Revealing Breakthrough: Pre-Clinical Data Shows Promise for CAR T Immunotherapy Against Solid Tumors

Cellectis, a clinical-stage biotechnology company using its groundbreaking gene-editing platform to develop revolutionary cell and gene therapies, recently revealed the impressive results of its TALEN® engineered FAP UCART-cells in an article published in Frontiers Bioengineering. This cutting-edge research demonstrated the efficacy of these cells in reducing cancer-associated fibroblast (CAF) levels, decreasing desmoplasia and tumor infiltration. With this breakthrough, Cellectis is paving the way to a potentially life-saving solution for cancer patients.

Adoptive cell therapy, based on the revolutionary chimeric antigen receptor-engineered T (CAR-T) cells, is providing hope and life-saving treatments to cancer patients across the globe. This groundbreaking technology is revolutionizing the way we think about treating cancer, providing a more effective and personalized approach to combating the disease.

CAR T-cell therapy has shown great promise as a potential treatment for many types of cancer, yet its efficacy has so far been limited to only a few malignancies. Solid tumours have proved particularly resistant to this form of therapy, due to difficulties with T cell infiltration and dysfunction in the immunosuppressive microenvironment. This has presented a major obstacle to successfully treating cancer with CAR T-cells.

Cancer-associated fibroblasts (CAFs) are an essential element of the tumor environment, secreting a wide range of cytokines and growth factors that actively contribute to the extracellular matrix and enable immune suppression.

However, their depletion in the tumor stroma can create an opportunity for CAR T-cell cytotoxicity, transforming immune evasive tumors into ones that are susceptible to tumor-antigen recognition. This process offers a promising new approach to fighting cancer.

Cellectis leveraged its cutting-edge TALEN® gene editing platform to engineer non-alloreactive and immune-evasive UCAR T-cells targeting Fibroblast Activation Protein, alpha (FAP) to explore if FAP UCAR T-cell pre-treatment can sensitize ‘cold’ tumors to subsequent CAR T-cell treatment.

Additionally, Cellectis generated non-alloreactive CAR T-cells targeting Mesothelin, an overexpressed tumor associated antigen (TAA) in mesothelioma, ovarian, breast, pancreatic and lung adenocarcinomas. This combination treatment strategy was tested in a pre-clinical mouse model of triple-negative breast cancer (TNBC), a stroma-rich and aggressive sub-type with a dismal prognosis and limited treatments at present.

CAR T-cell therapy is a promising new approach to treat epithelial cancers including breast, colorectal, pancreatic and lung adenocarcinomas, which express the CAF-specific surface marker, fibroblast activation protein α (FAP).

Cellectis has developed a novel and versatile combination CAR T-cell therapy that can be used to target cold tumors with relevant tumor-antigen CAR T-cells, which were previously unresponsive to cell therapy. This approach opens up a whole new range of possibilities for treating these difficult-to-treat cancers.

Preclinical data showed that:

In a mouse xenograft model, the successful implantation of injected CAFs in the tumors was confirmed by positive staining of spindle-like cells with human-specific FAP antibody. This successful implantation of CAFs has managed to recreate a TNBC tumor in a physiologically relevant manner, complete with both tumor and stromal compartments.

In a groundbreaking study, FAP UCART-cells have been found to have a profound effect on tumor growth, significantly reducing it. This is a revolutionary development that could potentially change the face of cancer treatments.

In vitro and in vivo experiments demonstrate that FAP UCART-cells can reprogram the cold, stroma-rich triple negative breast cancer (TNBC) TME, making it susceptible to the subsequent Meso UCAR T infiltration and cytotoxicity, thereby enhancing the antitumor activity of the treatment.

A combination therapy involving an anti-PD1 checkpoint inhibitor and UCAR T-cell treatment has been shown to provide the greatest anti-tumor activity and boost survival. This approach consists of first treating with FAP UCAR T-cells, followed by Meso UCAR T-cells. This powerful combination therapy has been proven to be highly effective in fighting cancer.

About Cellectis

Cellectis is a clinical-stage biotechnology company on a mission to develop life-saving cell and gene therapies. With over 23 years of experience and expertise in gene-editing, Cellectis utilizes its pioneering TALEN® technology and PulseAgile electroporation system to create off-the-shelf and ready-to-use CAR-T immunotherapies in oncology, as well as therapeutic gene editing in hemopoietic stem cells to treat a variety of diseases.

With headquarters located in Paris, France and offices in New York and Raleigh, North Carolina, Cellectis is listed on the Nasdaq Global Market (ticker: CLLS) and Euronext Growth (ticker: ALCLS), and is committed to finding new ways to harness the power of the immune system and provide treatments for those with unmet medical needs.

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