Andrej Ozaniak

Bio: Andrej Ozaniak is an academic researcher from First Faculty of Medicine, Charles University in Prague. The author has contributed to research in topics: Medicine & Immunotherapy. The author has an hindex of 2, co-authored 4 publications receiving 6 citations.

The TRAIL in the Treatment of Human Cancer: An Update on Clinical Trials.

Abstract: TRAIL (tumor-necrosis factor related apoptosis-inducing ligand, CD253) and its death receptors TRAIL-R1 and TRAIL-R2 selectively trigger the apoptotic cell death in tumor cells. For that reason, TRAIL has been extensively studied as a target of cancer therapy. In spite of the promising preclinical observations, the TRAIL-based therapies in humans have certain limitations. The two main therapeutic approaches are based on either an administration of TRAIL-receptor (TRAIL-R) agonists or a recombinant TRAIL. These approaches, however, seem to elicit a limited therapeutic efficacy, and only a few drugs have entered the phase II clinical trials. To deliver TRAIL-based therapies with higher anti-tumor potential several novel TRAIL-derivates and modifications have been designed. These novel drugs are, however, mostly preclinical, and many problems continue to be unraveled. We have reviewed the current status of all TRAIL-based monotherapies and combination therapies that have reached phase II and phase III clinical trials in humans. We have also aimed to introduce all novel approaches of TRAIL utilization in cancer treatment and discussed the most promising drugs which are likely to enter clinical trials in humans. To date, different strategies were introduced in order to activate anti-tumor immune responses with the aim of achieving the highest efficacy and minimal toxicity.In this review, we discuss the most promising TRAIL-based clinical trials and their therapeutic strategies.

Novel Insights into the Immunotherapy of Soft Tissue Sarcomas: Do We Need a Change of Perspective?

Abstract: Soft tissue sarcomas (STSs) are rare mesenchymal tumors. With more than 80 histological subtypes of STSs, data regarding novel biomarkers of strong prognostic and therapeutic value are very limited. To date, the most important prognostic factor is the tumor grade, and approximately 50% of patients that are diagnosed with high-grade STSs die of metastatic disease within five years. Systemic chemotherapy represents the mainstay of metastatic STSs treatment for decades but induces response in only 15–35% of the patients, irrespective of the histological subtype. In the era of immunotherapy, deciphering the immune cell signatures within the STSs tumors may discriminate immunotherapy responders from non-responders and different immunotherapeutic approaches could be combined based on the predominant cell subpopulations infiltrating the STS tumors. Furthermore, understanding the immune diversity of the STS tumor microenvironment (TME) in different histological subtypes may provide a rationale for stratifying patients according to the TME immune parameters. In this review, we introduce the most important immune cell types infiltrating the STSs tumors and discuss different immunotherapies, as well as promising clinical trials, that would target these immune cells to enhance the antitumor immune responses and improve the prognosis of metastatic STSs patients.

The Immune Contexture of Liposarcoma and Its Clinical Implications

Abstract: Simple Summary Liposarcomas (LPS) are malignancies arising from adipose tissue. Based on the histological appearance, five subtypes are distinguished: well-differentiated LPS, dedifferentiated LPS (DDLPS), myxoid LPS (MLPS), pleomorphic LPS, and myxoid pleomorphic LPS. Immune cells can infiltrate the tumor microenvironment (TME) of LPS and can either promote an efficient antitumor immune response or mediate immunosuppression paving the way for immune evasion of the tumor. The LPS subtypes display different TME characteristics and vary in regard to immune cell infiltration, ranging from the generally lowly infiltrated MLPS to the highly infiltrated DDLPS where immunological determinants predict response to novel antibody-based immunotherapy. Thus, immune cells in the TME can significantly affect response to therapy, disease progression, and patient survival. This review aims to decipher the immune contexture of LPS as well as its clinical association and highlights differences between the LPS subtypes that may have implications for the design of novel treatment strategies. Abstract Liposarcomas (LPS) are the most frequent malignancies in the soft tissue sarcoma family and consist of five distinctive histological subtypes, termed well-differentiated LPS, dedifferentiated LPS (DDLPS), myxoid LPS (MLPS), pleomorphic LPS, and myxoid pleomorphic LPS. They display variations in genetic alterations, clinical behavior, and prognostic course. While accumulating evidence implicates a crucial role of the tumor immune contexture in shaping the response to anticancer treatments, the immunological landscape of LPS is highly variable across different subtypes. Thus, DDLPS is characterized by a higher abundance of infiltrating T cells, yet the opposite was reported for MLPS. Interestingly, a recent study indicated that the frequency of pre-existing T cells in soft tissue sarcomas has a predictive value for immune checkpoint inhibitor (CPI) therapy. Additionally, B cells and tertiary lymphoid structures were identified as potential biomarkers for the clinical outcome of LPS patients and response to CPI therapy. Furthermore, it was demonstrated that macrophages, predominantly of M2 polarization, are frequently associated with poor prognosis. An improved understanding of the complex LPS immune contexture enables the design and refinement of novel immunotherapeutic approaches. Here, we summarize recent studies focusing on the clinicopathological, genetic, and immunological determinants of LPS.

