Exploiting tumor-immune dynamics to inform curative combination therapy for follicular lymphoma
Mark Murakami
MDDana-Farber Cancer Institute
Project Term: July 1, 2024 - June 30, 2027
Follicular lymphoma is a common form of blood cancer, affecting 15,000 new patients annually in the United States, but it remains incurable with conventional treatments. Bispecific antibodies represent a new class of therapies that engage the immune system to attack lymphoma cells and have shown promising effectiveness in inducing remissions in patients with this disease, but even they are unlikely to be curative. Researchers from the Dana-Farber Cancer Institute here propose to analyze lymphoma cells from patients undergoing treatment with bispecific antibodies on several complementary clinical trials to determine how these cells evade the immune system and develop resistance. It is believed that such mechanisms of resistance may reveal vulnerabilities within the lymphoma cells that novel treatments can overcome in combination with bispecific antibodies to cure patients with follicular lymphoma.
Follicular lymphoma is a common form of blood cancer, affecting 15,000 new individuals per year in the United States. Standard treatment comprises an immune molecule called a monoclonal antibody with or without chemotherapy. At the cost of side effects like allergic reactions, low blood counts, infections, and others, most patients achieve remissions, but these are temporary. Virtually all eventually relapse. Moreover, one of every five patients experiences worsening of disease much sooner than normal, with very unfavorable implications for response to subsequent treatments and overall survival. We currently lack tools with which to predict outcomes for individual patients prior to treatment with sufficient precision to influence treatment decisions. Thus, among the most urgent unmet needs for individuals with follicular lymphoma are well-tolerated, curative treatment options and the predictive tools to guide their optimal use.
Bispecific antibodies represent a novel class of therapies that bring immune cells into physical proximity with lymphoma cells to promote their elimination. They have demonstrated a very promising ability to clear the lymphoma that is detectable with conventional imaging tests like PET CT scans in patients whose lymphoma has proven resistant to or progressed on initial treatments. They also seem to induce less toxicity than conventional chemotherapy. However, data from clinical trials suggest that bispecific antibodies will require combination with other drugs and novel dosing strategies to maximize their potential benefit and minimize toxicity for patients. The Dana-Farber Cancer Institute is conducting multiple clinical trials of bispecific antibodies for follicular lymphoma, including two that are well underway for individuals with previously untreated disease. Our laboratory scientists work seamlessly with clinical investigator colleagues to inform precision approaches that channel biological discoveries into new combination treatments in pursuit of a cure for follicular lymphoma.
Here we propose to analyze bone marrow and blood from individuals with follicular lymphoma prior to treatment, on-treatment in a deep remission, and at the time of progression (when this occurs) on bispecific antibodies. By defining how lymphoma cells change over time using advanced molecular approaches, we will pinpoint vulnerabilities to target with combination therapies to prevent or overcome resistance. Critically, we will also determine how the immune system changes during this time to inform approaches for maintaining or even enhancing the anti-tumor immune response. This is important because many cancer treatments can suppress immune function. We will test potential new combination treatments within laboratory model systems that simulate the biology of follicular lymphoma. Successful execution of this proposal will reveal the most promising combination partners for bispecific antibodies for investigation in future clinical trials.