While some life science companies are researching the new and exciting field of RNA technologies, which offer incredible advantages in drug discovery, one company, Gritstone Oncology is already applying it to its ground-breaking immunotherapy platform to fight cancer.

Based in Emeryville, California, Gritstone’s goal is to eradicate cancer by developing personalized immunotherapies to fight multiple cancer types. Their approach focuses on the individual nature of a patient’s tumor, seeking to generate a therapeutic immune response by unleashing the natural power of a patient’s own immune system to recognize tumor antigens and destroy cancer cells. These antigens – called tumor-specific neoantigens, which are made through RNA technology – offer attractive therapeutic targets because they are non-self and tumor-specific, and elicit a potent immune response.

Leading Gritstone’s oncology programs is Executive Vice President of Research and Chief Scientific Officer Dr. Karin Jooss, who has served in that role since April 2016. Prior to Gritstone, from May 2009 to April 2016, Dr. Jooss served as head of cancer immuno-therapeutics in the vaccine immuno-therapeutics department at Pfizer, Inc., and as vice president of research at Cell Genesys Inc., Dr. Jooss received her diploma in theoretical medicine from the University of Marburg in Germany, as well as a Ph.D. in molecular biology.

As part of the new WuXi AppTec Innovator series we discussed the advantages of using RNA technology in developing new and novel drugs that could make a difference in people’s lives and how Gritstone is using RNA to bolster their immunotherapy cancer research.

WuXi: What are RNA-based therapeutics and what differentiates them from DNA-based therapeutics?

Karin Jooss: Messenger RNA (mRNA) is a carrier of genetic information from DNA to instruct the human body to produce its own proteins that are necessary for carrying out the body’s functions. RNA-based therapeutics can deliver mRNAs to instruct a patient’s own cells to produce proteins that could prevent, treat, or cure disease. RNA-based therapeutics can also bind to mRNAs and inhibit the overproduction or abnormal production of disease-causing proteins.

RNA-based therapeutics are different from DNA-based therapeutics in a number of ways. First, delivery of therapeutic DNA to the cell requires the DNA to go through a longer pathway than RNA prior to translation into therapeutic proteins or vaccines. These extra steps involve the delivery of the DNA to the nucleus, RNA transcription, export of RNA to the cytoplasm, and translation into target proteins/polypeptides. This pathway is generally inefficient and requires large amounts of DNA. RNA-based therapeutics bypass this multi-step requirement and upon delivery to the cytoplasm of a cell, they can immediately serve as templates for protein production.

In addition, RNA can be engineered to self-amplify increasing the amount of RNA templates available for translation, and thus enhancing their efficacy. Due to its intrinsic properties, RNA immediately begins translation or self-amplification upon entry into the cell cytoplasm; therefore, the amount of nucleic acid required for therapeutic benefit can in theory be significantly less than that for DNA therapeutics. With mRNA therapeutics, transient dose-dependent protein expression can be achieved, and there is no risk of integrating therapeutic DNA into the patient’s genome. Finally, RNA is less stable than DNA but RNA can be stabilized chemically.

WuXi: Do researchers know the full impact/potential of RNA on diseases, or is there much more to learn?

Karin Jooss: There is still much to learn about the full impact of mRNA therapeutics on disease as this therapeutic field is still in its infancy.

WuXi: Will RNA technologies emerge as a dominant treatment modality and if so, how soon?

Karin Jooss: Yes, we believe RNA technologies will become one of the dominant therapeutics within the next five years due to several advantages. First, they have multiple product opportunities with new targets, both novel and validated, along with unprecedented development capabilities for combination therapy and expedited evaluations. Second, the speed of manufacturing means accelerated timelines — faster to human, and faster to market. Finally, their cost is lower due to step-change capital and cost efficiency in manufacturing, so you have large molecule targets at small molecule prices.

WuXi: What are the leading RNA technologies and what diseases do they target?

Karin Jooss: The leading RNA technologies include modified self-amplifying mRNA (samRNA), messenger RNA (mRNA), small interfering RNA (siRNA), and antisense oligonucleotide. The RNA technologies target infectious diseases, immuno-oncology, cardiovascular diseases, auto-immune, and rare genetic diseases.

WuXi: What scientific advances are needed to make RNA technologies more effective medicines?

