Chimeric Antigen Receptor (CAR) T-cell therapy has achieved transformative success in treating blood cancers, with certain B-cell malignancies showing complete remission rates exceeding 80%. However, applying this potent immunotherapy to solid tumors remains a formidable challenge.
The primary hurdles stem from the hostile tumor microenvironment (TME), which features heterogeneous antigen expression, physical barriers to T-cell infiltration, and an immunosuppressive nature that causes T-cell exhaustion. To overcome these obstacles, research is focused on continually refining the CAR T-cell design itself.
The field has advanced significantly through five successive generations of CAR design.
- First-Generation CARs established the concept, but lacked the necessary co-stimulatory signals for sustained T-cell activation and persistence.
- Second-generation CARs incorporated a single co-stimulatory domain (such as CD28 or 4-1BB), significantly improving T-cell proliferation and long-term durability.
- Third-generation CARs combined multiple co-stimulatory domains to further amplify activation and ensure robust activation, proliferation, and durability following antigen engagement.
- Fourth-Generation CARs (also known as “TRUCKS”), are engineered with an “armored” feature that allows them to secrete transgenic cytokines (like IL-12 or IL-18) directly at the tumor site. This payload is vital for enhancing T-cell activation and overcoming the immunosuppressive TME.
- Fifth-Generation CARs further incorporate sophisticated elements like dual-targeting and synthetic Notch (synNotch) receptors. This ensures CAR T-cells are only triggered when two distinct tumor markers are present, improving specificity and minimizing off-tumor toxicity
The personalized process for manufacturing autologous CAR T-cells (using a patient’s own cells) is lengthy and costly. Therefore, the development of allogeneic or “off-the-shelf” CAR T-cells from healthy donors is a major priority, promising superior scalability and immediate availability. Modern tools like CRISPR-Cas9 gene editing are critical in creating these universal cells by enabling precise genetic modifications to knock out endogenous T-cell receptors and other immunogenic markers, reducing the risk of immune rejection.
Despite the challenges, the potential of engineered T-cell therapy in solid tumors is now transitioning from experimental to clinical reality. 2024 saw the accelerated FDA approval approval of two different genetically modified T-cell therapies for solid cancers. The T-cell receptor (TCR) therapy afamitresgene autoleucel (afami-cel) was approved for advanced synovial sarcoma. Concurrently, the Tumor-Infiltrating Lymphocyte (TIL) therapy lifileucel was approved for unresectable or metastatic melanoma. These FDA approvals validate the potential for T-cell-based immunotherapies in solid tumors.
Future directions focus on regional delivery, combination treatments with checkpoint inhibitors, and the use of artificial intelligence (AI) for optimizing target discovery and trial design. With ongoing technological innovation, CAR T-cell therapy is poised to fundamentally reshape the future landscape of cancer immunotherapy for a wider patient population.
Reference Source:
Rafii, S.; Mukherji, D.; Komaranchath, A.S.; Khalil, C.; Iqbal, F.; Abdelwahab, S.I.; Abyad, A.; Abuhelwa, A.Y.; Gandikota, L.; Al-Shamsi, H.O. Advancing CAR T-Cell Therapy in Solid Tumors: Current Landscape and Future Directions. Cancers 2025, 17, 2898. DOI https://doi.org/10.3390/cancers17172898
