Geert Cauwenbergh Dr.Med.Sc. President and CEO RXi Pharmaceuticals

Approach Seems to Present a Promising Matchup

Cancer immunotherapy has made significant strides in recent years, especially in the development of treatments for solid tumors. Of the several approaches to immunotherapy, two are particularly promising and advanced in the clinic: immune checkpoint inhibition and immune cell-based therapies.

One emerging immune cell-based therapy method focuses on adoptive cell transfer (ACT), where immune cells, such as T lymphocytes, are isolated and then expanded and processed to express tumor-binding receptors to destroy cancer cells. These immune cells can be harvested from patients, such as tumor infiltrating lymphocytes (TILs) and natural killer (NK) cells, or genetically engineered like chimeric antigen receptors (CAR T) and T-cell receptors (TCR).

R&D initiatives are underway for new cancer immunotherapies to combine the ACT method with immune checkpoint inhibition by harnessing the power of RNA interference (RNAi) aiming to weaponize therapeutic immune effector cells to attack cancer.

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

Utilizing a New Immunotherapy Approach

The use of ACT involves the ex vivo processing of immune cells during which sd-rxRNA therapeutic compounds can be used to eliminate the expression of immunosuppressive receptors or proteins from the therapeutic immune cells, making them less sensitive to tumor resistance mechanisms and thus improving their ability to destroy tumor cells.

This sd-rxRNA approach of treating immune cells ex vivo before reinfusion to a patient provides key advantages over systemic use of combinations of antibody immunotherapeutic treatments. These combination antibody therapies can lead to the breaking of immune self-tolerance, inflammatory events in multiple organ systems and other side effects. Furthermore, there are only a few approved checkpoint inhibitors whereas there are many different immune checkpoints in different types of cancer. So instead of using systemic treatment with antibody combinations, ex-vivo reprogramming of immune cells used in ACT, which can easily be done with sd-rxRNA for multiple checkpoints, is a more promising approach.

The use of sd-rxRNA with the adoptive transfer of cells, in which one or multiple immune checkpoints have been silenced by using a proprietary RNAi technique, potentially combines the advantages of the two most promising approaches to immunotherapy, while reducing the inherent side effects related to other treatment options.

Where Do We Go Next?

sd-rxRNA compounds are currently being developed to target PD-1, TIGIT,and other receptors in solid tumors. There is a potential for the sd-rxRNA approach to enter the clinic within the next 12 to 18 months aiming to be a key player in a large market with significant unmet needs. Based on projections, cancer deaths will continue to rise from an estimated 9 million people dying from cancer in 2015, to an estimated 11.4 million people dying in 2030.4  The goal is to provide patients battling terminal cancers with a powerful new treatment option that goes beyond current treatment modalities.

The encouraging work done to date in ACT has stimulated a newfound awareness among oncologists of the potential antitumor activity of a patient’s endogenous immune system once the “brakes” elicited by the immune system have been released. The rapid progress in cancer immunotherapy, coupled with a growing understanding of the potential of emerging therapies such as sd-rxRNA in this area of medicine, may result in improved treatment for a variety of cancers in the not-too-distant future.

Geert Cauwenbergh, Dr.Med.Sc. ([email protected]), is president and CEO of RXi Pharmaceuticals, a biotechnology company developing immuno-oncology therapeutics based on its self-delivering RNAi (sd-rxRNA®) therapeutic platform.

1 Paradoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2016; 12(4):252-264
2 Van Zuidam J. Delving into RXi’s delivery platform. Drug Discovery & Development. 2017 Nov 16.
3 RXi Pharmaceuticals. RXi’s immunotherapy approach.
4 Gavhane YN et al. Solid Tumors: Facts, Challenges and Solutions. International Journal of Pharma Sciences and Research (IJPSR). 2011;2(1):1-12.



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