Dr Spiegel on the Challenges Associated With CAR T-Cell Therapy in Solid Tumors

Jay Spiegel, MD, assistant professor, Miami Miller School of Medicine, transplant and cellular therapy physician, Sylvester Comprehensive Cancer Center, discusses some of the challenges of using CAR T-cell therapy in patients with solid tumors.

Challenges in using cellular therapy in solid tumors have been notable, particularly concerning CAR T-cell therapy, Spiegel begins, adding that CAR T-cell therapy remains in early-phase studies and is associated with significant hurdles. This therapeutic approach involves the genetic reengineering of a patient's own T cells to target cancer cells. Conversely, an older method involves tumor infiltrating lymphocytes (TILs), which are immune cells that are already present within tumors, Spiegel states. Unlike CAR T cells, TILs have the advantage of residing within the tumor, potentially recognizing unique tumor presentations that may be challenging for CAR T cells to target, he elucidates. Following cell extraction, processing, and growth, TILs are transformed into a cell therapy product and administered back to the patient, he notes

The February 2024 FDA approval of lifileucel (Amtagvi), a TIL therapy, for adult patients with unresectable or metastatic melanoma marks a significant milestone in the development of cell therapy for solid tumors, Spiegel continues. This treatment approach has had considerable success, contrasting with the limitations of CAR T-cell therapy. CAR T-cell therapy can only target extracellular proteins; thus, its scope is limited compared with that of TILs, which can target intracellular antigens, offering broader applicability, he reports.

Moreover, CAR T-cell therapy faces hurdles penetrating the tumor microenvironment, a challenge shared with TIL therapy but particularly pronounced in the CAR T-cell context, Spiegel expands. Additionally, CAR T-cell therapy's ability to simultaneously target only 1 or 2 antigens complicates treatment, given the complexity of solid tumors. Unlike hematologic cancers, where specific targets, such as CD19, are present primarily on cancerous cells, solid tumors often express targets also found in healthy tissues, he explains. Using agents directed at these targets can lead to significant off-tumor toxicities, as demonstrated by mesothelin-targeting CAR T-cell therapy, which can inadvertently damage lung tissue, according to Spiegel. These challenges underscore the complexities and limitations confronting CAR T-cell therapy in the treatment of solid tumors, Spiegel concludes.