Karin Jooss: Continued research and development in the following areas will expedite making RNA technologies more effective medicines. First, there is a need for more rapid and direct synthesis of RNAs without the need to use DNA intermediates and transcription step. Second, is the ability to design and synthesize highly pure mRNA which minimizes the undesirable activation of the immune system by mRNA and maximizes the potency of mRNA once in the target cells. Third, is the continued development of delivery technologies to protect mRNA from extracellular enzymes and harsh environments that would degrade it. This means mRNA can be delivered to the desired tissues, and facilitate the transport of mRNA across cell membranes to the translational machinery inside the cell. Finally, the industry needs to pursue manufacturing processes to optimize these features for potential mRNA therapeutics and to develop the technical capability to scale mRNA for clinical development.

WuXi: Considering the wide variety of treatment modalities, where would you rank RNA-based technologies in importance?

Karin Jooss: We believe that the field of RNA therapeutics will continue to grow rapidly due to the advantages RNA technologies offer.

WuXi: After two decades of research, the first RNAi therapeutic was approved in 2018. How will this class of medicines evolve over the next five years?

Karin Jooss: We expect mRNA engineering, delivery technologies, and manufacturing processes will continuously evolve to overcome the challenges of delivering the right amount of mRNA to the right tissue. More notably, we anticipate significant progress in the delivery technology from current LNP delivery to cell or tissue specific ligand conjugated delivery technology.

WuXi: What RNA-based technology is your company pursuing and what are your disease targets?

Karin Jooss: Gritstone uses self-amplifying mRNA (samRNA) encapsulated in a Lipid Nanoparticle (LNP, a synthetic delivery system) to develop neoantigen-based immunotherapies. Our Gritstone EDGETM artificial intelligence platform is designed to predict the tumor-specific neoantigens that are presented on tumor cells. We take these neoantigens and engineer them into a sequential prime/boost regimen. The prime is based on an adenoviral vector that has been shown to be highly immunogenic in humans in other disease settings. The boost is a self-amplifying RNA vector. Together, the goal is to elicit rapid and sustained antigen-specific T cell responses against tumor cells.

WuXi: Can you further describe how Gritstone is using its RNA technology in developing cancer immune-oncology therapies?

Karin Jooss: The mRNA vector we use comprises RNA that encodes the selected target antigens, such as tumor-specific neoantigens (TSNA), plus an RNA polymerase. After injection into muscle and uptake into host cells, the RNA is translated into a protein, and the RNA polymerase starts to replicate the originally injected source RNA, amplifying the number of copies within the cells dramatically. This leads to the production of large amounts of the delivered target antigens. During the RNA replication, RNA structures that are foreign to normal cells are generated, which drives a strong danger signal to surrounding immune cells, triggering an early immune reaction (innate immune response). The presence of large quantities of antigen in an immune-stimulating environment drives profound antigen-specific T cell responses–adaptive immune responses.

The goal of our immunotherapy is to drive a large and sustained T cell response against the delivered tumor-specific neoantigens.

WuXi: What regulatory challenges do you face? Are they different from DNA-based therapeutics and other types of drugs?

Karin Jooss: We face many of the usual challenges that others face with the introduction of new/complex biologics. They are not that different from DNA-based therapeutics at this early stage.

WuXi: What kinds of manufacturing challenges do you face?

Karin Jooss: Currently, the samRNA that we manufacture requires plasmid and RNA manufacture, followed by formulation. Manufacturing it in-house requires a large, diverse team with broad expertise in multiple technical areas.

WuXi: What will Gritstone’s upcoming milestones and what role will they play in Gritstone’s development

Karin Jooss: Our two immunotherapy product candidates that leverage our prime/boost technology include GRANITE-001, which is manufactured uniquely for each cancer patient, and SLATE-001, which is designed for selected subsets of patients with common tumor neoantigens.

We initiated a Phase 1/2 clinical trial of GRANITE-001, evaluating it in the treatment of common solid tumors, including metastatic non-small cell lung cancer, or NSCLC, and gastroesophageal, bladder and microsatellite stable, or MSS, colorectal cancers, and in each case in combination with checkpoint inhibitors. GRANITE-001 was granted Fast Track designation by the U.S. Food and Drug Administration for the indication of colorectal cancer. We expect to present some early data from this study at the end of this year. This data will be the first human data that the company has generated.

We also expect to advance SLATE-001, our first off-the-shelf, TSNA-directed immunotherapy product candidate, into the clinic this year.

Beyond our prime/boost-based immunotherapies, we are also using our EDGETM artificial intelligence platform to identify tumor-specific targets and natural T-cell receptors that have applications for other treatment modalities, including cellular-based therapies, as evidenced by our first cell therapy collaboration with bluebird bio.

Additionally, we have an internal bispecific antibody program in lead optimization phase. We expect to identify a lead development candidate directed towards solid tumors later this year.