations (children and adult patients were enrolled in the American trial, while young children were not included in the European study) and the method used to evaluate β-cell function (the mixed meal test in the American trial versus the clamp test in the European trial) greatly affected the results obtained, generating the apparent discrepancies. We still believe that the significant effect on insulin doses we observed 18 months after just a 6-day treatment in the absence of generalized immunosuppression is in strong support of operational tolerance induction in these patients, whatever the future outcome may be. Of course, we agree with Drs. Bresson and von Herrath that unfortunately at present there are no reliable antigen-specific T cell assays that can directly prove the presence of active tolerance in CD3 antibody-treated responder patients. Because of our long-standing interest in CD3 antibodies not only in autoimmunity, but also in transplantation, we are very pleased that several groups are now interested in applying and refining the strategies for their use. The larger the critical mass around their clinical development, the better the chances that CD3 antibodies may reach the approval stage by regulatory authorities. This is the real struggle we are facing today before we can proceed to a large-scale use of these antibodies that, at least in our view, are endowed with unique tolerogenic properties that no other biological agents have shown so far. Are we wrong? Are we right? Only time will show.

OKT3 therapy for prevention or reversal of allograft rejection has been associated with a constellation of acute systemic side effects, defined as an OKT3 first-dose reaction. Specific neurologic syndromes, including aseptic meningitis and diffuse encephalitis, have also been observed. This report describes a 12-year-old girl with steroid-resistant renal allograft rejection who developed hemiparesis associated with initiation of OKT3 therapy.

Purpose: The molecular markers cluster of differentiation (CD)24, CD44, adenosine tri-phosphate (ATP) binding cassette protein G2 (ABCG2), and epithelial cell adhesion molecule (EpCAM) are widely used, individually or in combination, to characterize some types of cancer stem cells. In this study we characterized the EpCAM + retinoblastoma (RB) cells for their cancer stem-like properties in vitro. Additionally, we targeted RB tumor cells via redirecting T cells using bispecific EpCAM�CD3 antibody. Methods: Flow cytometry was used to study the co-expression of EpCAM with putative cancer stem cell markers, such as CD44, CD24, and ABCG2, in RB primary tumors. In vitro methyl thiazol tetrazolium (MTT) assay, invasion assay, and neurosphere formation assay were performed to characterize EpCAM + cells for their cancer stem/progenitor cell-like properties. We assessed the in vitro efficacy of bispecific EpCAM�CD3 antibody on RB tumor cell proliferation and validated the results by evaluating effector cytokine production in the culture medium with the ELISA method. Results: EpCAM was co-expressed with all cancer stem cell markers (CD44, CD24, and ABCG2) in primary RB tumors. EpCAM + cells showed significantly higher proliferative invasive potential and neurosphere formation in vitro compared to EpCAM - Y79 cells. EpCAM + cells showed higher ?-catenin expression compared to EpCAM- cells. EpCAM�CD3 significantly retarded proliferation of RB primary tumor cells. EpCAM�CD3 effectively induced the secretion of effector cytokines, such as interferon (IFN)-?, tumor necrosis factor (TNF)-?, interleukin (IL)-10, IL-2, and transforming growth factor (TGF)-?1, and also perforin levels by pre-activated lymphocytes. Conclusions: EpCAM might be a novel cancer stem cell marker in RB. EpCAM�CD3 antibody redirecting T cells to attack RB tumor cells may prove effective in RB management. Further preclinical studies are needed to confirm the initial findings of our study. � 2012 Molecular Vision.