Solitary fibrous tumor

Abstract: Solitary fibrous tumor (SFT) is a rare tumor of mesenchymal origin that account for less than 2% of all soft tissue masses. Initially identified in the pleura, SFT has been identified in multiple anatomic locations and can arise anywhere in the body. The varying histologic features along with non-specific means of identification have led SFT to be associated with several different names. Over the last several decades, sustained advances through research and technology have led to more reliable methods for differentiating this distinct soft tissue tumor. Advances specifically in immunohistochemistry and molecular diagnostics have identified CD34 as the most consistent marker in SFT, however even this lacks specificity to conclusively narrow down the broad differential for exact identification. More recently the discovery of the NAB2-STAT6 fusion gene has led to more precise diagnosis of SFT. Like many other soft tissue tumors, surgical management is the mainstay of treatment for SFT with emphasis on obtaining tumor-negative margins. Radiation therapy and chemotherapy regimens have not demonstrated global effectiveness, and thus no standardized treatments have been identified. Given the rarity of SFT and current supportive evidence for therapies, management should be focused on tumor extirpation. Nonetheless, individualized therapy, determined within a multidisciplinary setting should be considered.

Harnessing TRAIL-Induced Apoptosis Pathway for Cancer Immunotherapy and Associated Challenges.

Abstract: The immune cytokine tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has attracted rapidly evolving attention as a cancer treatment modality because of its competence to selectively eliminate tumor cells without instigating toxicity in vivo. TRAIL has revealed encouraging promise in preclinical reports in animal models as a cancer treatment option; however, the foremost constraint of the TRAIL therapy is the advancement of TRAIL resistance through a myriad of mechanisms in tumor cells. Investigations have documented that improvement of the expression of anti-apoptotic proteins and survival or proliferation involved signaling pathways concurrently suppressing the expression of pro-apoptotic proteins along with down-regulation of expression of TRAILR1 and TRAILR2, also known as death receptor 4 and 5 (DR4/5) are reliable for tumor cells resistance to TRAIL. Therefore, it seems that the development of a therapeutic approach for overcoming TRAIL resistance is of paramount importance. Studies currently have shown that combined treatment with anti-tumor agents, ranging from synthetic agents to natural products, and TRAIL could result in induction of apoptosis in TRAIL-resistant cells. Also, human mesenchymal stem/stromal cells (MSCs) engineered to generate and deliver TRAIL can provide both targeted and continued delivery of this apoptosis-inducing cytokine. Similarly, nanoparticle (NPs)-based TRAIL delivery offers novel platforms to defeat barricades to TRAIL therapeutic delivery. In the current review, we will focus on underlying mechanisms contributed to inducing resistance to TRAIL in tumor cells, and also discuss recent findings concerning the therapeutic efficacy of combined treatment of TRAIL with other antitumor compounds, and also TRAIL-delivery using human MSCs and NPs to overcome tumor cells resistance to TRAIL.

Combating Cancer Stem-Like Cell-Derived Resistance to Anticancer Protein by Liposome-Mediated Acclimatization Strategy.

Abstract: Antibody-based therapeutics, which induce apoptosis of malignant cells by selectively binding to their receptors, hold tremendous promise for clinical cancer therapy. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has received considerable interest due to its favorable capability of activating apoptosis in cancer cells by interacting with death receptors (DRs). However, cancer stem-like cells (CSCs) show deficient or lower DR and are highly resistant to TRAIL-mediated apoptosis limiting the therapeutic efficacy. Here, we report a liposome-mediated acclimatization strategy to overcome the CSC-emanated TRAIL resistance. The liposomal assemblies coencapsulating plasmid DNA encoding TRAIL and salinomycin enable cancer cells as protein generators to express TRAIL, and more importantly, can acclimatize resistant CSCs to be sensitized to the TRAIL-triggered apoptosis by salinomycin-induced upregulation of DR expression on CSCs. This programmable liposome-based drug codelivery system shows the potential to efficiently eliminate CSCs and inhibit CSC-enriched tumor growth in the orthotopic colon tumor mouse model.