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RXII: sd-rxRNA: A Flexible Platform for Oncology



Immunotherapy is one of the most exciting areas in biotechnology today.  It holds the promise of improved efficacy and greater safety by augmenting and enhancing the body’s innate ability to fight disease, seek out damaged cells and either destroy or repair them.  The applications span from cancer to heart disease, neurodegenerative to autoimmune disorders and many others.  Recently, the FDA has granted two groundbreaking approvals in a type of adoptive cell therapy (ACT) known as chimeric antigen receptor T-cell (CAR-T) therapy.  FDA approvals were given in two categories of hematological cancers using CAR-T and have validated ACT as a viable approach in immunotherapy.  CAR-T has been in the vanguard in the ACT space, however there are other approaches that show promise.  ACT is especially conducive to combination therapy with interference RNA (RNAi) as it can augment ACT’s efficacy, impact expression of immune cell proteins and maintain immune cells in a stem-like state which enhances their propagation and longevity.  

RXi Pharmaceutical’s (NASDAQ:RXII) proprietary sd-rxRNA has shown promise in the ex vivo treatment of therapeutic cells and also with direct application.  RXi has lead candidate RXI-109 in Phase II trials for two indications employing direct use of sd-rxRNA.  The company’s opportunity set is extensive and in this piece we focus on some of the exciting collaborations that are possible between RXi’s sd-rxRNA and adoptive cell therapy.


Adoptive Cell Transfer Therapy

Two new adoptive cell transfer (ACT) biologics were approved this year, making them the first examples of gene therapy available in the United States.  Novartis’ (NYSE: NVS) Kymriah for B-cell acute lymphoblastic leukemia and Gilead’s (NASDAQ: GILD) Yescarta for large B-cell lymphoma were given the go-ahead by the FDA just months ago.  The specific type of ACT known as CAR-T treatment involves the isolation and ex vivo expansion of immune cells which are engineered in the laboratory.  The process involves extracting these cells from a patient and expanding their population in the lab.  After expansion and modification, the cells are reinfused into patients to treat their cancer.  While the most popular therapies are autologous and extract cells from the same patient they treat, ACT can also be allogenic using cells from genetically compatible donors.  

There are several types of ACT therapy, including endogenous T-cell therapy, where tumor-specific T-cells are grown from blood; TIL therapy, where T-cells are grown from those that exist in the tumor cell itself; TCR transduced T-cells where a T-cell receptor gene is engineered to recognize a tumor and CAR-T, where a chimeric antibody is expressed on T-cells.  Most research is focused on the TIL and CAR-T space.  CAR-T therapy is predominantly focused on leukemia, lymphoma and other blood cancers, while TIL therapy is most commonly applied to melanoma and solid cancers.  

Self-delivering Interference RNA (sd-rxRNA)

RXi can combine its sd-rxRNA platform with these ACT processes to enhance their effectiveness and durability.  The sd-rxRNA platform is able to safely transfect therapeutic cells and modify the expression of immune checkpoints and inhibitory pathways as well as alter other targets intracellularly by silencing proteins.  The platform also has potential to slow the differentiation of T-cells and maintain them in their more valuable stem cell memory state.  RXi’s technology is more efficient than other transfection approaches in ex vivo treatment of cells.  Competing approaches such as electroporation are 70 to 80% efficient with 50 to 60% cell viability compared to sd-rxRNA with near 100% transfection efficiency with little to no loss in cell viability.  An advantage of combining via the ex vivo approach is that it is non-invasive and does not interfere with the in-place manufacturing processes.  

CAR-T Therapy

In August 2017, the FDA approved the first chimeric antigen receptor (CAR) –T cell therapy named Kymriah (tisagenlecleucel) for young patients with acute lymphoblastic leukemia.  This was followed by another CAR-T approval in October for Yescarta (axicabtagene ciloleucel) for adults with large B-cell lymphoma.  

