Anaplastic large cell lymphoma, a type of non-Hodgkin lymphoma, is the most common aggressive lymphoma in children. While chemotherapy and radiation can't cure around 30% of cases, ALK inhibitors like crizotinib are highly effective in blocking tumor growth when tumors are driven by the oncogene ALK, which is the case for most children. However, these ALK inhibitors are expensive, costing about $80,000 per year, and need to be taken indefinitely since stopping them results in the lymphoma's return.
Roberto Chiarle, MD, a hematopathologist and researcher at Boston Children's Hospital, sought to understand why lymphoma cells persist for so long even when controlled by ALK inhibitors. His findings, published in Science Translational Medicine, have led to plans for testing a new combination therapy in patients with relapsed anaplastic large cell lymphoma. If successful, this therapy may potentially eliminate the need for chemotherapy in the future.
Probing a lymphoma's safe haven
Roberto Chiarle and his team at the University of Torino discovered that persisting lymphoma cells tend to cluster around blood and lymphatic vessels, providing them protection. They created a microfluidic model to simulate vessels on a chip and found that when lymphoma cells were lodged within the vessel, ALK inhibitors couldn't kill them.
Further investigation revealed that endothelial cells lining the vessels produce two proteins, CCL19 and CCL21, which support the survival of lymphoma cells, even when ALK inhibitors prevent their growth and spread. The survival signal is weak but sufficient to keep the cells alive, and when the proteins were removed in lab experiments, the cells underwent apoptosis and died.
The team identified that the CCL19 and CCL21 signals activate PI3K through the CCR7 receptor. Blocking this pathway by deleting the receptor gene or inhibiting PI3K led to the death of the persisting lymphoma cells.
Fortunately, a clinically used PI3K inhibitor, duvelisib, showed promising results in combination with crizotinib when tested on mice with human anaplastic large cell lymphoma. Many mice were cured, while others experienced delayed recurrence. The researchers aim to optimize this combination therapy to increase the percentage of cured cases and potentially reduce the need for chemotherapy in the future.
Clinical trial planned
Exciting progress is being made in the fight against anaplastic large cell lymphoma, with a Phase 1 clinical study of crizotinib and duvelisib combination therapy in the works. This study aims to include both children and adults for whom chemotherapy has been unsuccessful. The Leukemia & Lymphoma Society's multicenter grant network may support the trial.
Dr. Roberto Chiarle is hopeful that these efforts will lead to effective treatments without the need for chemotherapy, reducing toxicity and the risk of secondary cancers. ALK inhibitors have shown great promise in other cancer types, and the combination with duvelisib holds potential for providing a chemotherapy-free cure for a significant proportion of anaplastic large cell lymphoma cases. This is particularly crucial for children, ensuring they have a chance for a healthier and longer life.
Source: Children's Hospital Boston