Targeting CXCR1/2 Does Not Improve Insulin Secretion After Pancreatic Islet Transplantation: A Phase 3, Double-Blind, Randomized, Placebo-Controlled Trial in Type 1 Diabetes

Maffi, Paola; Lundgren, Torbjörn; Tufveson, Gunnar; Rafael, Ehab; Shaw, James; Liew, Aaron; Saudek, František; Witkowski, Piotr; Gołąb, Karolina; Bertuzzi, Federico; Gustafsson, Bengt; Daffonchio, L.; Ruffini, Pier Adelchi; Piemonti, Lorenzo

doi:10.2337/dc19-1480

Cited by 45 publications

(42 citation statements)

References 34 publications

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“…IAK was associated with better glucose control and a slower decrease in eGFR than standard insulin therapy in patients with type 1 diabetes and a functioning kidney transplant (Maanaoui et al, 2020). In this first doubleblind randomized trial, the islet transplant evidence obtained with reparixin does not support the role of CXCR1/2 inhibition in preventing inflammationmediated damage to the islet (Maffi et al, 2020).…”

Section: Islet Transplantationmentioning

confidence: 85%

The Role of Gene Therapy in the Treatments of Type 1 Diabetes Mellitus: a review

Smail

2020

BIOMEDNATPROCH

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The main aims of this review were to understand the roles of gene therapy in the treatment and prevention of type 1 diabetes mellitus and I will discuss a brief history, approaches, vector types with the future of diabetes following clinical use. Type 1 diabetes mellitus is a metabolic condition that is identified by insufficient insulin development due to pancreatic damage to beta cells. Control, long life, and diagnosis of these metabolic disorders have become vital sources for many scientists and researchers. After 2000, the latest approaches to molecular medicine were introduced as one of the possible therapeutic options for diabetes type 1 diagnosis. Many genes have been reported as a clinical trial so that damaged genes can be treated and three main approaches shown about 50 years ago are islet transplantation, β cell regeneration, and insulin gene therapy to cure and prevent diabetes type. Treating diabetes through gene therapy can promise children and adolescents, but more clinical applications are needed to recognize it as a permanent route.

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Section: Islet Transplantationmentioning

confidence: 85%

The Role of Gene Therapy in the Treatments of Type 1 Diabetes Mellitus: a review

Smail

2020

BIOMEDNATPROCH

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“…Islet engraftment and function was assessed on day 75 ± 5 after islet infusion using the mixed meal tolerance test (MMTT) 8 . Patients were followed for 1 year after the last islet infusion 5 .…”

Section: Methodsmentioning

confidence: 99%

“…Reparixin is a potent CXCR1/2 inhibitor and thus it was hypothesized that it could limit IBMIR and improve islet engraftment. Despite success in preclinical and single center clinical studies 3 – 5 , a recent phase 3 multicenter trial did not confirm this beneficial effect of Reparixin. However, the trial was performed without the standardization of donor selection, islet processing, and immunosuppression regimens among the participating centers 5 .…”

Section: Introductionmentioning

confidence: 99%

Post-Hoc Analysis of a Randomized, Double Blind, Prospective Study at the University of Chicago: Additional Standardizations of Trial Protocol are Needed to Evaluate the Effect of a CXCR1/2 Inhibitor in Islet Allotransplantation

et al. 2021

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A recent randomized, multicenter trial did not show benefit of a CXCR1/2 receptor inhibitor (Reparixin) when analysis included marginal islet mass (>3,000 IEQ/kg) for allotransplantation and when immunosuppression regimens were not standardized among participating centers. We present a post-hoc analysis of trial patients from our center at the University of Chicago who received an islet mass of over 5,000 IEQ/kg and a standardized immunosuppression regimen of anti-thymocyte globulin (ATG) for induction. Twelve islet allotransplantation (ITx) recipients were randomized (2:1) to receive Reparixin ( N = 8) or placebo ( N = 4) in accordance with the multicenter trial protocol. Pancreas and donor characteristics did not differ between Reparixin and placebo groups. Five (62.5%) patients who received Reparixin, compared to none in the placebo group, achieved insulin independence after only one islet infusion and remained insulin-free for over 2 years ( P = 0.08). Following the first ITx with ATG induction, distinct cytokine, chemokine, and miR-375 release profiles were observed for both the Reparixin and placebo groups. After excluding procedures with complications, islet engraftment on post-operative day 75 after a single transplant was higher in the Reparixin group ( n = 7) than in the placebo ( n = 3) group ( P = 0.03) when islet graft function was measured by the ratio of the area under the curve (AUC) for c-peptide to glucose in mixed meal tolerance test (MMTT). Additionally, the rate of engraftment was higher when determined via BETA-2 score instead of MMTT ( P = 0.01). Our analysis suggests that Reparixin may have improved outcomes compared to placebo when sufficient islet mass is transplanted and when standardized immunosuppression with ATG is used for induction. However, further studies are warranted. Investigation of Reparixin and other novel agents under more standardized and optimized conditions would help exclude confounding factors and allow for a more definitive evaluation of their role in improving outcomes in islet transplantation. Clinical trial reg. no. NCT01817959, clinicaltrials.gov

