Anti-tumor efficacy of a combination therapy with PD-L1 targeted alpha therapy and adoptive cell transfer of PD-1 deficient melanoma-specific human T-lymphocytes.

The optimization of adoptive transfer approaches of anti-tumor T cells requires both the functional improvement of the injected T cells and the modulation of the tumor microenvironment, favoring the recruitment of these T cells and their activation. We have recently shown the therapeutic benefit of two approaches tested individually in a melanoma model wich were on one hand the adoptive transfer of specific T cells deficient for the expression of the inhibitory receptor PD-1, and on the other hand PD-L1 targeted alpha therapy (TAT). In this study, we sought to investigate the efficacy of these two therapies combined, compared to each monotherapy, in order to evaluate the synergy between these two approaches, in the same melanoma model. Here we used melanoma-specific T-cell clones, previously validated for the edition of PDCD1 gene and with previously demonstrated superior anti-tumor activity than their wild-type counterparts, after adoptive transfer in NSG mice engrafted with PD-L1 expressing human melanoma tumors. We also used a previously validated TAT approach, using a 213Bi-anti-human-PD-L1 mAb, alone or in combination with adoptive cell transfer, in the same mouse model. We confirmed previous results obtained with each monotherapy and documented the safety and the superior ability of a combination between the adoptive transfer of PD-1 deficient T cells and TAT targeting PD-L1 to control the growth of melanoma tumors in NSG mice. This study provides the first proof-of-concept of the efficacy of a combination therapy using TAT, adoptive cell transfer and genomic editing of IC-coding genes.

Mycolactone toxin induces an inflammatory response by targeting the IL-1ß pathway: Mechanistic insight into Buruli ulcer pathophysiology.

Mycolactone, a lipid-like toxin, is the major virulence factor of Mycobacterium ulcerans, the etiological agent of Buruli ulcer. Its involvement in lesion development has been widely described in early stages of the disease, through its cytotoxic and immunosuppressive activities, but less is known about later stages. Here, we revisit the role of mycolactone in disease outcome and provide the first demonstration of the pro-inflammatory potential of this toxin. We found that the mycolactone-containing mycobacterial extracellular vesicles produced by M. ulcerans induced the production of IL-1ß, a potent pro-inflammatory cytokine, in a TLR2-dependent manner, targeting NLRP3/1 inflammasomes. We show our data to be relevant in a physiological context. The in vivo injection of these mycolactone-containing vesicles induced a strong local inflammatory response and tissue damage, which were prevented by corticosteroids. Finally, several soluble pro-inflammatory factors, including IL-1ß, were detected in infected tissues from mice and Buruli ulcer patients. Our results revisit Buruli ulcer pathophysiology by providing new insight, thus paving the way for the development of new therapeutic strategies taking the pro-inflammatory potential of mycolactone into account.

[Anterior fibrovascular proliferation. A rare complication of vitrectomy for proliferative diabetic retinopathy]. / La prolifération fibro-vasculaire antérieure. Une complication rare de la vitrectomie pour rétinopathie diabétique proliférante.

PURPOSE: To present clinical and therapeutic features of anterior fibrovascular proliferation, a severe complication of vitrectomy for diabetic retinopathy. METHODS: Among 153 vitrectomies for complication of diabetic proliferative vitreo-retinopathy, six cases of anterior fibro-vascular proliferation were found. All presented initially with a tractional retinal detachment associated in some cases with a vitreous hemorrhage. The complication occurred after a mean follow-up of three months after initial vitrectomy, marked by intravitreal bleeding, rubeosis iridis and hypotony. A reoperation with peeling of proliferation, lensectomy, extensive panretinal photocoagulation, encircling band and silicone oil injection allowed reattachment of the anterior retina in all the six cases. RESULTS: A reproliferation occurred in five cases, requiring revision of dissection. Finally, silicone oil was removed in three cases, was definitively left in one eye and was not removed in two eyes. Final visual acuities range from 1/50 to 2/10. CONCLUSION: Anterior fibrovascular proliferation is an unfrequent complication after vitrectomy for diabetic retinopathy. The prognosis is poor, in spite of aggressive vitreoretinal surgery including repeated dissection and extensive photocoagulation.

[Cystic dystrophy of the excretory-urinary mucosa. Apropos of a case of caliceal localization]. / La dystrophie kystique de la muqueuse excréto-urinaire. A propos d'un cas de localisation calicielle.

Cystic dystrophy of the excretory-urinary mucosa is a rare condition causing chronic suffering of the urinary system, which sometimes leads to an alteration of the renal function. The diagnostic problems can be solved with endoscopic urological examinations, and the treatment must be conservative if this is possible.