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Canine atopic dermatitis (cAD) is a common allergic skin condition among dogs that may respond to treatment with mesenchymal stromal cells (MSCs). The aim of this pilot study was to evaluate the safety and efficacy of allogeneic uterine tissue-derived MSCs (UMSCs) for the reduction and control of clinical signs associated with cAD. At two sites, seven client-owned dogs with cAD received two doses of approximately 3.6 x 107 UMSCs given intravenously over 30 min, on Day 0 and Day 14, with monthly clinical follow-up until Day 90 and optional owner phone interview on Day 180. Primary outcomes were pruritus and skin lesions. Pruritus was measured by the owner-assessed Pruritus Visual Analog Scale (PVAS), with treatment success defined as a 2-point reduction in PVAS score at any timepoint after treatment. Skin lesions were evaluated by two veterinarians according to the Canine Atopic Dermatitis Extent and Severity Index (CADESI-4). The secondary outcome was safety, which was evaluated via physical exam and hematology, including complete blood count (CBC), serum chemistry, and urinalysis (UA). Treatment was generally well tolerated and associated with a significant reduction in PVAS on Day 30 that was maintained through Day 180. On Day 60, five dogs (71%) achieved treatment success (at least 2-point reduction in PVAS), and three dogs (43%) had a PVAS improvement of 4-5 points. Mean CADESI-4 score was significantly improved on Day 14, Day 30, Day 60, and Day 90, with the lowest mean score observed on Day 60. Three dogs exhibited mild and transient adverse events. These findings suggest that IV-administered allogeneic UMSCs reduce and control clinical signs of cAD, with a durable benefit lasting 3–6 months.

Background Previous data suggests that anti-OX40 mAb can elicit anti-tumor effects in mice through deletion of Tregs. However, OX40 also has powerful costimulatory effects on T cells which could evoke therapeutic responses. Human trials with anti-OX40 antibodies have shown that these entities are well tolerated but to date have delivered disappointing clinical responses, indicating that the rules for the optimal use of anti-human OX40 (hOX40) antibodies is not yet fully understood. Changes to timing and dosages may lead to improved outcomes; however, here we focus on addressing the role of agonism versus depleting activity in determining therapeutic outcomes. We investigated a novel panel of anti-hOX40 mAb to understand how these reagents and mechanisms may be optimized for therapeutic benefit.Methods This study examines the binding activity and in vitro activity of a panel of anti-hOX40 antibodies. They were further evaluated in several in vivo models to address how isotype and epitope determine mechanism of action and efficacy of anti-hOX40 mAb.Results Binding analysis revealed the antibodies to be high affinity, with epitopes spanning all four cysteine-rich domains of the OX40 extracellular domain. In vivo analysis showed that their activities relate directly to two key properties: (1) isotype—with mIgG1 mAb evoking receptor agonism and CD8+ T-cell expansion and mIgG2a mAb evoking deletion of Treg and (2) epitope—with membrane-proximal mAb delivering more powerful agonism. Intriguingly, both isotypes acted therapeutically in tumor models by engaging these different mechanisms.Conclusion These findings highlight the significant impact of isotype and epitope on the modulation of anti-hOX40 mAb therapy, and indicate that CD8+ T-cell expansion or Treg depletion might be preferred according to the composition of different tumors. As many of the current clinical trials using OX40 antibodies are now using combination therapies, this understanding of how to manipulate therapeutic activity will be vital in directing new combinations that are more likely to improve efficacy and clinical outcomes.

Chronic inflammation contributes to tumor initiation in colitis-associated colorectal cancer (CRC). Indeed, inflammatory bowel disease (IBD) patients show an increased risk of developing CRC. Cancer immune evasion is a major issue in CRC and preclinical and clinical evidence has defined a critical role for myeloid-derived suppressor cells (MDSCs) that contribute to tumor growth and progression by suppressing T-cells and modulating innate immune responses. MDSCs comprise a heterogeneous population of immature myeloid cells that can be distinct in two subtypes: CD11b+Ly6G+Ly6Clow with granulocytic phenotype (G-MDSCs) and CD11b+Ly6G−Ly6Chigh with monocytic phenotype (M-MDSCs). Hydrogen sulfide (H2S) is an endogenous gaseous signaling molecule that regulates various physiological and pathophysiological functions. In particular, several studies support its anti-inflammatory activity in experimental colitis and ulcer. However, the role of the H2S pathway in innate immune-mediated IBD has not yet been elucidated. To better define a possible link between MDSCs and H2S pathway in colitis-associated CRC development, we used an innate immune-mediated IBD model induced by infection with the bacterium Helicobacter hepaticus (Hh), closely resembling human IBD. Here, we demonstrated an involvement of MDSCs in colitis development. A significant time-dependent increase of both G-MDSCs and M-MDSCs was observed in the colon and in the spleen of Hh-infected mice. Following, we observed that chronic oral administration of the H2S donor DATS reduced colon inflammation by limiting the recruitment of G-MDSCs in the colon of Hh-infected mice. Thus, we identify the metabolic pathway l-cysteine/H2S as a possible new player in the immunosuppressive mechanism responsible for the MDSCs-promoted colitis-associated cancer development.