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“…This treatment opportunity should be tested in patients with COVID‐19 at the time of hospital admission to halt or decrease progression of respiratory insufficiency and prevent the need for intensive care support 20 . Considering other treatments under evaluation to avoid IBMIR in islet transplantation (although not yet commercially available) the chemokine receptor 2 (CXCR2) inhibitor reparixin appears of interest 21,22 . In fact, numerous studies have confirmed a key role of CXCR1/CXCR2 receptor as potential therapeutic target in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) 23,24 .…”

Section: Microvascular Covid‐19 Lung Vessels Obstructive Thrombo‐inflmentioning

confidence: 99%

COVID-19 and islet transplantation: Different twins

Piemonti

Landoni

2020

American Journal of Transplantation

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Abbreviations: ALI, acute lung injury; ARDS, acute respiratory distress syndrome; BAL, bronchoalveolar lavage; CRP, C-reactive protein; IBMIR, instant blood mediated inflammatory reaction; LDH, lactate dehydrogenase; microCLOTS, microvascular COVID-19 lung vessels obstructive thrombo-inflammatory syndrome; NHP, non human primate; PaO 2 /FiO 2 , ratio of arterial partial pressure of oxygen/fraction of inspired oxygen; XDP, serum crosslinked fibrin.For those who work in the field of islet transplantation, the microvascular coronavirus disease 2019 (COVID-19) lung vessels obstructive thrombo-inflammatory syndrome (recently referred to as MicroCLOTS) is familiar, as one cannot fail to recognize the presence of similarities with the instant blood mediated inflammatory reaction (IBMIR) occurring in the liver hours and days after islet infusion. Evidence in both MicroCLOTS and IBMIR suggests the involvement of the coagulation cascade and complement system activation and proinflammatory chemokines/cytokines release. Identification and targeting of pathway(s) playing a role as "master regulator(s)" in the post-islet transplant detrimental inflammatory events could be potentially useful to suggest innovative COVID-19 treatments and vice versa. Scientific organizations across the world are fighting the COVID-19 pandemic. Islet transplantation, and more generally the transplantation scientific community, could contribute by suggesting strategies for innovative approaches. At the same time, in the near future, clinical trials in COVID-19 patients will produce an enormous quantity of clinical and translational data on the control of inflammation and complement/microthrombosis activation. These data will represent a legacy to be transformed into innovation in the transplant field. It will be our contribution to change a dramatic event into advancement for the transplant field and ultimately for our patients. K E Y W O R D S clinical decision-making, clinical trial design, cytokines/cytokine receptors, editorial/personal viewpoint, immune regulation, infection and infectious agents -viral, infectious disease, islet transplantation S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section.

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Targeting CXCR1/2 Does Not Improve Insulin Secretion After Pancreatic Islet Transplantation: A Phase 3, Double-Blind, Randomized, Placebo-Controlled Trial in Type 1 Diabetes

Cited by 45 publications

References 34 publications

The Role of Gene Therapy in the Treatments of Type 1 Diabetes Mellitus: a review

The Role of Gene Therapy in the Treatments of Type 1 Diabetes Mellitus: a review

Post-Hoc Analysis of a Randomized, Double Blind, Prospective Study at the University of Chicago: Additional Standardizations of Trial Protocol are Needed to Evaluate the Effect of a CXCR1/2 Inhibitor in Islet Allotransplantation

COVID-19 and islet transplantation: Different twins

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