Advanced Anti-Tumor Immunotherapy Platform with Translational Potential

Immunotherapy has revolutionized cancer treatment by giving doctors a way to train or strengthen a patient's immune system to fight against malignant tumors. While the immune system can usually identify most cancers, so-called "cold tumors" evade detection.

While immune checkpoint inhibitors form the backbone of several immunotherapies, they are ineffective against cold tumors. The latest study comes from the Brigham and Women's Hospital and focuses on a protein called serine protease inhibitor B9 (SerpinB9, Sb9), whose potential significance in cancer cells has been underappreciated but which may pave the way for the development of novel immunotherapies.

BsAbs for thrombopoiesis modulation

They used a number of animal models and found that inhibiting Sb9 with tiny compounds significantly decreased the development of tumors. This was accomplished by reducing the effectiveness of cold tumor defense systems and causing cell death within the tumors themselves. These findings were recently presented in an article titled "Direct Tumor Killing and Immunotherapy through Anti-SerpinB9 Therapy".

According to Reza Abdi, MD, of the Division of Nephrology at Brigham and Women's Hospital, who was the paper's corresponding author, "In this work, we provide proof of concept utilizing a small molecule that is designed to destroy cancer via its own lytic enzyme mechanism.  Immunotherapies, such as monoclonal antibodies or immune checkpoint inhibitors, are promising approaches that have garnered a substantial portion of research. On the other hand, antibodies are difficult to genetically manipulate and can potentially be harmful to patients. It's possible that developing smaller compounds that limit Sb9 activity will be easier, and that they'll also be more effective."

These researchers used the gene editing tool known as CRISPR-Cas9 to produce tumors in mice that lacked Sb9 and discovered that the growth of these tumors was slowed down significantly. Nevertheless, scientists also saw that Sb9 was expressed in cancer-associated fibroblasts as well as immunosuppressive cells that surrounded the tumors. This allowed the cancer to flourish by dampening the immune system's reaction to the disease, which in turn supported its development.

These researchers have known for a long time that Sb9, when present in normal immune cells, acts to protect these cells against their own damaging enzyme, which is termed granzyme B. (GrB). These cells produce an enzyme known as GrB, which is then released in order to combat invading cells. On the other hand, the fact that cancer cells include Sb9 and GrB is not commonly understood. The researchers discovered a high expression of Sb9 in a variety of human and animal malignancies. This protein makes it possible for tumors to withstand an onslaught by GrB.

Abdi stated, "The initial findings suggested that tumors missing the Sb9 protein developed more slowly. On the other hand, when we implanted knockdown Sb9 tumors in mice that lacked Sb9, we noticed a more dramatic reduction in the growth of the tumor. Based on these findings, it appears that if we are successful in locating a drug that can systematically inhibit this protein in both tumors and host cells, then we will be able to simultaneously target the various pathogenic weapons that are involved in the formation of tumors. These weapons include cancer-associated fibroblasts and immunosuppressive cells. This will allow us to achieve synergistic effects."

These researchers came up with a unique small-molecule inhibitor that binds to Sb9 and stops the protein from performing its function in mice. Particularly noteworthy is the fact that this small molecule inhibitor successfully controlled a number of solid tumor mouse models.

Abdi recognizes that much more study is needed to enhance the binding kinetics of this small molecule inhibitor of Sb9 and to establish the molecular basis of this interaction, as well as that thorough toxicity testing must be conducted before the drug can enter clinical trials.