Strand Therapeutics: Creating programmable mRNA
The field of cancer immunotherapy has witnessed remarkable advancements in recent years, with the emergence of technologies like CAR T-cell therapy offering new hope for patients battling aggressive cancers, as well as extensions of mRNA technologies to oncology. However, despite these approaches, challenges remain in terms of their complexity, cost, and ability to generate durable responses in a wide range of patients. Enter Strand Therapeutics, an MIT spinout that is revolutionizing the landscape of cancer immunotherapy with its programmable mRNA platform.
At the heart of Strand's approach lies a deep understanding of the biology of messenger RNA (mRNA) and the immune system. By leveraging computational biology, the company has developed a proprietary mRNA 'programming language' that enables the design of smart mRNA therapies capable of sensing their environment and modulating their behavior accordingly.
Why mRNA matters
mRNA technology is, in itself, extremely important. It can be used to create a diverse array of proteins, including intracellular, extracellular, and transmembrane proteins, expanding the possibilities beyond what current biologics can achieve. Therapies can be developed relatively quickly compared to traditional drugs, as they rely on the body's own machinery to produce the therapeutic protein. Rapid development can be particularly valuable in responding to our present health crisis of chronic disease. These drugs can be combined with other treatments, such as checkpoint inhibitors or chemotherapy, to enhance their effectiveness and overcome resistance mechanisms in cancer cells. Finally, mRNA therapies can be tailored to individual patients' genetic makeup, allowing for more personalized treatment approaches.
Self-replicating mRNA: a hot concept
First-generation mRNA vaccines work in a well-understood way. For instance, COVID-19 vaccines mimic natural mRNA function, expressing a single protein for a short time - therefore, these therapies are fundamentally limited by shorter half-lives and inability to generate sustained effects. This is suitable for vaccines but limiting for therapies that require prolonged protein expression, like activating an anti-tumor immune response .
One of the key innovations of Strand's platform is its ability to create self-replicating mRNA molecules that can persist and express therapeutic proteins for extended periods within target cells. Albeit other companies such as Arcturus-CSL (Fig. 1) and Replicate Bioscience are working on self-replicating mRNA across dimensions , Strand is unique in using this technology in programmable RNA.
By enabling long-term protein expression within cancer cells, Strand's approach has the potential to elicit robust, durable immune responses that effectively eliminate tumors. Strand is also testing circular RNA in its pipeline, which may allow effects for up to weeks at length.
A first programmable language
Strand has created the first programming language for mRNA, allowing for "smart" therapies that can sense and respond to specific cancer biomarkers, expressing therapeutic proteins only when certain conditions are met. As a result, Strand mRNA is often described as "mRNA 2.0", elucidating its dimensional effects. The current mechanism is explained in the next sections. Broadly, the mRNA programming language also enables the construction of multi-functional therapies that can simultaneously target different aspects of cancer biology, creating sophisticated cancer-fighting circuits that can modulate the immune system, remodel the tumor microenvironment, and directly kill cancer cells in a coordinated and synergistic manner.
Current delivery mechanisms
The initial applications of mRNA technology, such as vaccines, did not require the same level of specificity as therapeutic applications. Vaccines can be administered locally to the muscle, where they induce the production of the encoded viral protein without the need for targeted delivery. Future mRNA therapeutics will likely incorporate externally controlled genetic logic circuits and advanced transfection delivery vehicles, such as ionizable lipid nanoparticles, to achieve targeted and controlled protein expression.
For Strand, a self-stated first goal is 'mRNA therapies that act through multiple mechanisms to deliver potentially curative treatments for solid tumors.' This implies a systemic delivery mechanism which delivers tumor microenvironment (TMI)-modifying mRNA to tumor sites and immune cells. STX-003 and STX-006 (Fig. 3) offer systemic delivery solutions using a modality of self-replicating mRNA circuits for intravenous, non-liver delivery (as compared to the past - this was done through I.V. infusion into the liver).
On the other hand, STX-001 - the first Strand technology - is a local delivery mechanism, delivered directly to the tumor microenvironment intratumorally. Some of the novel delivery mechanisms employed by Strand were licensed to BeiGene, a global leader in cancer diagnostics, to commercialize multi-functional mRNA treatments for solid tumors in various parts of the world, especially in Asia (2021).
