PDF file - 198K, Figure 1. Characterization of the anti-OX40 mAb (9B12). Figure 2. Total peripheral lymphocyte counts. Figure 3. Pharmacokinetics of CD134 (anti-OX40) mAb in patients. Figure 4. Direct ex vivo detection of the murine anti-OX40 mAb bound to T cells in treated patients. Figure 5. Regression of a pulmonary metastasis in a patient with renal carcinoma enrolled in cohort 1. Figure 6. Changes in Ki-67 expression within CD4+ and CD8+ T cell subsets examined over time after anti-OX40 from patients in cohorts 1 and 2. Figure 7. Increased proliferation of CD4+ Foxp3- T cells and CD8+ T cells correlates with a decrease or stabilization of tumor burden. Figure 8. Ki-67 expression by monkey CD4+ and CD8+ memory T cells after the administration of anti-OX40 , mouse Immunoglobulin or monkey OX40L:Ig. Figure 9. Determination of the Endpoint Titer for anti-KLH Ab.

PDF file - 68K, Details clinical trial, flow cytometry and monkey experiments referred to in the manuscript.

Background TGF-beta is an immunosuppressive cytokine that is upregulated in colorectal cancer. TGF-beta blockade improved response to chemoradiotherapy in preclinical models of colorectal adenocarcinoma. We aimed to test the hypothesis that adding the TGF-beta type I receptor kinase inhibitor galunisertib to neoadjuvant chemoradiotherapy would improve pathological complete response rates in patients with locally advanced rectal cancer. Methods This was an investigator-initiated, single-arm, phase 2 study done in two medical centres in Portland (OR, USA). Eligible patients had previously untreated, locally advanced, rectal adenocarcinoma, stage IIA-IIIC or IV as per the American Joint Committee on Cancer; Eastern Cooperative Oncology Group status 0-2; and were aged 18 years or older. Participants completed two 14-day courses of oral galunisertib 150 mg twice daily, before and during fluorouracil-based chemoradiotherapy (intravenous fluorouracil 225 mg/m(2) over 24 h daily 7 days per week during radiotherapy or oral capecitabine 825 mg/m(2) twice per day 5 days per week during radiotherapy; radiotherapy consisted of 50middot4-54middot0 Gy in 28-30 fractions). 5-9 weeks later, patients underwent response assessment. Patients with a complete response could opt for non-operative management and proceed to modified FOLFOX6 (intravenous leucovorin 400 mg/m(2) on day 1, intravenous fluorouracil 400 mg/m(2) on day 1 then 2400 mg/m(2) over 46 h, and intravenous oxaliplatin 85 mg/m(2) on day 1 delivered every 2 weeks for eight cycles) or CAPEOX (intravenous oxaliplatin 130 mg/m(2) on day 1 and oral capecitabine 1000 mg/m(2) twice daily for 14 days every 3 weeks for four cycles). Patients with less than complete response underwent surgical resection. The primary endpoint was complete response rate, which was a composite of pathological complete response in patients who proceeded to surgery, or clinical complete response maintained at 1 year after last therapy in patients with non-operative management. Safety was a coprimary endpoint. Both endpoints were assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02688712, and is active but not recruiting. Findings Between Oct 19, 2016, and Aug 31, 2020, 38 participants were enrolled. 25 (71%) of the 35 patients who completed chemoradiotherapy proceeded to total mesorectal excision surgery, five (20%) of whom had pathological complete responses. Ten (29%) patients had non-operative management, three (30%) of whom ultimately chose to have total mesorectal excision. Two (67%) of those three patients had pathological complete responses. Of the remaining seven patients in the non-operative management group, five (71%) had clinical complete responses at 1 year after their last modified FOLFOX6 infusion. In total, 12 (32% [one-sided 95% CI & GE;19%]) of 38 patients had a complete response. Common grade 3 adverse events during treatment included diarrhoea in six (16%) of 38 patients, and haematological toxicity in seven (18%) patients. Two (5%) patients had grade 4 adverse events, one related to chemoradiotherapy-induced diarrhoea and dehydration, and the other an intraoperative ischaemic event. No treatment-related deaths occurred. Interpretation The addition of galunisertib to neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer improved the complete response rate to 32%, was well tolerated, and warrants further assessment in randomised trials. Copyright (C) 2022 Published by Elsevier Ltd. All rights reserved.

AbstractOX40 is a potent costimulatory receptor that can potentiate T-cell receptor signaling on the surface of T lymphocytes, leading to their activation by a specifically recognized antigen. In particular, OX40 engagement by ligands present on dendritic cells dramatically increases the proliferation, effector function, and survival of T cells. Preclinical studies have shown that OX40 agonists increase antitumor immunity and improve tumor-free survival. In this study, we performed a phase I clinical trial using a mouse monoclonal antibody (mAb) that agonizes human OX40 signaling in patients with advanced cancer. Patients treated with one course of the anti-OX40 mAb showed an acceptable toxicity profile and regression of at least one metastatic lesion in 12 of 30 patients. Mechanistically, this treatment increased T and B cell responses to reporter antigen immunizations, led to preferential upregulation of OX40 on CD4+ FoxP3+ regulatory T cells in tumor-infiltrating lymphocytes, and increased the antitumor reactivity of T and B cells in patients with melanoma. Our findings clinically validate OX40 as a potent immune-stimulating target for treatment in patients with cancer, providing a generalizable tool to favorably influence the antitumor properties of circulating T cells, B cells, and intratumoral regulatory T cells. Cancer Res; 73(24); 7189–98. ©2013 AACR.

It is controversial whether high protein diets induce renal damage. We hypothesized that urinary microalbumin concentrations (a marker of renal damage) would not be significantly elevated in a group of protein‐seeking male resistance trainers (PRO, n=12) compared to non‐protein‐seeking counterparts (NPRO, n=10). The diets of male resistance trainers (healthy, ≥3 y of weight training) were analyzed using seven‐day food diaries. Compared to NPRO, PRO consumed a larger amount of absolute and relative protein for a self reported mean duration of nine years (250.2 ± 87 g/day [2.5 ± 0.8 g/kg] vs. 104.5 ± 23g/day [1.3 ± 0.3 g/kg]). Fasting urine samples were taken at 0800 h, while 12‐hour collections extended through 2000 h. Microalbumin values did not differ (p>0.05) and were normal in the fasting samples (PRO 9.7 ± 10 mg/L vs. NPRO 12.8 ± 18.1 mg/L) and in the 12H collection (PRO 6.2 ± 3.2 mg/L vs. NPRO 15.0 ± 19.6 mg/L). Per‐kg comparisons were also non‐significant. The groups did not differ in training intensity (perceived exertion) or volume (kcal expended weekly). Within the limitations of this design, we conclude that a long‐term ample protein diet did not result in renal damage. Supported by The University of Akron Research Office, Akron, OH.