Reprogramming myeloid cells and restoring T cell fitness in checkpoint inhibitor resistant melanoma patients.

[BACKGROUND] Immune checkpoint inhibitor (ICI) resistance remains a clinical hurdle in malignant melanoma (MM). Remodeling the tumor microenvironment (TME) have been proposed a revenue to overcome ICI resistance. The present study aimed to test the hypothesis that treatment with LOAd703, a TMZ-CD40L/4-1BBL-expressing gene engineering vector, reprograms the immune landscape in ICI refractory MM patients to restore ICI responsiveness.

[METHODS] LOKON003 a multi-center, single-armed phase I/II clinical trial recruited 24 patients with confirmed stage IV cutaneous MM (n = 23) and mucosal MM (n = 1) who had progressed on one, or several, treatments with anti-PD-1 inhibitors with or without supplementary anti-CTLA-4 inhibitor or experimental immunotherapy treatment. LOAd703 (1 × 10 or 5 × 10 viral particles) was administered by ultrasound guided intratumoral injections and atezolizumab was administered intravenously (1200 mg). Patients were treated every third week for a maximum of 12 LOAd703/anti-PD-L1 treatments cycles, possibly followed by up to seven single treatments with atezolizumab. Peripheral blood mononuclear cells (PBMCs), plasma, and tumor biopsies were collected before and at nine (PBMC, plasma, and tumor biopsies), 18 (plasma), and 27 (tumor biopsies) weeks post treatment onset. Tumor biopsies were examined for expression of 770 immune and oncology related genes by NanoString, PBMC samples were immunophenotyped by flow cytometry, and proteomic analysis of 172 immune and oncology markers were assessed by Olink.

[RESULTS] The results suggest that treatment with LOAd703 and atezolizumab renders a local and systemic immune signature in ICI resistant MM patients resembling what has previously been reported correlative with ICI response. This includes an increased TME expression of DC-associated biomarkers, an enhanced level of circulating CD40 DC-like cells, an increase in biomarkers associated with T cell infiltration and T cells in the TME, elevation of circulating CD8 T cells with an EM phenotype, and reduced circulating levels of CD4 T cells including Tregs.

[CONCLUSIONS] Collectively, the results propose that treatment with LOAd703 and atezolizumab induce an immune phenotype of ICI resistant patients that has previously been reported associative with ICI responsiveness. These results merits further clinical investigation of supplementary LOAd703 treatment to accomplish ICI sensitivity in ICI resistant MM.

[TRIAL REGISTRATION] Clinicaltrials.gov ID, NCT04123470. First posted 2019-10-11.