Effective immunotherapy for relapsed or treatment-resistant leukemia

From Dr. Jordan Gauthier and colleagues, Clinical Research Division

Leukemias are a group of cancers involving the white blood cells. One subtype, chronic lymphocytic leukemia (CLL), specifically produces defective lymphocytes, a type of white blood cell. While many people with CLL have an indolent disease, those with specific genetic mutations or other high-risk features may have rapidly developing disease in which immune function is ineffective and cancer cells have exacerbated growth. This limits the expansion of normal cells in the bone marrow and in the blood. Individuals with severe CLL develop enlarged lymph nodes and opportunistic infections. If treatment is necessary for high-risk CLL, a commonly used medication is ibrutinib, a Bruton’s tyrosine kinase inhibitor that initially at least slows growth of CLL cells. Yet, with this and other therapies, CLL relapse or resistance to therapy inevitably occurs. Immunotherapies, which are therapies that help one’s immune system recognize and attack cancer cells, are now a well-studied alternative to chemotherapy and other cancer therapies and can be used in combination with other treatments. Autologous Chimeric antigen receptor-modified (CAR) T-cell therapy is a type of immunotherapy where a patient’s T cells are removed and engineered to better detect cancer cells, before putting them back into the patient. In the case of CLL, the T cells are genetically engineered to recognize the CD19 antigen, a protein present on the surface of these leukemia cells. CD19 CAR T-cell therapy has been shown to be an effective short-term treatment for relapsed/refractory CLL but had not been comprehensively evaluated for its long-term outcomes.

To extend this work, first author Dr. Emily Liang, a hematology/oncology fellow at the University of Washington and Fred Hutchinson Cancer Center, Dr. Jordan Gauthier, an attending physician and Associate Professor in the Clinical Research Division at Fred Hutch, and their colleagues evaluated the long-term effectiveness of CD19 CAR T-cell therapy for the treatment of relapsed/refractory CLL. They studied the outcomes of patients with relapsed/refractory CLL who had been treated with an investigational CD19 CAR T-cell product (JCAR014) on a clinical trial conducted at Fred Hutch. Forty-nine relapsed/refractory CLL patients, with a median age of 61, were enrolled and treated between 2014 and 2018. These individuals had received a median of 5 prior therapies before the clinical trial began and roughly 40% of patients were taking ibrutinib at the start of the trial. Patients were evaluated for initial response to treatment and CAR T-cell persistence in the blood 28 days post-immunotherapy infusion and were followed for about 6.5 years to understand the factors associated with long-term effectiveness. The researchers found that the median duration of response was about 1.5 years and about 26% of patients continued to positively respond to immunotherapy treatment for 6 years or longer which mirrored survival percentages. These findings were published in Blood Advances.

Long-term (over 6 years) response evaluation workflow of CD19 CAR T-cell therapy to treat relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) in a phase I/II clinical trial.
Long-term (over 6 years) response evaluation workflow of CD19 CAR T-cell therapy to treat relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) in a phase I/II clinical trial. Image provided by Dr. Liang

“We demonstrate that CD19 CAR T-cell therapy can induce durable responses in patients with heavily pre-treated and high-risk relapsed/refractory CLL,” stated Dr. Liang. About 70% of the patients evaluated had evidence of persistent CAR T cells for up to or longer than 1 year following initial infusion and the longest time observed was over 7 years of persistent CAR T cells. The median overall survival of this patient cohort was about 2 years and about 30% of patients lived for 6 years or longer after the initial immunotherapy infusion.

“We found that pre-treatment factors such as bulky disease and high [standardized uptake value] SUV on PET CT scan can predict patients who are at high risk of relapse after CAR T-cell therapy,” stated Dr. Liang. “This suggests that it would be beneficial to reduce disease burden as much as possible before CAR T-cell therapy and that early referral to CAR T-cell therapy center might be beneficial. We also found that post-treatment factors such as depth of response, CAR T-cell expansion, and CAR T-cell persistence predict longer remission after CAR T-cell therapy. This highlights that strategies improving CAR T-cell fitness will be key to improve patient outcomes. Our work also helps contextualize the findings of the TRANSCEND CLL 004 trial, which we anticipate will lead to the first FDA approval of CAR T-cell therapy for CLL.”

“These findings raise questions of how to optimize CAR T-cell therapy,” shared Dr. Liang. “For example, what are the optimal ways to reduce disease burden before CAR T-cell therapy? How can we engineer CAR T-cells so that they are more effective and last longer in the body? Our research group and others at the Fred Hutch are currently studying these questions.” Importantly, this clinical trial was performed with a collaborative group of researchers and physicians. In addition to these individuals, “the Cancer Consortium Collaboration has enabled this research by creating a strong clinical research program,” stated Dr. Liang. “Through the Consortium, we treated nearly 50 CLL patients on this clinical trial and were able to perform in-depth correlative studies to assess associations with long-term outcomes.”

The spotlighted research was funded by the National Institutes of Health, the Life Sciences Discovery Fund, the Bezos Family Foundation, the University of British Columbia Clinical Investigator Program, and Juno Therapeutics, a Bristol Myers Squibb Company.

Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Alexandre Hirayama, Andrew Portuguese, Aude Chapuis, Mazyar Shadman, Brian Till, Ryan Cassaday, Filippo Milano, Hans-Peter Kiem, Stanley Riddell, David Maloney, and Jordan Gauthier contributed to this work.

Liang EC, Albittar A, Huang JJ, Hirayama AV, Kimble EL, Portuguese AJ, Chapuis AG, Shadman M, Till BG, Cassaday RD, Milano F, Kiem HP, Riddell SR, Turtle CJ, Maloney DG, Gauthier J. 2023. Factors associated with long-term outcomes of CD19 CAR T-cell therapy for relapsed/refractory CLL. Blood Adv. bloodadvances.2023011399.