Fighting cancer with immunomodulatory nanobodies and interleukin-12 delivered with DNA and RNA vectors

Resum

Immunotherapy has revolutionized the treatment of cancer. However, many patients fail to respond to these therapies, and others develop adverse events that can be life-threatening. The use of systemic administration of immunomodulatory molecules, such as cytokines and immune checkpoint inhibitors, can increase the risk of toxicity and decrease the antitumor efficacy of these therapies. Local delivery could solve these limitations and generate a more potent and safe therapy. In this thesis, we have developed new nanobodies (single-domain antibodies derived from llama) against programmed death 1 (PD-1) and its main ligand PD-L1, an important regulatory pathway that is involved in tumor immune escape. We have tested their antitumor potential by delivering them using a self-amplifying RNA non-propagating viral vector based on Semliki Forest Virus (SFV). Since the SFV system could also be used as a non-viral vector taking advantage of the self-amplifying capacity of the RNA, we tested this possibility by optimizing the conditions for local delivery of RNA using in vivo electroporation, and validated the therapeutic potential of this approach using interleukin-12 as the therapeutic agent.