BNIP3L Is a New Autophagy Related Prognostic Biomarker for Melanoma Patients Treated With AGI-101H

Abstract

Background/Aim: Skin melanoma belongs to the most invasive malignancies with no cure for a progressing disease. Personalized therapy would allow for the selection of patients that will benefit from treatment. For this purpose, proper predictive biomarkers must be defined. Materials and Methods: Allogeneic whole-cell gene-modified therapeutic melanoma vaccine (AGI-101H) was applied in advanced melanoma patients. Humoral responses were analyzed using SEREX, and in silico gene expression analysis in TCGA melanoma patients was performed. Results: A specific antibody response was raised against an antigen identified as BNIP3L, which correlated with a good prognosis. Moreover, AGI-101H directs an immune response against autophagy, as BNIP3L is a marker of this process. Medium and high expression of BNIP3L was also linked with longer overall survival. Conclusion: BNIP3L is a candidate prognostic marker of clinical outcome of melanoma patients treated with AGI-101H, and may be considered as a prediction marker for patient survival.Cutaneous melanoma is responsible for 75% of skin cancerrelated deaths, and its incidence has been steadily increasing worldwide (1). Metastatic melanoma is highly resistant to conventional therapies. However, novel systemic therapy approaches such as targeted therapy with BRAF and MEK inhibitors (2) or various immunotherapy approaches have been exploited. These therapies include the adoptive transfer of immune cells (3), cancer vaccines, peptides, DNA, and the use of immune checkpoint inhibitors (ICI) such as anti-CTLA-4 or programmed death factor 1 (PD-1) monoclonal antibodies (4). The latter ones significantly improved the prognosis of melanoma patients; however, as monotherapy, they still demonstrate some limitations. Accordingly, combinatorial strategies are given the most attention nowadays. They include the combination of different ICI, ICI with cancer vaccines, kinase inhibitors etc. (5). However, the predictive and prognostic biomarkers are still required (6, 7).The specific adaptive anti-cancer immune response comprises two phases-induction and effector. The induction phase can be activated and maintained by cancer vaccines. Moreover, in combined immunotherapy approaches, cancer vaccination generates tumor specific effector T cells. Since 1997, we have been investigating the therapeutic efficacy of whole cell melanoma vaccine (AGI-101H) in patients with advanced melanoma. AGI-101H (the first in its class) is an allogeneic tumor cell vaccine consisting of two human melanoma cell lines: Mich-1 and Mich-2, which were genetically modified to secrete designer cytokine Hyper-IL6 (H6), which serves as molecular adjuvant (8). H6 is a fusion protein of interleukin 6 (IL-6) and its soluble receptor (sIL-6R, gp80). It directly targets gp130, a signal-transducing subunit, and activates the JAK1/STAT3-P/Oct4 pathway both in the paracrine and autocrine manners. Exposure of vaccine cells to H6 led to the conversion of their phenotype into melanoma stem cell (MSC) -like with high ALDH1H1 3723This art...

Biological role and diagnostic utility of ribosomal protein L23a pseudogene 53 in cutaneous melanoma

“…The expression levels of transcripts were analyzed depending on the clinicopathological parameters, such as: sample type (primary vs. metastasis), cancer type (cutaneous melanoma vs. other), cancer localization (extremities vs. trunk vs. regional lymph node vs. head and neck vs. distant metastasis vs. cutaneous or subcutaneous tissue vs. other), gender (women vs. men), age (< 58 vs. > 58), ulceration (absent vs. present), Clark level (I vs. II vs. III-IV vs. V), Breslow depth (< 1 vs. 1-2 vs. 2.1-4 vs. > 4), mitotic rate (0-2 vs. 2-3 vs. > 4), cancer stage (0 vs. I + II vs. III + IV), M-stage (M0 vs. M1), T-stage (T0 vs. T1 + T2 vs. T3 + T4), similarly as described previously [28]. Next, from a group of 472 patients, highand low-expressing groups of RPL23AP53 were obtained using the quartile expression as a cutoff: low (< 25) and high (> 75).…”

“…The expression level was analyzed in the group of all patients, as the median of RPL23AP53 and separately depending on BRAF status, with mutation (MUT) and wild type (WT). Progression-free interval (PFI) and overall survival (OS) were assessed in these subgroups, similarly as described previously [28].…”

Cancer Vaccine Therapeutics: Limitations and Effectiveness—A Literature Review

“…Even more recently, Kwiatkowska-Borowczyk et al, (2018) revealed that immunization of patients resulted in the generation of cytotoxic CD8+ T cells specific for Aldehyde Dehydrogenase 1 Family Member A1 (ALDH1A1) along with the production of specific anti-ALDH1 antibodies [54]. Kazimierczak et al, (2020) discovered a new biological marker for monitoring melanoma immunotherapy, where there is a positive correlation between the production of antibodies to BNIP3L/NIX and the clinical outcome of melanoma patients treated with the AGI-101H vaccine [55]. Increased expression of BNIP3L is also positively correlated with patient overall survival (OS) in melanoma.…”

“…Increased expression of BNIP3L is also positively correlated with patient overall survival (OS) in melanoma. BNIP3L is induced by tumor suppressor p53 and, in response to hypoxic TME conditions, plays a crucial role in the clearance of damaged mitochondria with mitochondrial autophagy [55].…”