The transition from complex and costly ex vivo strategies to platforms that enable direct cellular intervention within the body, known as in vivo therapies, is marking a paradigm change in the field of gene and cell therapies by simplifying manufacturing, improving tissue targeting and expanding clinical access to treatments.

As the many challenges facing cell therapies are being addressed, the CAR T field continues to evolve beyond its original design of T cells engineered to target hematological malignancies. During the 32nd Annual Congress of the European Society of Gene and Cell Therapy (ESGCT), held in Seville Oct. 7-10, several studies showed how this technology is being redefined as programmable and adaptable immune cells with expanded functional versatility.

Individuals with the inherited disorder Fanconi anemia cannot properly repair damage to their DNA, increasing risk of cancers such as head and neck squamous cell carcinoma (HNSCC).

Two independent studies applied CRISPR-based genetic editing – one to treat leukemia and the other to target myeloma – to overcome the challenges faced by CAR T cells, such as exhaustion, impaired activation and fratricide, a phenomenon in which they attack each other.

Renal cell carcinoma accounts for approximately 90% of kidney cancers, and current treatments fail to prevent metastasis in up to 40% of patients. Potentially effective is immunotherapy based on CAR T cells that recognize CD70, which is little expressed in normal tissues but is expressed in more than 80% of renal cell carcinomas. However, such CAR T immunotherapy has so far not shown overwhelming success against renal cell carcinoma, and the therapeutic cells must be derived for each patient individually.

Aera Therapeutics Inc. has nominated AERA-109, a targeted in vivo CAR T therapy designed to treat multiple B cell-mediated autoimmune diseases, as the company’s first development candidate. AERA-109 leverages Aera’s proprietary targeted lipid nanoparticle (tLNP) delivery platform and CAR T technology.

Glioblastoma, the most aggressive and lethal form of brain cancer in adults, has long evaded effective treatment due to its resistance to standard therapies, including surgical resection, radiation, chemotherapy and targeted agents.

Metastatic and relapsed osteosarcoma remains challenging to treat despite the introduction of advanced surgical techniques, intensified chemotherapy and targeted therapies. Adoptive immunotherapies such as CAR T cells, despite being in nascent stages, are considered a potential option for treating aggressive solid tumors such as osteosarcoma.

Researchers from Xi’an Jiaotong University and Southern University of Science and Technology have conducted a comprehensive preclinical study to evaluate the efficacy and safety of a second-generation CAR T therapy targeting trophoblast cell-surface antigen 2 (TROP2) for the treatment of triple-negative breast cancer.

CAR T-cell therapy works by engineering a patient’s T cells to express synthetic receptors that recognize and kill cancer cells without relying on HLA presentation. This approach has shown remarkable success in relapsed or refractory B-cell cancers and multiple myeloma, resulting in several approved treatments. However, no CAR T therapy is currently approved for acute myeloid leukemia (AML) or T-cell acute lymphoblastic leukemia (T-ALL).