New Jersey Patent of the Month – June 2023
Dendritic cell (DC) therapies have emerged as a promising avenue in cancer treatment, offering personalized and tailored approaches for patients. Over the past decade, the adoptive transfer of autologous ex vivo cultured hematopoietic progenitor cells or monocyte-derived DCs has shown encouraging results as cancer vaccines. These vaccines have been found to induce expansion of tumor-specific CD4+ and CD8+ T cells, leading to objective clinical responses and long-lasting remissions in some patients. Furthermore, preclinical studies using animal models have demonstrated the preventive and therapeutic benefits of DC-based cellular therapies loaded with tumor antigens. However, there remain challenges to overcome in order to optimize the efficacy of these therapies.
PDS Biotechnology Corporation, a notable inventor in the field, has made significant contributions to the exploitation of the antigen-presenting properties of DCs for the development of effective cancer immunotherapies. Clinical trials using their cellular product, sipuleucel-T (Provenge®), have shown prolonged median survival in metastatic prostate cancer patients. This product, approved by the US FDA, paved the way for the next generation of cellular immunotherapy products. Other studies involving activated DCs loaded with tumor-antigen peptides have demonstrated antigen-specific T cell responses in metastatic melanoma patients. Despite these promising developments, clinical responses have often been disappointing, with objective anti-tumor response rates rarely exceeding 15%.
One crucial aspect to address is the selection of tumor antigens for loading DCs. While non-mutated self-antigens have been preferred for generating broadly applicable therapies, they can deplete the population of high-avidity clones through negative selection. In contrast, using mutated antigens derived from RNA sequencing technologies allows for tailoring the therapy to the specific patient.
Another challenge lies in the effective presentation of antigens to DCs, particularly via the MHC class I pathway for CD8+ T cell activation. Current approaches have been suboptimal, limiting the potency and robustness of T cell responses. However, recent research has shown that cationic lipids can enhance antigen uptake and processing by DCs, leading to improved cross-presentation on MHC class I. These lipids facilitate rapid binding to DCs, uptake into early endosomes, and subsequent destabilization of endosomes for content delivery into the cytoplasm, enhancing class I processing. Furthermore, cationic lipids provide immunological danger signals, inducing the production of cytokines and chemokines that activate T cells and promote migration to lymph nodes.
In addition to overcoming antigen presentation challenges, the inhibitory microenvironment within tumors poses another hurdle. Clinical trials have been performed in the adjuvant setting to minimize immune suppression and maximize anti-tumor responses. Early-stage immunization aims to capitalize on a fully competent immune system capable of developing robust responses and minimize T cell inactivation within immune-suppressive tumor environments.
PDS Biotechnology’s innovative approach focuses on the development of non-DNA/RNA-based dendritic cell vaccines, utilizing cationic lipids to enhance antigen uptake and processing while limiting toxicity towards DCs. By activating DCs with lipids and tumor antigens ex vivo, they have demonstrated the ability to alter the tumor microenvironment, increasing tumor-specific CD8+ T cells while reducing the suppressive Treg cell population. This leads to a significantly reduced Treg to CD8+ T cell ratio and potentially improved therapeutic outcomes. By addressing challenges in antigen selection, antigen presentation, and overcoming immune suppression within tumors, these innovative approaches have the
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