A collaborative ACT

RXi Pharmaceuticals and Karolinska Institutet collaborate on development of sd-rxRNA compounds to improve functionality and persistence of T cells and NK cells

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MARLBOROUGH, Mass.—RXi Pharmaceuticals Corporation announced today that it has entered into a research collaboration with the Karolinska Institutet in Stockholm, Sweden. This collaboration will explore RXi’s sd-rxRNA compounds against targets involved in T cell and NK cell differentiation and/or in the immune cell tumor-induced stress response with the aim of producing anti-tumor adoptive cell therapy grafts with improved functionality and persistence.
RXi Pharmaceuticals is a biotechnology company focused on developing sd-rxRNA therapeutic compounds to be used with an adoptive cell transfer (ACT) approach. This process uses immune cells, such as T-lymphocytes that are isolated from the patient or retrieved from allogeneic immune cell banks, and then expanded and in some cases processed to express tumor-binding receptors.
Dr. Gerrit Dispersyn, Chief Development Officer of RXi Pharmaceuticals said, “We are pleased to expand our collaboration with Dr. Kiessling’s group, to further harness their expertise in oncology and to expand on the successful research they have previously done with our sd-rxRNA technology platform in immuno-oncology. The combination of their prior results and the anticipated research results from this new collaboration are critical elements for a rapid advancement of sd-rxRNA immuno-oncology therapeutics into the clinic, further supported by our prior clinical experience with sd-rxRNA in other indications.”
The work with the Karolinska Institutet will expand on the results from Dr. Kiessling and his research group that were recently published in Molecular Therapy. The article demonstrated that an sd-rxRNA targeting PD-1 can enhance tumor-infiltrating lymphocytes (TIL) antitumor activity against melanoma cells in vitro, and further showed that ex vivo treatment with the sd-rxRNA compounds was easily incorporated into a clinically relevant rapid expansion protocol for TILs.

“The use of RNAi to protect/enhance action of immune cells in ACT has been proposed previously, with the major hurdle being the difficulty of utilizing RNAi to transfect T cells. The commonly used transfection methods, such as lipid-mediated delivery or electroporation, result in significant loss of T cell viability and non-specific activation,” the article explains.
“Self-deliverable RNAi technology based on the chemical modification of siRNAs successfully resolves the cellular delivery issue. The combination of backbone modifications with asymmetric siRNA structure and a hydrophobic ligand allows sdRNAs to penetrate cultured mammalian cells without additional formulations and methods by simple addition to the culture media, capitalizing on the nuclease stability of sdRNAs. This stability allows the support of constant levels of RNAi-mediated knockdown of target gene activity simply by maintaining the active concentration of sdRNA in the media.”
“We have demonstrated the persistence for 8 days after transfection of more than 70% knockdown of PD-1 expression in rapidly dividing T cells,” continues the article. “This knockdown would provide infused T cells with a head start, avoiding immediate suppression by the PD1/PD-L1 pathway. Additionally, and due to the benign safety profile involved, multiple infusions of a TIL product (as suggested by Rosenberg et al.) would ensure that a potent in vivo effect could be established by the use of sdRNA. Altogether, PD-1 knockdown efficacy, persistence, and safety profile present sdRNA silencing of PD-1 as an attractive method to use for production of TILs for clinical trials.”
“Our results to date provide direct clinical relevance for the use of sd-rxRNA technology to improve ACT. In this collaboration, we look forward to exploring using sd-rxRNA to modulate targets outside of checkpoints to improve efficacy of immune effector cells such as T cells and NK cells,” noted Rolf Kiessling, MD, PhD, Senior Professor in Experimental Oncology at the Karolinska Institutet, Senior Chief Physician at the Oncology clinic at the Karolinska University Hospital and member of RXi's Scientific Advisory Board.

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