3D illustration of a tumor on a black background. The tumor has recruited blood vessels to grow into it from a main artery running at the bottom of the photo. Around the tumor, purple, pink, and blue immune cells try to enter the tumor microenvironment but are stopped.
Article

Inducible CAR T Cells Target Solid Tumors Better

Researchers at Cellectis leveraged gene editing to create a CAR T cell that acts in an IF/THEN system.

Shelby Bradford, PhD
| 2 min read
Image credit© istock.com, Marcin Klapczynski

Chimeric antigen receptor (CAR) T cell therapy leverages patients’ immune systems to fight cancer. This immunotherapy greatly expanded treatment options for cancers like leukemia and lymphoma. However, traditional CAR T cell therapy has had limited success in solid tumors. Shipra Das, an immunooncologist at Cellectis, discussed a novel approach using transcription activation-like effector nucleases (TALENs) gene editing to overcome these shortcomings by making CAR T cell activity inducible.

What have been the challenges in CAR T cell therapy?

Traditional methods to develop CAR T cells that use the patient’s cells introduce challenges because in some cases these cells may be in low number or have already been negatively affected by the cancer or other treatments. Additionally, it takes time to produce these cells once they are isolated from the patient, and that’s not ideal in a disease like cancer. For solid tumors, CAR T cell therapy has struggled because the therapeutic cells cannot access their target efficiently due to the suppressive tumor microenvironment (TME). Finally, since many of the antigens that are used in CAR T cell therapy can be expressed, although at a lower concentration, on other cells, there is the concern of these therapeutic cells targeting nontumor cells.

How has your team addressed these issues?

Previously, we removed the T cell receptor gene from our donor stem cells using TALEN gene editing, which eliminated the ability for it to recognize and attack the patient’s cells, giving us a pool of universal CAR T cells to use in more patients.1 Recently, we took advantage of the cancer-associated fibroblasts present in the TME to use them as an activator for our inducible CAR T cells.2 A constitutively expressed receptor for one of these fibroblast proteins engages with its ligand in the TME. Normally, this would induce the expression of a suppressive T cell protein, but we replaced that gene with the sequence for our second CAR, which targets a tumor-associated protein. In this way, we have a CAR T cell that is only active at the tumor, breaks through the TME, and that can be used in multiple patients. Another advantage of this system is that it is modular, so we can create these IF/THEN-gated CAR T cells to be regulated by or respond to different antigens.

Cellectis holds the patent for TALEN technology and other technologies used in this work.