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One of the biggest hurdles that stall new developments in cancer therapy is how to effectively deliver the treatment to the tumor. Most commonly, pharmaceutical agents and immunotherapies make their way to the tumor via the bloodstream. Hence, the successful emigration of these agents out of the blood vessels into the deeper tissue dictates the efficacy of the treatment. While cancer vasculature is alleged to be leakier, a lot of life-threatening cancers still show resistance against common cancer therapies, including chemotherapy and T cell therapies, like CAR-T cell therapy. So how do scientists overcome this delivery obstacle after devoting decades of efforts in developing the treatment?
Despite its great success in blood cancers like leukemia, CAR-T cell therapy has been of little help with brain tumors. These engineered T cells have a hard time exiting the blood vessels in the brain to attack the glioblastoma mass residing deeper in the brain. Blood vessels in the brain are known for their tight junction, forming a protective barrier around our most delicate and essential organ. The strictly regulated blood-brain-barrier restricts the movement of cells and molecules between the blood circulation and the surrounding nervous system. Additionally, compared to other types of immune cells, T cells require longer adhesion to the endothelial cells that make up the blood vessels before they can pass into the brain, reducing the likelihood that they make this journey. This extended cell-cell interaction phase is presumed to help the T cell identify the prime spot to cross the vessel barrier. To facilitate T cell transmigration, endothelial cells also need to be stimulated to express more surface cell adhesion molecules to trap the circulating T cells. This increased expression of adhesion molecules is normally regulated by inflammation, a natural scenario for T cell exiting the blood vessel to fight off infections in the tissue. Given the complicated cell-cell interactions required for successful T cell migration, it is not surprising to see that engineered T cells can’t exit the blood vessels in the brain.
Tackling this problem, scientists and doctors around the world have collaborated and put forward an improved treatment prototype for GBM patients. Published in Nature in September of this year, and discussed in an earlier OncoBites piece, this paper proposed the concept of a homing system for the engineered T cells to improve T cell therapy. Through a thorough examination of the blood vasculature characteristics in the cancerous environment, scientists found that tumor endothelial cells express a unique set of adhesion molecules that includes activated leukocyte cell adhesion molecule (ALCAM). By engineering the therapeutic T cells to express the natural binding partner of ALCAM, CD6, the researchers were able to trigger T cell to adhere to the tumor endothelial cells. This enhanced cell-cell engagement then initiates T cell transmigration and exiting the blood vessels to attack tumor cells in the brain. Allowing for more efficient emigration of therapeutic T cells, this ALCAM-specific homing system led to tumor regression and extended survival in mice. Similarly engineered T cells are under clinical trial for various solid tumor cases in humans.
Similarly, in the chemotherapy realm of cancer therapy, most nanoparticle drug carriers also depend on the increased vascular permeability in the tumor environment to efficiently deliver pharmaceutical compounds to cancer cells. Difficulty in crossing the endothelial barrier has greatly limited the clinical benefits of nanoparticle cancer drugs. Applying a similar methodology, a group of Asian scientists from various institutes in China, South Korea, and the US has developed an improved nanoparticle that can deliver drugs more effectively to cancer cells. Published in November’s issue of Small, this study took advantage of the unique characteristics of tumor endothelial cells in improving nanoparticle carrier structure. Having detected an increased expression of selectins, another type of cell-cell adhesion molecules, on the endothelial cells in tumor vasculature, the scientists added a known selectin binding partner, quinic acid, to the current nanoparticles used for drug delivery. Engagement of selectin molecules on the endothelial cells by the quinic acid on the nanoparticles allowed the nanoparticle and the drug to traverse the endothelial barrier. Compared to traditional nanoparticles carrying the same drug, the quinic acid nanoparticles significantly increased survival in a cancer model in mouse, suggesting the potential of this new nanoparticle in improving the clinical benefits of chemotherapies in patients.
The extremely high similarity in the methodology behind the two studies provokes me to ponder on the importance of interdisciplinary collaboration in life science and research in general. After identifying and producing the agents for cancer therapy, how to introduce them safely and effectively into the patients has become on the bottleneck limiting progress in the field. Needless to say, research in both processes should go hand in hand, yet possessing a more comprehensive physiological and pathological view is also crucial. One can never anticipate from which angle the creative solution might derive from. These two recent studies are inspiring examples that demonstrate how science outside of direct cancer research can contribute to its advancement.
Samaha, H., Pignata, A., Fousek, K., Ren, J., Lam, F. W., Stossi, F., . . . Ahmed, N. (2018). A homing system targets therapeutic T cells to brain cancer. Nature, 561(7723), 331-337.
Xu, J., Lee, S. S.-Y., Seo, H., Pang, L., Jun, Y., Zhang, R.-Y., . . . Yeo, Y. Quinic Acid-Conjugated Nanoparticles Enhance Drug Delivery to Solid Tumors via Interactions with Endothelial Selectins. Small, 0(0), 1803601.
Tumor blood vessels are leaky and have many gaps. Created with BioRender by Sara Musetti