Targeting the microenvironment to increase immunity and immunotherapy response in DLBCL
Leandro Cerchietti
MDWeill Cornell Medicine
Project Term: July 1, 2024 - June 30, 2027
To survive and proliferate lymphoma cells must co-opt normal cells residing the tumor microenvironment. This process results in the suppression of the activity of immune cells that otherwise will attack cancer cells. In this project we will develop a novel oral treatment that by acting on the microenvironment will restore lymphoma immunity and increase the activity of immunotherapy.
This proposal is about targeting the most common aggressive B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL). DLBCLs are composed of malignant (i.e., lymphoma cells) and non-malignant cells (i.e., microenvironment cells). Over these past years we are elucidating the role of microenvironment cells in lymphoma progression. One of the mechanism these cells employ to allow favor tumor survival and progression is to decrease the ability of the immune cells (e.g., T cells) to attack the lymphoma cells. This local immunosuppression is created by the crosstalk between lymphoma and microenvironment cells in a self-perpetuating vicious circle. Targeting lymphoma cells may affect this crosstalk and transiently improve immunity but is usually not enough to eradicate the tumor. Moreover, when immunotherapies that increase the number of T cells encounter this type of microenvironment their efficacy is also decreased. We identified a mechanism by which lymphoma and microenvironment cells maintain this milieu. By using a novel oral drug that specifically target this pathway (called QPCTL) we found that the whole microenvironment is modified potentiating the activity of immune cells as well as improving the efficacy of antibody based clinical treatments like rituximab. In this proposal, we will conduct studies of patients’ samples and animal models to understand what patients are more likely to respond from this treatment and what type of immunotherapy will benefit from adding this drug. Our goal is to develop a non-toxic chemotherapy-free treatment for patients with DLBCL.