Genetically modified mesenchymal stem cells for cancer immunotherapy

Mesenchymal Stromal Stem Cells (MSC) are increasingly recognized for their potential in tumor-targeted gene delivery of diverse anti-cancer payloads. This potential arises not from their inherent regenerative capacities but from their suitability for ex vivo manipulation, low immunogenicity, scalability and certain degree of intrinsic tumor-homing abilities. Engineered MSCs have been tailored to express various anti-cancer agents, including interleukins, interferons, tumor-killing proteins like TRAIL and oncolytic viruses. They have exhibited promising efficacy in preclinical studies and are starting to pave their way in clinical trials. The evolving landscape of oncological therapy, underscored by advancements in understanding immune surveillance and the tumor microenvironment, has invigorated interest in combinatorial approaches. Herein, MSC-based gene therapy offers a pivotal advancement by enabling localized, targeted delivery of effector molecules, thereby enhancing selectivity and mitigating systemic toxicity. However, existing research predominantly focuses on individual modifications targeting specific immune pathways, consequently overlooking the potential of a comprehensive approach.

Addressing this gap, we propose a multidimensional genetic modification strategy of MSCs, aiming to harness the full spectrum of immune effector pathways. By integrating target identification, direct cytotoxicity, and paracrine immunostimulation, our approach seeks to augment anti-cancer efficacy through synergistic interactions and modulation of the tumor microenvironment. Importantly, enhancing tumor homing and retention via target identification represents a novel avenue in context of MSC with significant therapeutic potential.

Moreover, while viral vectors have been predominantly employed for genetic modification of MSC, concerns regarding safety and production limitations prompt exploration of non-viral alternatives. Our proposed research aims to focus on electroporation techniques and vector optimization, to generate a cost-effective and safer platform with desirable effectiveness. The primary objective of the proposed project is to establish a platform for design, validation, manufacture and preclinical evaluation of next-generation MSC-based gene therapy products for oncological applications. We aim to encompass the three major pathways of immunotherapeutic efficacy, namely 1) target identification, 2) direct cytotoxicity, and 3) paracrine immunostimulation. Our study therefore aims to maximize anti-cancer efficacy and customization for specific tumor types. Ultimately, we want to apply the results of this study for future scale-up of GMP-compliant manufacturing of MSC-based gene therapy for implementation of early phase clinical trials at our centers.