Weill Cornell Medicine
Project Term: October 1, 2021 - September 30, 2024
Follicular lymphomas (FL) depend on stromal cells for survival and proliferation and evade T-cell immune surveillance. Although indolent, most FLs eventually undergo either progression or transformation to an aggressive lymphoma. Effective treatments to prevent this remain a critical unmet need. This proposal will develop novel, mechanism-based therapeutic regimens for FL that overcome defective immune surveillance, prevent FLs from receiving stromal support and prevent disease progression.
Follicular lymphoma (FL) is a cancer that affects white blood cell, specifically B-lymphocytes, which normally help our body fight infections. These malignant B-cells can disseminate throughout the human body, where they can lodge in various tissues to form tumors. Malignant FL cells cannot live in isolation, and instead must hijack normal cells from other branches of the immune system to maintain their growth and survival. This mixture of tumor cells and their supporting normal cells is known as the tumor “microenvironment”. Although FLs initially grow slowly and may not need to be treated immediately, they often pick up speed and progress to a more dangerous state. Eventually, as many as 45% of FL cases undergo transformation to a highly aggressive, fast-growing and generally treatment-resistant form of lymphoma. Because of this, it is of paramount importance to develop improved therapies that can prevent FL progression and aggressive transformation, and we believe that the best route to achieve this is through understanding how this disease works so we can kill these tumors cells by disrupting their microenvironment and denying their capacity to survive.
Approximately 30% of FLs contain a mutation in a gene called EZH2. We have recently shown that these mutations completely reprogram the way that B-cells interact with the immune microenvironment to create typical malignant FL tumors. Interestingly, this includes enabling the FL cells to evade contact with tumor-killing T-cells, while enhancing their direct interaction a kind of immune supportive cell called “follicular dendritic cells” (FDCs). Indeed, FLs typically contain extensive networks of these follicular dendritic cells that send out projections to interact with practically every malignant cell within these tumors.
Herein, we will define the precise set of mechanisms through which these FDC networks maintain FLs to enable their progression and transformation. We predict that blocking the ability of specific molecular interactions that we identified as being crucial for mutant B-cells to be supported by FDCs will cause these tumors to collapse. We propose that further addition of drugs that target EZH2 will cause normal T-cells to regain their ability to attack and kill FL cells, and this killing effect will be further enhanced through use of drugs that suppress any residual survival capacity of the FL cells. Importantly, the three types of drugs we plan to deploy are already available for use in humans and do not have any overlapping toxicities, allowing them to be readily combined without causing significant side effects. Overall we expect this unique and innovative mechanistic therapy approach will eradicate FLs and eliminate the danger of progression and transformation.