Gustavo Borjas

12-CK Score from RNA Sequencing

Study Representativeness Table

Purpose:Immune checkpoint blockade holds promise for treating bacillus Calmette-Guerin (BCG)-unresponsive non–muscle-invasive bladder cancer (NMIBC). In this phase II study, we investigated the safety and efficacy of durvalumab, a human IgG1 monoclonal antibody, against BCG-unresponsive carcinoma in situ (CIS).Patients and Methods:Patients with BCG-unresponsive CIS-containing NMIBC received durvalumab IV at 1,500 mg every 4 weeks for up to 12 months. The primary endpoint was complete response (CR) rate at month 6, defined by negative cystoscopy, urine cytology, and absence of high-grade recurrence on bladder mapping biopsy. The null hypothesis specified a CR rate of 18% and alternative hypothesis of 40%. According to the Simon two-stage design, if ≤3/13 patients achieved CR during stage 1, the trial is stopped due to futility.Results:Between March 8, 2017, and January 24, 2020, 17 patients were accrued whereas 4 withdrew from study treatment after bladder biopsy at month 3 was positive for CIS. Two of 17 (12%) achieved a CR at month 6, with duration of response of 10 and 18 months, respectively. A single grade 3 lipase elevation was attributed to durvalumab, and immune-related adverse events were observed in 7/17 (41%) patients. Only 1/17 patients had high programmed death-ligand 1 expression pretreatment. On RNA sequencing, complement activation genes were elevated posttreatment, along with enrichment of tumor-associated macrophage signature.Conclusions:Durvalumab monotherapy conferred minimal efficacy in treating BCG-unresponsive CIS of the bladder, with 6-month CR of 12%. Complement activation is a potential mechanism behind treatment resistance.

Study Representativeness Table

12-CK Score from RNA Sequencing

12-CK Score from RNA Sequencing

Purpose: Immune checkpoint blockade holds promise for treating BCG-unresponsive non-muscle invasive bladder cancer. In this phase II study, we investigated the safety and efficacy of durvalumab, a human IgG1 monoclonal antibody, against BCG-unresponsive CIS. Patients and Methods: Patients with BCG-unresponsive CIS containing non-muscle invasive bladder cancer received durvalumab IV at 1500 mg every 4 weeks for up to 12 months. The primary endpoint was complete response rate at month 6, defined by negative cystoscopy, urine cytology and absence of high-grade recurrence on bladder mapping biopsy. The null hypothesis specified a complete response rate of 18% and alternative hypothesis 40%. According to the Simon 2-stage design, if ≤3/13 patients achieved complete response during stage 1, the trial is stopped due to futility. Results: Between 03/8/2017 and 1/24/2020, 17 patients were accrued while 4 withdrew from study treatment after bladder biopsy at month 3 was positive for CIS. 2 of 17 (12%) achieved a complete response at month 6, with duration of response of 10 and 18 months, respectively. A single Grade 3 lipase elevation was attributed to durvalumab, and immune related adverse events were observed in 7/17 (41%) patients. Only 1/17 patients had high PD-L1 expression pre-treatment. On RNAseq, complement activation genes were elevated post-treatment, along with enrichment of tumor associated macrophage signature. Conclusions: Durvalumab monotherapy conferred minimal efficacy in treating BCG-unresponsive CIS of the bladder, with 6mo complete response of 12%. Complement activation is a potential mechanism behind treatment resistance.

Study Representativeness Table

Atherosclerosis is a chronic inflammatory disease associated with the accumulation of low-density lipoprotein (LDL) in arterial walls. Higher levels of the anti-inflammatory cytokine IL-10 in serum are correlated with reduced plaque burden. However, cytokine therapies have not translated well to the clinic, partially due to their rapid clearance and pleiotropic nature. Here, we engineered IL-10 to overcome these challenges by hitchhiking on LDL to atherosclerotic plaques. Specifically, we constructed fusion proteins in which one domain is IL-10 and the other is an antibody fragment (Fab) that binds to protein epitopes of LDL. In murine models of atherosclerosis, we show that systemically administered Fab-IL-10 constructs bind circulating LDL and traffic to atherosclerotic plaques. One such construct, 2D03-IL-10, significantly reduces aortic immune cell infiltration to levels comparable to healthy mice, whereas non-targeted IL-10 has no therapeutic effect. Mechanistically, we demonstrate that 2D03-IL-10 preferentially associates with foamy macrophages and reduces pro-inflammatory activation markers. This platform technology can be applied to a variety of therapeutics and shows promise as a potential targeted anti-inflammatory therapy in atherosclerosis.