PD1 blockade alone and in combination with BTK/ITK inhibition in patients with refractory and recurrent primary central nervous system lymphoma
Dana-Farber Cancer Institute
Project Term: July 1, 2018 - June 30, 2023
We study a rare and aggressive brain cancer called primary central nervous system lymphoma (PCNSL). We are using an emerging knowledge of the genetic basis of PCNSL to develop novel clinical trials exploring the use of targeted and immunotherapy agents in PCNSL patients. These trials include assessment of the activity of a PD-1 inhibitor by itself and in combination with a BTK inhibitor in PCNSL patients, as well as identifying any mechanisms of treatment resistance that may develop. The goal of our clinical research is to enhance survival and improve neurologic function in PCNSL patients.
Primary central nervous system lymphoma (PCNSL) is an aggressive non-Hodgkin’s lymphoma associated with poor outcomes. Standard treatment involves high-dose chemotherapy followed by whole brain radiation or stem cell transplant. However, this treatment approach is intolerable to some patients, while others either do not respond initially or stop responding after extended treatment. There are no definitive treatment options for those patients who do not respond or whose disease has recurred. The majority of patients ultimately die of their disease, underscoring the fact that PCNSL remains a major unmet need in oncology today. New treatment approaches using our emerging understanding of the genetic basis of PCNSL are critical to improve outcomes for these patients. The immune system is capable of recognizing and killing tumor cells. However, tumor cells have identified mechanisms to evade the immune system, including the use of molecules called checkpoint proteins that dampen the effects of the immune system. Genetic analysis of PCNSL has identified genetic abnormalities involving checkpoint proteins. Another common mutation involves signaling pathways using the protein BTK. These genetic features suggest a compound treatment approach for PCNSL: blockade of the checkpoint protein PD-1 and inhibition of BTK, with both approaches using drugs already approved by the FDA for other cancers. A small number of PCNSL patients who were not responsive to standard therapies responded to PD-1 blockade. Therefore, we are extending these studies to assess the activity of a PD-1 inhibitor by itself and in combination with the BTK inhibitor ibrutinib in patients with PCNSL. Since patients can develop resistance to targeted therapy, we will assess any mechanisms of resistance that may develop by using a variety of laboratory studies. A primary symptom of brain tumors is the development of neurologic symptoms such as paralysis or impairment of language, memory, or vision, which may be permanent if not treated. Standard neurologic function testing is often subjective and variable, so we developed an assessment tool to measure neurologic function that can be easily performed by neurologists and non-neurologists. This tool is called NANO (neurologic assessment in neurooncology). We will evaluate neurologic function using NANO and response in patients with PCNSL treated with these drugs. The goal of my clinical research is to enhance survival and improve neurologic function in PCNSL patients treated with targeted therapies.