Finally a proxy for tracking responses in chronic lymphocytic leukemia

A new study published in the Proceedings of the National Academy of Sciences suggests it may finally be possible to predict when patients are becoming resistant to a common treatment used in chronic lymphocytic leukemia (CLL).

Despite treatment advances, CLL remains incurable. Managing CLL has been complicated by the fact that no one to now has found a way to predict when a treatment has stopped working. There was no known biomarker—such as a protein in blood or urine—that could be monitored to determine treatment effectiveness or failure. Such a biomarker is useful for gauging disease progression and guiding treatment decisions.

CLL is a form of non-Hodgkin lymphoma that originates from B lymphocytes (B cells), a type of white blood cells, leading to abnormal increases of these cells in the blood, bone marrow, lymph nodes and other organs. Treatment depends on the disease’s characteristics and the patient’s overall health. Options include newer drugs that target the cancer cells’ growth and survival mechanisms or immunotherapies.

The new research, led by Winship and Emory University scientists, found that nearly all activated and growing CLL cells express PD-1, an important protein that is normally seen in some T cells but not in B cells. They showed that CLL cells express PD-1 after they receive growth signals that can actually be blocked by Bruton’s tyrosine kinase inhibitors (BTKi), an important class of drugs commonly used to treat CLL.

“Indeed, the percentage of CLL cells that have PD-1 in the blood correlated with BTKi treatment response and progression,” says study lead Andres Chang, MD, PhD. “This suggests that PD-1 expression could be a useful biomarker to predict response and resistance to BTKi therapy. Additionally, eliminating CLL cells that express PD-1 could be a potentially useful therapeutic strategy.” Chang is a member of the multidisciplinary care team in Winship’s Bone Marrow and Stem Cell Transplant Center and assistant professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine.

“This research started from the ground up at Emory,” Chang says. “It began with the discovery of PD-1+ CLL cells while looking at PD-1 expression in T cells.” Besides its being unique, Chang says the study provides a good marker that identifies proliferating CLL cells and their relationship with BTK.

“This allows us to better study the growing cells using blood samples and without invasive biopsies,” Chang says. “It also gives us the opportunity to track disease response to BTK inhibitors and opens up opportunities to explore new therapeutic targets.”

Rafi Ahmed, PhD, co-leader of Winship’s Cancer Immunology Research Program, director of the Emory Vaccine Center and professor in the Department of Microbiology and Immunology at Emory University School of Medicine, says, “This study not only provides a biomarker for monitoring responsiveness to lymphoma treatment but also suggests new therapeutic approaches for eliminating the most actively dividing lymphoma cancer cells.”

Chang says researchers’ next steps will be “determining what PD-1 does in CLL cells and in other B cell cancers and exploring ways to target those cells for therapeutic purposes.” CLL can sometimes transform into an aggressive B cell lymphoma, a process known as Richter’s Transformation. These aggressive lymphomas are deadly and highly resistant to current therapies. However, PD-1 expression is retained in this aggressive cancer and may be a promising therapeutic target, according to Chang.

The study has potentially enormous implications for people with CLL. “This study can potentially have a great impact on the care of patients with CLL as it opens up a way in which we could monitor treatment response,” Chang says. “It also provides opportunities to identify novel therapeutic targets for this incurable disease.”

Besides Chang, Winship collaborators included Rafi Ahmed, PhD, Amy Ayers, Jean Koff, MD, MS, Alyssa M.K. Leal, Michael C. Churnetski, Colin B. O’Leary, David A. Frank, MD, PhD, Jonathon B. Cohen, MD, MS, Rafick-Pierre Sékaly, PhD, and Jeffrey M. Switchenko, PhD, MS. Also from Emory were Carl Davis, PhD, Donald J. McGuire, PhD, and Adam N. Pelletier with the Emory Vaccine Center. The research team also included former Winship member Christopher R. Flowers, MD, MSc, with MD Anderson; and Maria Tsagiopoulou, PhD, Maria Karipidou, MSc, and Kostas Stamatopoulos, MD, PhD, with the Institute of Applied Biosciences at the Centre for Research and Technology Hellas, in Thessaloniki, Greece.

This work was supported by Winship institutional funds and awards from the National Institutes of Health (K08AI178093, T32CA160040, K12CA237806, P51OD011132, P30CA138292, S10OD026799, UL1TR002378), the Georgia Clinical & Translational Science Alliance, the American Society of Hematology, the CLL Society, the Hellenic Foundation for Research and Innovation, and Horizon Europe. This project was also supported by the Emory NHP Genomics Core, the Emory Integrated Genomics Core, the Winship Cancer Tissue and Pathology Shared Resource and the Emory Flow Cytometry Core. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.