Cellectis Advances Immunotherapy Strategy for Tackling Solid Malignancies Through Gene-Edited CAR T-Cells

Overcoming the Solid Tumor Challenge

While CAR T-cell immunotherapies have demonstrated remarkable success in treating hematologic malignancies, their application against solid tumors remains constrained by significant biological obstacles. The tumor microenvironment (TME) creates a fundamentally hostile landscape—one characterized by immunosuppressive signals that prevent T-cells from penetrating tumor tissue. Beyond this barrier, researchers face additional complications: heterogeneous tumor antigen expression, limited availability of suitable CAR-targeted tumor-associated antigens (TAA), and the persistent risk of off-target cytotoxicity affecting healthy tissues. These limitations collectively undermine therapeutic efficacy and raise safety concerns that have historically hindered solid tumor applications.

Cellectis’ Multi-Pronged Approach

Cellectis is pursuing an innovative framework to address these interconnected challenges using TALEN®-based gene editing to engineer allogeneic CAR T-cells capable of functioning within the immunosuppressive solid tumor setting. The company’s strategy involves several complementary modifications:

The first approach leverages FAP-dependent expression systems, a mechanism that tethers CAR cytotoxic activity directly to the tumor microenvironment. Through both laboratory and animal models, researchers demonstrated that this spatial targeting dramatically reduces the risk of on-target off-tumor toxicity—a critical safety advantage—while maintaining concentrated anti-tumor activity within the lesion itself.

The second strategy combines IL-12 integration into PD-1 regulatory elements with TGFBR2 inactivation. By confining IL-12 secretion to the TME and simultaneously blocking TGFB1-mediated immunosuppression, this approach enhances CAR T-cell proliferation and infiltration capacity. The result is improved tumor burden reduction coupled with diminished systemic side effects.

Bridging Efficacy and Safety

These parallel approaches underscore a fundamental principle: repurposing natural immune regulatory pathways can create armored cell therapies that maintain potency while minimizing collateral damage. Cellectis’ data suggest that this framework could unlock meaningful therapeutic options for patients with solid malignancies—a population that has remained largely underserved by current CAR T-cell platforms.

Research Presentation

These findings will be presented at the Society for Immunotherapy of Cancer’s 39th Annual Meeting (SITC 2024), scheduled for November 6-10 in Houston, Texas. The poster presentation—titled “Breaking barriers in solid tumors with SMART allogeneic CAR T-cells”—will be displayed November 9th, 2024 from 9:00am to 8:30pm ET, poster number 254. Beatriz Aranda-Orgilles, Associate Director of Immuno Oncology at Cellectis, will present the research outcomes.

About Cellectis

Cellectis is a clinical-stage biotechnology firm specializing in gene-edited cellular and gene therapies. The company pioneered the allogeneic CAR-T model, creating off-the-shelf, ready-to-use gene-edited CAR T-cells for cancer treatment, alongside a platform for therapeutic gene editing in hematopoietic stem cells targeting various diseases. With 25 years of gene-editing expertise, Cellectis employs TALEN® technology and PulseAgile electroporation systems to harness immune function for treating unmet medical conditions. The company maintains headquarters in Paris with operations in New York and Raleigh, North Carolina, trading on both Nasdaq (CLLS) and Euronext Growth (ALCLS).