Immuno Oncology

Off-the-shelf immunotherapies
based on allogeneic gene-edited CAR T-cells (UCART)

Cellectis is a pioneering gene editing company, employing core proprietary technologies to develop off-the-shelf immunotherapies to target and eradicate cancer cells. Our product candidates, based on gene-edited T-cells that express Chimeric Antigen Receptors, or CARs, harness the power of the immune system. A key to this effort is a type of white blood cell known as the T-cell, which plays an important role in identifying and killing cancer cells. Unfortunately, cancer cells often develop mechanisms to evade the immune system. CARs, which are engineered receptors that can be expressed on the surface of the T-cell, provide the T-cell with a specific targeting mechanism, thereby enhancing its ability to seek, identify, interact with and destroy cancer cells bearing the selected antigen.

Cellectis is designing next generation immunotherapies based on gene-edited CAR T-cells. Our gene editing technologies allow us to create allogeneic or off-the-shelf CAR T-cells, meaning they are derived from healthy donors rather than the patients themselves. Gene editing is a type of genetic engineering in which DNA is inserted, deleted, repaired or replaced from a precise location in the genome. The most fundamental challenge of gene editing is the need to specifically and efficiently target a precise DNA sequence within a gene. Our proprietary nuclease-based gene editing technologies, combined with 17 years of gene editing experience, makes it possible to edit any gene with highly precise insertion, deletion, repair and replacement of DNA sequences. Our nucleases act like DNA scissors to edit genes at precise target sites and allow us to design allogeneic CAR T-cells.

Our gene editing expertise also enables us to develop product candidates with additional safety and efficacy attributes, including control properties designed to prevent them from attacking healthy tissues, to enable them to tolerate standard oncology treatments, and to equip them to resist mechanisms that inhibit immune system activity.

The immune system protects the body from any foreign matters that might cause any damage. The success of the immune system depends on its ability to discriminate between foreign (non self) and host (self) cells. Cancer cells thrive, in part, because they trick the immune system into treating them as self, even though they express abnormal antigens, and thus immune tolerance occurs when the immune system fails to recognize and attack tumors. Breaking immune tolerance is an important aspect of most immuno-oncology based therapeutics because it enables the immune system to recognize and treat tumors as non-self and lead to tumor destruction.

Our therapeutics programs are focused on developing products using our gene editing platform to develop gene edited T-cells that express a Chimeric Antigen Receptors (CAR) and are designed to target and destroy cancer cells. CARs are artificial molecules that, when present at the surface of immune effector cells, will enable them to recognize a desired protein, or antigen, and trigger the killing of cells harboring this antigen at their surface (target cells). Immune cells -most usually T lymphocytes- can be engineered to express a CAR able to recognize proteins present at the surface of cancer cells. Upon cell-to-cell contact between effector and targeted cells, antigen recognition will activate the effectors, giving them the signal to attack their targets, and leading ultimately to the killing of cancer cells.

CARs are engineered molecules that, when present at the surface of T-cells, enable them to recognize specific proteins or antigens that are present on the surface of other cells. These receptors are typically used to graft the specificity of an antibody derived from a single cell, or a monoclonal antibody, onto a T-cell and provide it with a specific targeting mechanism to seek, identify, interact with and destroy the tumor cells bearing a selected antigen associated with that tumor also known as the tumor-associated antigen, or TAA.

These receptors are today one of the most promising approaches to fight cancer, through the development of immunotherapies. Indeed, immune cells (most usually T-lymphocytes) can be engineered to express a CAR able to recognize proteins present at the surface of cancer cells. Upon cell-to-cell contact between effector and targeted cells, antigen recognition will activate the effectors, giving them the signal to attack their targets, and leading ultimately to the killing of cancer cells.

CARs are constructed by assembling domains from different proteins, each of which enables the chimeric molecule to carry out specific functions. The most common CAR architecture comprises an extracellular domain containing a region that recognizes the targeted antigen and a spacer region that links it to the transmembrane domain (the part of the protein that spans the cellular membrane). This is then followed by an intracellular domain, responsible for transmitting an activation signal to the cell upon antigen recognition, causing the CAR engineered cell to attack the tumor cell.

The target-binding moiety is usually derived from an antibody, while the intracellular portion can include, besides the domain leading to cell activation and cytotoxic response, one or more domains from co-stimulatory receptor proteins that could enhance the proliferative capacity and survival of the “therapeutic” cells.

Cellectis is currently developing a collection of CARs targeting antigens present on cells from various types of cancer, as well as a proprietary multi-chain architecture of these artificial receptors, aiming to further increase the efficacy of adoptive cell therapies in the future.