Join our 20.000 subscribers and receive the monthly newsletter for free!

RELATED ARTICLES
Cancer immunotherapy: the ultimate ally in the tumor war

Can immunotherapy cure cancer? Fighting cancer with our own immune system. It sounds promising. At the end of the 1800s, the controversial Dr. Wil…


Engineered immune cells to fight cancer

Our own immune T-cells can be one of the best defense lines against cancer. Walloon biopharmaceutical company Celyad is using an innovative approa…


Damya Laoui at the forefront of cancer immunotherapy

Photo copyright: VUB / Thierry Geenen Last year, Damya Laoui received the prestigious American MIT-prize for young innovators under 35 for her…

POPULAR TAGS

Very promising cancer treatment: RNAi immunotherapy

Written by DS on in the category Insights with the tags , , .


RXi Pharmaceuticals was co-founded by Craig Mello, PhD, the co-recipient of the 2006 Nobel Prize in Medicine for the discovery of RNA interference (RNAi). To advance the use of RNAi into therapeutics, RXi has developed a novel and proprietary self-delivering RNAi platform, termed sd-rxRNA®, that has many advantages over its competitors in the RNAi space. A robust pipeline and extensive patent estate provide for the development and commercialization of advanced RNAi therapeutics across numerous therapeutic areas.

The company’s sd-rxRNA technology has demonstrated very efficient cellular uptake in many cell types, including cells of the skin and eye and also T cells, to name but a few. Current clinical programs include two phase II trials in dermatology, a phase 1/2 trial in ophthalmology, and R&D activities (because of a recent acquisition) in the area of cell- based immuno-oncology.

RNAi: a recap

RNAi compounds are oligonucleotides that can be used to very specifically reduce the level of proteins that are undesirable or produced in excessive amounts. For cell-based immuno-oncology, RNAi compounds may be extremely useful for immune checkpoint modulation. A checkpoint is a protein on an immune cell that reduces its ability to destroy tumor cells. “RXi’s goal is to reduce the mRNA coding for a specific checkpoint using its sd-rxRNA platform, leading to a reduction of the targeted checkpoint and allowing the immune system to carry out its normal function of killing cancer cells,” explains Dr. Geert Cauwenbergh, President and CEO of RXi Pharmaceuticals. “With our technology, multiple checkpoints can be targeted at the same time. Whereas the cumulative toxicity of multiple antibodies can be significant, RNAi compounds may not lead to that same problem.”

Results to date have demonstrated that our sd-rxRNA platform is uniquely suited for immune checkpoint modulation in cellular immuno-oncology therapies, such as CAR T cells. The targeted knockdown is achieved quickly and is very potent.
 

Let’s put RNAi in CAR T cells!

MirImmune, a company that was active in the field of cell-based cancer immunotherapy very early on, grasped the potential of this technology. They received a license from RXi to use their innovative RNAi compounds in cell-based immunotherapy to treat cancer. Within 18 months, MirImmune identified potent RNAi compounds against six different checkpoints, some of them extracellular and others intracellular.

Several RNAi compounds targeting different checkpoints can even be used at the same time for the same cells, be it extra- or intracellular, maintaining each compound’s effectiveness without diminishing cell viability.”
 

First in vivo tests

MirImmune tested the effect of anti-PD-1 RNAi compounds in a mouse model for ovarian cancer. (PD-1 is a well-known immune checkpoint.) They transfected Meso CAR T cells (T cells engineered to target mesothelin, which is overexpressed on many solid tumors) with an anti-PD-1 sd-rxRNA compound. Then they injected these engineered CAR T cells into human ovarian cancer tumors that had been implanted in mice and observed the animals for 1 month. The results were quite remarkable. In mice treated with the CAR T cells modified with anti-PD-1 sd-rxRNA, there was a significant reduction of tumor growth compared to untreated tumors. Treatment with non-modified CAR T cells as a control did not significantly reduce tumor growth. Moreover, at the end of the study, the reduction of PD-1 protein in the modified CAR T cells isolated from the mice was still close to 100%, indicating a potentially long-lasting effect.

The anti-PD1-sd-rxRNA was also tested for activity in tumor-infiltrating lymphocytes (TILs). The potential of TILs transfected with the anti-PD-1 compound to kill melanoma cells was evaluated in vitro. Two different dose levels were tested and compared with a PD-1 antibody. The antibody and the lower RNAi dose appeared to have about an equipotent killing effect on tumor cells. The killing activity of TILs treated with the higher dose of sd-rxRNA on the melanoma cells was substantially increased compared to the lower dose and the antibody.

If we can demonstrate that we can block a checkpoint in T cells for 3 months, the average lifetime of a T cell, we might be able to replace antibodies with RNAi compounds.
 

When will we know if it works in humans?

“Our intent is to start a clinical trial as soon as possible, and we are working to optimize RNAi compounds as we speak,” says Cauwenbergh. “We would like to collaborate with an institute in China that is very active in cell therapy. In the US, we plan to collaborate with a prominent cancer center in Boston and other leading academic centers. In one of our programs, we will be focusing on the improvement of standard of care cell therapies that are already approved by the FDA. The only thing we have to do is introduce our checkpoint inhibitor to the existing ex vivo cell treatment protocol. If all goes well, the first clinical entry could be happening within the next 2 years.”

Conventional chemotherapy may become a last instead of a first resort.
 

RXi Pharmaceuticals has a $15 million market cap, but Cauwenbergh would not even sell it for double the price: “I don’t want our RNAi technology to be used for only one specific aspect of human disease. It has potential in so many therapeutic areas. I want to make sure that it will be used to its full potential, and this sentiment is behind our ongoing expansion into cancer immunotherapy and to other disease areas in the near-term future.”

“The nice thing about working in this space,” concludes Cauwenbergh, “is that the FDA, academia, and industry really work hand-in-hand. They know that the road isn’t straight. It’s like being an explorer discovering a new continent. We don’t know what to expect and what rules and regulations are appropriate.

We are progressing carefully, and together we’re building the plane while we’re flying it.
 

This article appears in the BioVox White Paper on Immunotherapy, May 2017. Download the complete work here for free.

Read more about: , , .

RELATED ARTICLES
Cancer immunotherapy: the ultimate ally in the tumor war

Can immunotherapy cure cancer? Fighting cancer with our own immune system. It sounds promising. At the end of the 1800s, the controversial Dr. Wil…


Engineered immune cells to fight cancer

Our own immune T-cells can be one of the best defense lines against cancer. Walloon biopharmaceutical company Celyad is using an innovative approa…


Damya Laoui at the forefront of cancer immunotherapy

Photo copyright: VUB / Thierry Geenen Last year, Damya Laoui received the prestigious American MIT-prize for young innovators under 35 for her…

POPULAR TAGS

Sign up to our Mailing List to receive updates
of our latest News, Events & Magazines

Turnstone Flanders.bio Janssen Biowin V-Bio Ventures Itera Life Science GSK UGent XpandInnovation KU Leuven

ABOUT BIOVOX - Sharing Life Sciences Innovations

BioVox showcases interesting life sciences breakthroughs for and from Belgian innovators. Through our partnership with BioCentury we share relevant worldwide innovations and business updates while our local journalists focus on regional highlights. 

Interested to get involved? Get in touch! We are looking for content, writers and partners! Blogs are available for research institutes, companies and freelance experts.

You want to reach out to the biotechnology and life sciences community, targetting selected audiences? Discover our sponsor and publication opportunities as well as tailored packages!

Contact BioVox via news@biovox.be or by completing the contact form.