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CD19 CAR T cells induce high response rate in advanced ALL
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Nearly all patients with advanced B-cell acute lymphoblastic leukemia treated with genetically engineered chimeric antigen receptor T cells achieved remission, according to study results published in The Journal of Clinical Investigation.
However, some remissions were transient and some patients became immune to the targeted immunotherapy, results showed.
“Patients who come onto this trial have really limited options for treatment,” Cameron J. Turtle, MD, PhD, research associate at Fred Hutchinson Cancer Research Center and acting instructor at University of Washington School of Medicine, said in a press release. “They have refractory, acute leukemia. So the fact that we are getting so many into remission is giving these people a way forward.”
Genetically modified T cells expressing a CD19–specific chimeric antigen receptor (CAR) have shown antitumor activity in B-cell malignancies, according to study background.
Prior studies have shown difficulty in identifying factors that determine safety and efficacy of these T cells, in which phenotypically heterogeneous CAR T-cell products were prepared from unselected T cells.
Turtle and colleagues conducted an early-phase trial that included data from 32 adult patients with advanced B-cell ALL (median age, 40 years; range, 20-73). They manufactured CD19 CAR T cells from defined CD4– and CD8–positive T-cell subsets, which they administered in a defined CD4–/CD8–positive composition after lymphodepletion chemotherapy.
The trial studied three dose levels — 2 x 105/kg, 2 x 106/kg and 2 x 107/kg — administered between 48 hours and 96 hours after lymphodepleting chemotherapy. The researchers did not observe any severe toxicities within 2 hours of infusion. However, dose level 3 was deemed too toxic and was discontinued after the first two patients treated at that level developed severe toxicities, including one patient who died.
The researchers observed high incidences of cytokine release syndrome, which occurred in 25 of 30 patients evaluable for toxicity, and severe neurotoxicity (n = 15), occurring concurrently with or after the resolution of cytokine release syndrome.
Toxicity burden appeared to decrease with the use of risk-stratified CAR T-cell dosing based on bone marrow disease burden.
However, among 11 patients who underwent prior allogeneic hematopoietic stem cell transplantation, there was no observable difference in the rate or severity of toxicity.
Of 29 evaluable patients, 27 (93%) achieved complete bone marrow remission after infusion, with no detectable leukemia by flow cytometry; the CAR T cells further eliminated cancers anywhere they appeared in the bodies of these patients.
Seven patients who achieved remission eventually relapsed. One patient who relapsed had CD19–negative leukemia; the remaining six had CD19–positive disease, which suggested a loss of CAR T-cell immunosurveillance.
Better DFS outcomes and improved CAR T-cell persistence were seen in the 17 patients who received fludarabine as part of their lymphodepleting chemotherapy, with all but one of these patients achieving complete remission.
The researchers acknowledged study limitations, including the small patient population at this phase. The trial also was not designed to provide definitive evidence of the therapy’s effectiveness against cancer.
The trial remains ongoing and continues to enroll patients, and the researchers plan to publish results from a larger series in the future.
“This is just the beginning,” Turtle said. “It sounds fantastic to say that we get over 90% remissions, but there’s so much more work to do to make sure they’re durable remissions, to work out who’s going to benefit the most, and extend this work to other disease.” – by Cameron Kelsall
Disclosure: The NCI and Juno Therapeutics provided funding for this study. Turtle reports research funding from Juno Therapeutics. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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David L. Porter , MD
This report from Turtle and colleagues confirms the very high response rate seen in adult patients with very advanced and refractory acute lymphoblastic leukemia, but also is really the first attempt at administering CAR T cells with a defined cell population. However, at this point, we dont yet know what constitutes an ideal cell product. Being able to define and engineer the product to include specific cell populations has the potential to enhance both the activity and safety of this approach.
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