Promoting healing of skin and mucosa by immunomodulation using CXCL12 producing lactic acid bacteria : From bench to bedside

Sammanfattning: Immunotherapies direct the immune system to respond in a certain way, such as to fight cancer or to dampen inflammation. In this thesis, a new immunotherapy, ILP100, is developed using a technology that allows for local production of short-lived immunoregulatory proteins that previously have been undruggable. Hence, we utilize Limosilactobacillus reuteri R2LC as a vector for local production and delivery of the chemokine CXCL12 to skin and mucosa. CXCL12 is a short-lived multifunctional chemokine that are involved in many processes including cell trafficking and wound healing. Preclinical studies in mice and minipigs where CXCL12-producing Limosilactobacillus reuteri R2LC (R2LC_CXCL12) or the formulated product (ILP100 Topical) were topically applied to full-thickness wounds demonstrated accelerated healing and a favourable safety profile. Following this, ILP100 Topical was investigated in a first-in-class randomised, double-blinded, placebo-controlled clinical trial were full-thickness wounds were induced on the upper arms of healthy volunteers and treated with ILP100 Topical. In this study, the average time to heal were reduced by 6 days, and by 10 days for wounds treated with highest dose of ILP100 Topical. The treatment was demonstrated to be safe and well tolerated with no systemic exposure of CXCL12 or bacterial translocation. Further, R2LC_CXCL12 was investigated preclinically as a treatment for colitis. Colitis affects millions of people worldwide, and the prevalence is increasing. In mice, peroral administration of R2LC_CXCL12 during overt DSS-induced colitis ameliorated disease activity already two days following start of treatment. Bench-marking experiments revealed that R2LC_CXCL12 exhibited superior effects when compared to established colitis treatments. Immune checkpoint inhibitors (ICIs) are revolutionizing oncology as they efficiently induce remission of several cancers, but these therapies are limited by serious immune-related adverse events, including colitis. Here, R2LC_CXCL12 was demonstrated to ameliorate ICI-colitis, where mice received a combination of DSS and ICIs (anti-PD1 and anti-CTLA-4). Further, peroral R2LC_CXCL12 treatment was well tolerated with no systemic exposure of CXCL12 or engraftment within the intestinal microbiota in mice or rabbit. In conclusion, R2LC_CXCL12 efficiently accelerates healing of skin wounds and ameliorates colitis symptoms, as well as has a favourable safety profile. Altogether, continued clinical development of ILP100 is strongly supported.