The CAR-T therapy process begins by taking T-cells out of the body in a process called leukapheresis and then introduces a modified and inactive virus into the extracted cells that is unable to cause disease, but does introduce genetic information.  This genetic code instructs the cell to produce chimeric antigen receptors on its surface which are able to detect cancer cells that express certain markers on their surface.  In the case of Kymriah and Yescarta the receptors detect CD-19 on malignant cells.  The cells are then expanded and the CAR-T cells are then re-infused in the patient, which then go on to identify and eliminate cancer cells.  However, some cancer cells may still be able to evade this army of enhanced soldiers by expressing checkpoint receptors that allow them to hide from the CAR-T cells.  The cancer can also persist if it outlasts the life cycle of the effector CAR-T cells, which cannot be replenished.  

To combat these two weaknesses, sd-rxRNA can step in to improve the effectiveness of CAR-T process by enhancing the cells’ qualities.  One of the ways is by blocking the production of checkpoint proteins on the surface of T-cells by reducing mRNA levels of the checkpoint.  With fewer suppressive receptors on the immune cell, it is less likely that the cancer cells will be able to escape detection.  

RXi is publicly pursuing two immune checkpoints in its development pipeline, PD-1 and TIGIT.  PD-1 inhibitors are most widely recognized as those targeted by Merck’s Keytruda and Bristol Meyers’ Opdivo; however, there are a variety of other immune checkpoints including LAG-3, CTLA-4 and T-cell immunoreceptor with Ig and ITIM domains (TIGIT) which also are able to hide cancer cells from the immune system.


The second way sd-rxRNA can improve CAR-T effectiveness is through keeping cells in a nascent stage of differentiation.  When the T-cells are taken from the patient, they are in all stages of development, from naïve to effector.  Less differentiated cells mature over time to a state where they do not divide as rapidly and have shorter lives.  Interference RNA can downregulate specific proteins in the cells during the ex vivo expansion process and maintain a greater number of cells in a less developed state, thereby influencing differentiation.  This less differentiated cell contains a memory of the specific antigen target and is able to abundantly divide along with its CAR features, and develop into active effector cells, increasing the duration of the CAR-T therapy.  

Influencing Differentiation

T memory stem cells (TSCMs) are a type of T-cell that is not yet mature enough to actively fight against malignant cells, but are antigen specific.  TSCMs have the important characteristics of self-renewal, extended longevity and ability to remember antigens that represent disease threats.  This immunological memory is a basic characteristic of adaptive immunity expressed in B and T lymphocytes.  One of the areas where TSCM can play a beneficial role is in adoptive cell therapy, specifically in CAR-T.  This approach transfers genetically engineered tumor-reactive T lymphocytes to activate them against a specific cancer cell marker, such as the previously mentioned CD-19.  The engineering process extracts T-cells that are in all stages of differentiation, from naïve to effector cells.  Research on mice and men has shown that objective response rate is positively correlated with the level of T cell expansion and persistence; it may also be associated with durable remissions.  These higher levels of expansion and persistence are characteristics of less differentiated T-cells such as TSCMs.  

In the following exhibit, cell types are shown from least to most differentiated: naïve, memory stem cell, central memory, effector memory and effector T-cell from left to right.  The columns below the differentiated cells are the markers which identify each cell type.  The box at the bottom lists the attributes of less differentiated cells as compared to more differentiated ones.  TSCMs can enhance the performance of CAR-T therapy through their proliferative potential and longevity.


RXi is conducting preclinical research to demonstrate the ability of sd-rxRNA to maintain greater numbers of T cells in the TSCM differentiated state.  The company is working with partners to further develop this approach.

