The application of CAR T-cell therapy to solid tumors presents significant challenges that differ from those encountered in hematologic malignancies. Renier Brentjens, MD, PhD, highlights the critical issues of target antigen heterogeneity, immunosuppressive microenvironments, and fibrotic structures as key obstacles. Despite these hurdles, Brentjens remains optimistic about the future role of CAR T cells in treating solid tumors within the next decade. He likens the current state of this technology to a Model T Ford, suggesting that advancements are needed to transform it into a Mustang. This analogy underscores the necessity for technological improvements to make CAR T-cell therapy more effective against solid tumors.

Renier Brentjens, an esteemed oncologist and researcher, has dedicated much of his career to advancing CAR T-cell therapy. Initially focusing on blood cancers like acute lymphoblastic leukemia (ALL), Brentjens and his team successfully targeted the CD19 protein, which is abundantly present on ALL tumor cells. However, transitioning this approach to solid tumors proves more complex due to their structural differences. In solid tumors, such as colon, breast, or prostate cancer, there is considerable variability in the expression of target antigens. For instance, while some colon cancer cells may express carcinoembryonic antigen (CEA), others do not, complicating the targeting process.

Beyond antigen heterogeneity, solid tumors often create an immunosuppressive microenvironment by recruiting immune cells that hinder the effectiveness of CAR T cells. Additionally, these tumors are encased in fibroblasts, forming a physical barrier that obstructs the access of CAR T cells. These factors collectively contribute to the difficulty in applying CAR T-cell therapy to solid tumors using the same paradigms developed for blood cancers.

Researchers are exploring various strategies to overcome these challenges. One approach involves engineering dual-targeted CAR T cells, which carry two different receptors to minimize the risk of antigen escape. However, this method faces limitations as antigen heterogeneity persists. Another promising avenue is the development of armored CAR T cells, which are engineered to secrete proinflammatory cytokines. These cytokines help counteract the immunosuppressive environment and engage the patient's own immune system, similar to how immune checkpoint inhibitors function. Combining CAR T-cell therapy with conventional chemotherapy or other immune-based therapies also holds potential for enhancing treatment efficacy.

While significant progress has been made in applying CAR T-cell therapy to blood cancers, extending its benefits to solid tumors requires overcoming substantial scientific and technological barriers. Researchers are actively investigating innovative solutions, including armored CAR T cells and combination therapies, to address the unique challenges posed by solid tumors. As these efforts continue, the prospect of effectively treating solid tumors with CAR T-cell therapy becomes increasingly feasible, offering hope for improved patient outcomes in the near future.