Immuno-Oncology

Engineered cell therapies – after years of fighting cancer using small molecules and antibodies, we are entering the era of cell therapies against cancer. Using gene editing, we can engineer immune cells to kill cancer in a robust and specific way while avoiding many toxicities of traditional cancer therapies.

We believe that CRISPR-based gene editing will drive the next generation of immuno-oncology cell therapy. We are developing a portfolio of chimeric antigen receptor (CAR) T cell product candidates using our gene editing technology. CAR T cell therapy is a form of immunotherapy that uses specially altered T cells - a part of the immune system - to fight cancer. We believe that precise, efficient multiplexed gene editing may allow us to address some of the primary challenges with CAR T therapies that use patient-derived (autologous) cells. For instance, autologous CAR T cell therapies can take several weeks to manufacture, during which patients may experience disease progression, and the manufacturing process can fail to produce viable cells.

With CRISPR/Cas9, we can generate off-the-shelf (allogeneic) CAR T cells derived from healthy donors, which could have distinct advantages. In addition, we can use CRISPR/Cas9 to eliminate or insert genes to enhance the potency of CAR T products.

Allogeneic CAR T cell therapies enable:

• Immediate availability and broader access: administered off-the-shelf with no need for patient apheresis or bespoke manufacturing
• Greater consistency and manufacturability: each batch yields many doses using starting material derived from healthy donors
• Flexible dosing: ability to re-dose

Our next-generation CRISPR gene-edited allogeneic CAR T chassis

For our allogeneic gene-edited CAR T product candidates, we make multiple modifications to healthy donor T cells to allow our CAR T cells to be used off-the-shelf (shown below):

Regnase-1 knock-out: To help improve the potency of CAR T cells, we use CRISPR/Cas9 to knock-out the gene for Regnase-1. This disruption, or knock-out, is intended to increase functional persistence, cytokine secretion and various effector function of the CAR T cells at tumor sites, leading to potentially improved anti-tumor efficacy.

TGFBR2 knock-out: To help improve the effector function of CAR T cells at the tumor site, we also disrupt the gene for TGFBR2, which serves as part of the receptor for the negative immune regulator TGFb. This knockout is intended to keep the CAR T cells active against the tumor even in the presence of high levels of TGFb, which are often found in various cancers.

MHC 1 knock-out: To help 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) by disrupting, or knocking out, the β2M subunit. If present, MHC I could lead to rejection of the CAR T therapy by the patient’s own T cells.

CAR knock-in: The chimeric antigen receptor (CAR) allows CAR T cells to target and attack cancer cells. Autologous CAR T products use randomly integrating viruses to deliver the CAR construct to the DNA of T cells. We use CRISPR/Cas9 technology to insert the CAR construct precisely into the TCR alpha constant (TRAC) locus, with the goal of improving consistency and safety.

TCR knock-out: T cells use the T cell receptor (TCR) to recognize and attack “foreign” cells, which helps protect from infections. However, donor-derived T cells could also recognize a patient’s cells as foreign through this receptor, leading to a potential side effect known as graft versus host disease (GvHD). We use CRISPR/Cas9 to eliminate the TCR with high efficiency, which may reduce the risk of GvHD occurring during off-the-shelf use.