Background: The incidence of esophageal adenocarcinoma (EAC) is rapidly rising and has a 5-year survival rate of <20%. Beyond TNM (tumorenodeemetastasis) staging, no reliable risk stratification tools exist and no large-scale studies have profiled circulating tumor DNA (ctDNA) at relapse in EAC. Here we analyze the prognostic potential of ctDNA dynamics in EAC, taking into account clonal hematopoiesis with indeterminate potential (CHIP). Patients and methods: A total of 245 samples from 97 patients treated with neoadjuvant chemotherapy and surgery were identified from the prospective national UK Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) consortium data set. A pan-cancer ctDNA panel comprising 77 genes was used. Plasma and peripheral blood cell samples were sequenced to a mean depth of 7082Â (range 2196-28 524) and ctDNA results correlated with survival. Results: Characteristics of the 97 patients identified were as follows: 83/97 (86%) male, median age 68 years (SD 9.5 years), 100% cT3/T4, 75% cNþ. EAC-specific drivers had higher variant allele fractions than passenger mutations. Using stringent quality criteria 16/79 (20%) were ctDNA positive following resection; recurrence was observed in 12/16 (75%) of these. As much as 78/97 (80%) had CHIP analyses that enabled filtering for CHIP variants, which were found in 18/78 (23%) of cases. When CHIP was excluded, 10/63 (16%) patients were ctDNA positive and 9/10 of these (90%) recurred. With correction for CHIP, median cancer-specific survival for ctDNA-positive patients was 10.0 months versus 29.9 months for ctDNA-negative patients (hazard ratio 5.55, 95% confidence interval 2.42-12.71; P ¼ 0.0003). Similar outcomes were observed for disease-free survival. Conclusions: We demonstrate in a large, national, prospectively collected data set that ctDNA in plasma following surgery for EAC is prognostic for relapse. Inclusion of peripheral blood cell samples can reduce or eliminate false positives from CHIP. In future, post-operative ctDNA could be used to risk stratify patients into high-and low-risk groups for intensification or de-escalation of adjuvant chemotherapy.
Background: 4-1BB, also called TNF receptor super family member 9 or CD137, is mainly expressed on the surface of activated T, NK, and mononuclear cells. 4-1BB is activated by its ligand 4-1BBL or an activating 4-1BB monoclonal antibody, and stimulates T cell activation, proliferation and cytokine production. This co-stimulatory signal can also multiply antigen presenting cells and result in enhanced cell factor secretion. Experiments show that 4-1BB co-stimulation regulates T cell and antigen presenting cell function for antitumor immunity, providing new targets for tumor immunological therapies. Methods: Here, we developed a cohort of 4-1BB specific antibodies using the classic hybridoma technology. Then, we utilized humanized 4-1BB mice (B-h-4-1BB) and implanted syngeneic tumors subcutaneously, followed by treating mice with purified testing antibodies. Via this approach, we are able to discern several clones that effectively inhibited tumor growth without prior knowledge of their in vitro activities. These clones were further selected for humanization. The cohort of recombinant humanized 4-1BB antibodies were screened in B-h4-1BB mice. Results: A cohort of 4-1BB specific antibodies were successfully generated and purified. These purified antibodies were screened by their efficacy to stimulate anti-tumor activity in live animals using Biocytogen's humanized mouse platform. Top clones were humanized and screened by using B-h4-1BB mice. Both the Fv and Fc portion of the lead antibody were optimized using the B-h4-1BB mice, leading to the humanized form of the antibodies. Conclusions: We adopted an in vivo screen approach to discover candidates of 4-1BB specific antibodies that have potent anti-tumor activity. We discovered the leads with the most potent anti-tumor activity.Legal entity responsible for the study: Biocytogen Boston Corp.
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