Dose Escalation Study of Immunomodulatory Nanoparticles

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In the rapidly evolving treatment landscape of advanced solid tumors, immunotherapeutic approaches have revolutionized cancer care for patients. Despite these advances, there is an undiminished need for the development of novel immunotherapeutic treatment modalities that are able to orchestrate effe...

In the rapidly evolving treatment landscape of advanced solid tumors, immunotherapeutic approaches have revolutionized cancer care for patients. Despite these advances, there is an undiminished need for the development of novel immunotherapeutic treatment modalities that are able to orchestrate effective anti-tumor immune responses. The investigators study a new class of immunomodulatory nanomedicines: PLGA nanoparticles loaded with a tumor antigen and an iNKT cell agonist. PLGA is a biodegradable polymer with minimal (systemic) toxicity, approved by the Food and Drug Administration (FDA) as well as the European Medicines Agency (EMA) to be used in various drug-carrying platforms.Tumor antigens and immunomodulatory molecules can be co-encapsulated in PLGA-based nanoparticles. In preclinical studies, these PLGA-based nanoparticles can induce anti-tumor immune responses. The investigators aim to explore PLGA-based nanoparticles containing the tumor antigen NY-ESO-1 and the iNKT cell activator IMM60 for their capacity to induce anti-tumor responses in cancer patients. NY-ESO-1 is a cancer-testis antigen normally expressed in testicular germ cells and trophoblasts of the placenta. However, NY-ESO-1 is also expressed in a wide range of cancers with a high incidence (around 25-30% of several [advanced] cancers, such as melanoma [40%], lung [2-32%], bladder [32-35%], and ovarian [30%] cancer). NY-ESO-1 is able to elicit immune responses. Patients who have NY-ESO-1-positive tumors have spontaneous or vaccine-induced humoral and cellular immune responses against this antigen. Therefore, NY-ESO-1 is considered to be a suitable tumor antigen for further clinical evaluation. Clinical trials have already shown the safety and tolerability of the NY-ESO-1 protein and peptides in patients with advanced cancer. In order to generate NY-ESO-1-directed immune responses, the NY-ESO-1 protein is taken up by antigen-presenting cells (APCs) and processed in small protein fragments, peptides. Particular peptides can bind to patient-specific HLA molecules and, subsequently, this HLA-peptide complex is recognized at the cell membrane by the T cell receptor (TCR) of T cells. Once the TCR specifically binds to the HLA-peptide complex, the T cell becomes stimulated and exerts its function, i.e. tumor cell killing by CD8+ T cells. In 1, an overview of the peptides known to bind to certain HLA alleles and recognized by T cells, either by CD4+ or by CD8+ T cells, is presented. Particulate vaccines are known to elicit better immune responses due to higher uptake by APCs. Encapsulating antigens and adjuvants within the same polymeric nanoparticle can enhance T cell responses. In earlier studies, the NY-ESO-1 whole protein was encapsulated in adjuvant ISCOMATRIX and shown to induce specific T cell responses in a majority of patients. iNKT cell agonists are more suitable adjuvants due to their higher activity in low doses and activation of DCs by iNKT cells. In this respect, the investigators will employ PLGA nanoparticles loaded with the NY-ESO-1 antigen and the iNKT cell agonist IMM60 as a co-delivery system. To facilitate NY-ESO-1 antigen encapsulation, long (85-111(peptide #2) and 117-143(peptide #3)) and short (157-165(peptide #4)) peptides will be incorporated into nanoparticles. In combination, the three selected NY-ESO-1-derived peptides are presented in 80% of the class I and class II HLA alleles of the European population. Similar peptides (79-116 and 118-143) were previously loaded onto DCs together with ?-GalCer and delivered to cancer patients in a recent clinical trial. The results of that trial demonstrated iNKT cell expansion, CD4+ T cell responses against the 118-143 peptide in 7/8 patients, and CD8+ T cell responses against the 79-116 peptide in 3/8 patients (Gasser, Sharples et al. 2018). Here, an additional short peptide (157-165) is included, which is presented by the highly prevalent HLA-A2.1 molecule. Hence, higher CD8+ T cell responses against this epitope and superior activation of human iNKT cells by IMM60 are expected due to co-encapsulation.

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