Cancer Immunotherapy and RNA Interference

Source: Cancer Immunotherapy and RNA Interference

Problems and a Potential Solution

An essential part of any tumor progression is in the development of immune resistance mechanisms, including immune-inhibitory pathways, also called immune checkpoints. Immune checkpoints play an important role in the interaction between tumor cells and cytotoxic T-lymphocytes. One way to mitigate immunosuppression is to block the immune checkpoints by specifically designed agents, such as antibodies.

The clinical and commercial success of monoclonal antibodies targeting specific checkpoints such as PD-1/PD-L1 and CTLA-4 have validated the checkpoint targeting approach, but it has proven challenging to use antibodies to target multiple checkpoints. In addition, checkpoint inhibition is required for the interaction between tumor cells and cytotoxic T-lymphocytes, therefore systemic administration of immune checkpoint antibodies, which can result in “off target” side effects, may not the best approach.

A common challenge encountered in immunotherapeutic approaches like CAR T-cell therapy has been finding a way to inhibit the immunosuppressive signals that are present in the immunosuppressive tumor microenvironment. Initial clinical studies of CAR T cells in solid tumors have shown limited success due to the nature of the tumor environment.

It has been determined that multiple immune checkpoints are responsible for immunosuppression.¹  Blocking the blockade of the (multiple) immune checkpoint signaling in the immune effector cells is therefore a promising avenue to improve the anti-tumor efficacy these cells.

Today, there is an RNAi technology that has demonstrated the silencing of multiple immunosuppressive targets in a single therapeutic entity for both intra- and extra-cellular targets. Self-delivering RNAi (sd-rxRNA) is a therapeutic technology platform that provides a method to downregulate the immune checkpoint targets by destroying targeted RNAs before they can be translated into the proteins out of which the checkpoints are constructed.

Moreover, sd-rxRNA compounds do not require a delivery mechanism or delivery technique. Instead, the molecules are designed to be taken up by the cells without any other means, demonstrating near 100-percent efficiency and with no negative effects on the cells involved.²  For virtually any target, sd-rxRNA can be created with high knockdown efficiency, and the most active compounds can be validated within several months and selected for subsequent preclinical and clinical development.³

Published at Tue, 29 May 2018 19:30:17 +0000