Checkpoint blockade meets gene therapy: Opportunities to improve response and reduce toxicity

Immune checkpoint inhibitors (ICIs) based on monoclonal antibodies represent a breakthrough for the treatment of cancer. However, their efficacy varies among tumor types and patients, and they can lead to adverse effects due to on-target/off-tumor activity, since they are administered systemically at high doses. An alternative and attractive approach for the delivery of ICIs is the use of gene therapy vectors able to express them in vivo. This review focuses on the most recent studies using viral vectors able to express ICIs locally or systemically in preclinical models of cancer. These vectors include non-replicating viruses, oncolytic viruses able to propagate specifically in tumor cells and destroy them, and self-amplifying RNA vectors, armed with different formats of antibodies against immune checkpoints. Non-replicating vectors usually lead to long-term ICI expression, potentially eliminating the need for repeated administration. Vectors with replication capacity, although they have a shorter window of expression, can induce inflammation which enhances the antitumor effect. Finally, these engineered vectors can be used in combination with other immunostimulatory molecules or with CAR-T cells, further boosting the antitumor immune responses.