Tumor Infiltrating Lymphocyte Therapy

Another area of promise for RNAi therapy is augmenting the performance of tumor infiltrating lymphocytes (TILs).  TILs frequently address melanoma based on preclinical efficacy.  The existence of TILs indicates that the body has begun to fight the cancer as the cells have already become antigen specific to the markers on the existing tumor.  The process for TIL therapy extracts lymphocytes from a cancerous tumor and expands them in the lab.  The TILs are placed in culture and are stimulated for growth with a rapid expansion protocol (REP).  The REP uses interleukin-2 or other cytokine and additional factors to expand the population of cells and prepare them for reinfusion.  During this expansion process, interference RNA can be used to modify expression of both intra- and extracellular targets including multiple checkpoints and/or targets that influence cell differentiation.  The checkpoints act as a brake for the immune system when they are expressed by cancer cells.  If they are minimized, then it will allow the antigen primed TILs to better recognize and eliminate cancer cells.  

Direct Injection

Direct injection of sd-rxRNA is a process that is currently being used by RXi in several current clinical trials for skin and retinal scarring.  This method of administration can also be applied to cancerous tumors where the RNAi will downregulate the expression of surface markers on the immune cells and/or tumor cells.  


RXi has developed relationships over time with partners who are developing complementary processes to interference RNA and advancements in conjunction with ACT.  Partner entities include cancer centers and academic institutions that can help expand collaborative research and advance the result into the clinic.  On December 1st, RXi announced a research collaboration with the Danish Herlev Hospital which is developing ACT, TIL-based therapies, genetic engineering of T-cells and other programs which are expected to synergize with RXi’s platform.  Gustave Roussy is another partner added in the last month which has the distinction of being the largest cancer center in Europe.  Roussy expects to evaluate sd-rxRNA compounds in a human tumor xenograft model.  RXi is also collaborating with BioAxone BioSciences (private) who is evaluating the sd-rxRNA platform for treatment of spinal cord injury and has licensed its technology to Thera Neuropharma to develop therapeutics targeting the SOD1 gene for neurodegenerative diseases.  

Regulatory Guidelines for ACT

Adoptive cell therapy is only one of several areas in immunotherapy today which is innovating at an accelerating rate.  The FDA has recognized that there needs to be equilibrium between ensuring safety and efficacy and speeding life-saving treatments to patients who critically need them.  To address this delicate balance the FDA has provided guidance with additional clarity on the pathway for therapy development.  The relevant document drafted by the FDA outlines the criteria used to select programs for the Regenerative Medicine Advanced Therapy (RMAT) designation.  If a development program receives this award, then they will be able to work in closer collaboration with the FDA.  This collaboration should allow for beneficial adjustments to be made to processes and therapies while in clinical development.  This could include using sd-rxRNA to augment the ability of specific therapies such at CAR-T or ex vivo TIL expansion.  Surrogate endpoints, smaller trial sizes and faster time to market are other potential benefits.

The RMAT designation was created as part of the 21st Century Cures Act, which was signed into law in December 2016.  The designation is intended for regenerative medicine therapies which includes

➢ Cell therapies
➢ Therapeutic tissue engineering products
➢ Human cell and tissue products 
➢ Combination products
➢ Regenerative medicines that treat, modify, reverse or cure serious conditions

The investigational drug that is seeking the designation must also have preliminary clinical evidence that the therapy can address the unmet medical needs for the condition.  

With respect to regenerative medicine, the FDA has made it clear that it supports a material level of flexibility in the progress of regenerative medicine through the FDA approval process which can help developing technologies like sd-rxRNA get approved.  


Substantial advances have been made in immunotherapy recently and groundbreaking approvals in ACT are evidence of this.  RXi Pharmaceuticals’ sd-rxRNA approach has the ability to augment these already amazing results.  Interference RNA can enhance the performance of gene therapy by influencing differentiation and removing inhibitions responsible for hiding tumor cells.  It has applicability in CAR-T, TILs and direct injection providing a flexible platform to silence aberrant genes.  RXi’s pursuit of partners in these areas are expected to yield results that can enter into the clinic in the next year or two.  With the help of new rules and guidance provided by Congress and the FDA, the fast pace of advancement in immunotherapy space should continue providing new opportunities to improve the treatment of cancer and other diseases. 

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