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Sensing the right cells
A critical aspect of Strand's technology is its capacity for cell-type-specific targeting. By leveraging the unique microRNA (miRNA) signatures of different cell populations, the company can design mRNA therapies that specifically activate within cancer cells while remaining silent in healthy tissues. This level of precision not only enhances the potency of the therapeutic effect but also minimizes the risk of off-target effects , a major challenge in the development. More generally, genetic logic circuits that are developed within mRNA sequences are at the core of Strand's technologies for cancer immunotherapies.
These synthetic circuits can sense the environment of the cell they are in and activate protein expression only in the desired cell types. miRNA is just one of the biomarkers that's differentially expressed in various cell types; other biosensors can be input into this circuit model. This model also precisely regulate the location, timing, and intensity of therapeutic protein expression in the patient's body for accurate and controlled delivery.
"We built a database that says: ‘Here are all of the different cells that the mRNA could be delivered to, and here are all of their microRNA signatures,’ and then we use computational tools and machine learning to differentiate the cells. For instance, I need to make sure that the messenger RNA turns off when it's in the liver cell, and I need to make sure that it turns on when it's in a tumor cell or a T-cell. The bigger our cell-type specific datasets become, the better we are at differentiating cell types, which makes these molecules so targeted we can have a higher level of safety at higher doses and create stronger treatments." - Strand CEO Jacob Becraft .
STX-001: a locally-delivered mRNA therapy
Strand's lead candidate, STX-001, exemplifies the power of this targeted approach. As a self-replicating, lipid nanoparticle-based mRNA therapy encoding activation of the potent immune-stimulating cytokine IL-12, STX-001 is designed to selectively express high levels of IL-12 within the tumor microenvironment upon intratumoral injection.
By creating a local reservoir of this powerful cytokine, STX-001 can drive the recruitment and activation of immune cells, jumpstarting a cascading immune response against the tumor. The therapy's ability to generate such a response while confining its effects to the tumor site represents a significant advancement over previous IL-12-based strategies, which have been limited by systemic toxicity. Strand recently got clearance for solid tumor cancer trials.
The first clinical trial is targeting solid tumors like melanoma and triple-negative breast cancer. Some key features I noticed from pre-clinical data:
CAR-T applications
Strand Therapeutics is developing an innovative, off-the-shelf cell therapy using their proprietary mRNA platform to target CD19 and elicit a CAR-T response directly in the patient's body.
The company received a $400k Phase I NIH SBIR contract to develop mRNA- and circuit-based CAR-T Immunotherapy for non-Hodgkin’s lymphoma. Strand aims to target CD19 and elicit a CAR-T response directly within the patient's body. This approach aims to eliminate the need for ex vivo cell manipulation, reduce complexity and cost, allow for prolonged CAR expression, enable cell-type-specific targeting, minimize off-target effects, and potentially allow redosing without lymphodepletion. This innovative delivery method could make CAR-T therapies more accessible and cost-effective for a broader range of patients.
Future
The essence of Strand is two-fold: (1) amplified expression in (2) specific, programmed target cells.
As Strand continues to build upon its early successes and expand its pipeline, the potential applications of its mRNA platform extend far beyond cancer immunotherapy. By enabling targeted, long-lasting protein expression in specific cell types, the company's technology could open new avenues for the treatment of a wide range of diseases, from autoimmune disorders to genetic conditions.
The story of Strand Therapeutics is one of scientific innovation, entrepreneurial vision, and the power of cross-disciplinary collaboration. By bringing together experts in transcriptomics, immunology, computational biology, and synthetic biology, the company has positioned itself at the forefront of a new era in medicine, one in which programmable mRNA therapies can be tailored to the specific needs of individual patients and diseases. Due to their efforts, they were named one of the “Fierce 15” Biotech Companies of 2022 by Fierce Biotech.
As the field of cancer immunotherapy continues to evolve, Strand Therapeutics is poised to play a leading role in shaping its future. With cutting-edge science, precision targeting, and long-lasting therapeutic effects, the company's platform represents a major leap forward in the development of mRNA-based medicines. As STX-001 and other candidates from Strand's pipeline make their way into clinical trials (Fig. 3), the potential impact on the lives of patients worldwide cannot be overstated. In the years to come, Strand Therapeutics may well be remembered as the company that unlocked the full potential of mRNA technology in the fight against cancer and beyond.