Immuno-Oncology
CRISPR/Cas9 will drive the next generation of immuno-oncology cell therapy
Over the past several decades, scientists have sought to engineer immune cells to seek and destroy cancer cells. These efforts eventually led to the approval by the FDA of two chimeric antigen receptor (CAR) T cell therapies in 2017. At CRISPR Therapeutics, we are developing our own portfolio of CAR-T cell product candidates based on our gene-editing technology. We believe the precision and efficiency of multiplexed editing with CRISPR/Cas9 may ultimately allow us to overcome the primary challenges with the current generation of CAR-T therapies. For one, with CRISPR/Cas9, we can generate off-the-shelf (allogeneic) CAR-T cells, which have distinct advantages over the autologous (patient-derived) products currently on the market. In addition, we can use CRISPR/Cas9 to eliminate or insert genes to create new classes of CAR-T products with improved applicability to solid tumors.
Allogeneic CAR-T cell therapies have numerous advantages
Current autologous CAR-T cell therapies provide excellent treatment results for some patients, but take several weeks to manufacture, during which many patients experience disease progression. The manufacturing process may also fail, and even if successful, the CAR-T cells that result may have low potency. In contrast, we aim to create allogeneic CAR-T products that have similar or better efficacy and numerous other advantages, including:
- Immediate availability: administered off-the-shelf
- Increased potency: starting material derived from healthy donors
- Greater consistency: each batch yields many doses
- Improved access: no need for patient apheresis
- Flexible dosing: ability to titrate dosing or re-dose
Our CRISPR/Cas9-enabled allogeneic CAR-T design
For our initial allogeneic gene-edited CAR-T product candidates, such as our lead immuno-oncology program CTX110, we make three modifications to healthy donor T cells to allow our CAR-T cells to be used off-the-shelf:
CAR: The chimeric antigen receptor (CAR) allows CAR-T cells to target and kill cancer cells. A CAR has two key domains: one that binds to the surface of cancer cells and another that activates the T cell. The current generation of CAR-T products uses randomly-integrating viruses to deliver the CAR construct to the DNA of T cells. In contrast, we use CRISPR/Cas9 to insert the CAR construct precisely into the TCR alpha constant (TRAC) locus, which we expect to result in a safer, more consistent product
TCR: T cells use the T cell receptor (TCR) to recognize and kill cells presenting foreign antigens (a sign of infection), thereby providing immunity from disease. Donor T cells could also recognize a patient’s cells as foreign through this receptor, leading to an unwanted side effect known as graft versus host disease (GvHD). We use CRISPR/Cas9 to eliminate the TCR with high efficiency, which reduces the risk of GvHD occurring during off-the-shelf use
MHC I: To improve CAR-T cell persistence and increase the chance for durable remissions, we use CRISPR/Cas9 to eliminate the class I major histocompatibility complex (MHC I) expressed on the surface of our CAR-T product candidates. If present, MHC I could lead to rejection of the CAR-T product by the patient’s own T cells. Eliminating this molecule should mitigate that effect
Realizing the potential of CRISPR/Cas9 in immuno-oncology cell therapy
Our lead immuno-oncology cell therapy program, CTX110, brings a potentially best-in-class allogeneic approach to the validated tumor target CD19, an antigen expressed in various B-cell malignancies. Our next product candidate, CTX130, marks our transition from hematologic to solid tumors. CTX130 targets CD70, an antigen expressed on both hematologic cancers, including certain lymphomas, and solid tumors, including renal cell carcinoma. Following on these programs, we plan to use both novel targeting and advanced editing to develop gene-edited cell therapies to treat numerous other cancers.
Our immuno-oncology programs form an important pillar of our pipeline. Please visit the link below to see more
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