Researchers develop test to predict durable remissions after CAR-T for lymphoma
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Researchers have developed a novel quantitative assay that can predict which patients will achieve durable remissions after CD19-directed chimeric antigen receptor T-cell therapy for non-Hodgkin lymphoma.
Patients who had approximately 3,000 or more CD19 molecules on the surface of their cancer cells appeared more likely to have durable responses to CAR T-cell therapy, whereas patients with surface density below this threshold tended to experience disease relapse after treatment.
Investigators developed the assay to determine target antigen density on lymphoma cells as part of a phase 1 clinical trial designed to assess the safety, feasibility and efficacy of a novel bispecific CAR-T developed at Stanford University and manufactured onsite.
“It will guide future treatments — not just CAR-T, but also monoclonal antibodies and antibodies with payloads or any drug with a specific target antigen,” David B. Miklos, MD, PhD, clinical director of cancer cell therapy and professor in the department of medicine at Stanford University, told Healio. “This was the first study to examine how we can measure the amount of CD19 target on the surface of lymphoma.”
Background
Miklos and colleagues developed a bispecific CAR-T that targeted both CD19 and CD22 on the surface of cancer cells. The CAR-T performed like commercially available therapies, according to Miklos. However, a high proportion of patients experienced disease relapse despite investigator’s use of a dual-targeting approach.
The investigators had expected the results would show that bispecific CAR T cells effectively kill tumor cells the way they had in preclinical animal models, Miklos said.
"We had hoped to overcome the problem of CD19 antigen downregulation,” he added. “These results show the pressure of performing inside of a patient with cancer is different than what preclinical testing can show.”
The fact that loss of antigen expression among patients who received CAR-T for leukemia causes disease progression has been known for years but is in the process of being confirmed for lymphoma through preclinical research and ongoing studies like those his group is conducting, Miklos said.
The questions for researchers became whether they could measure the amount of CD19 target on the surface of lymphoma cells, and how they could make this information useful to clinical decision-making.
Methodology
To answer these questions, Miklos and colleagues evaluated a cohort of 44 consecutive patients who received axicabtagene ciloleucel (Yescarta; Kite Pharma/Gilead Sciences) — a CD19-directed CAR-T — to determine whether resistance to therapy among patients with large B-cell lymphoma is associated with CD19-negative or CD19-low relapse.
The investigators used immunohistochemical analysis of biopsied tumor samples to develop an H-score that determined the density of CD19 on the surface of lymphoma cells.
They subsequently deployed a more sensitive flow cytometry test developed at Stanford University that determined the number of CD19 molecules on the surface of a cancer cell.
The investigators developed the quantitative assay to evaluate whether any threshold level of antigen density on cancer cells could predict outcomes after treatment with axicabtagene ciloleucel, also known as axi-cel.
Key findings
Miklos and colleagues employed a penalized logistic regression model and found that patients with lower pretreatment median CD19 density had a significantly increased risk for disease progression after receiving axi-cel (P = .03).
Patients with 2,934 CD19 molecules or less on the surface of lymphoma cells had a 50% risk for disease progression. This led the investigators to establish a 3,000-molecule threshold to define CD19-positivity.
Three of four patients with large B-cell lymphoma who had a CD19 density of less than 3,000 molecules per cell experienced disease progression, compared with only one of 11 patients in the same cohort who had density above 3,000 CD19 molecules per cell.
Investigators found no association between CD19 positivity before treatment and durable response to therapy (Fisher’s exact test P = 1). Pretreatment H-scores evaluated as a continuous variable also failed to show any association with disease control after CAR T-cell therapy (t-test P = .32).
“These data demonstrate that progression after axi-cel therapy for [large B-cell lymphoma] is associated with emergent CD19-negative/CD19-low disease in a high percentage of patients, but pretreatment semiquantitative [immunohistochemical] measurement of CD19 expression does not identify patients at risk [for] relapse,” Miklos and colleagues wrote.
Clinical implications
Determining the antigen density of a patient’s lymphoma cells prior to treatment is useful and practical, and it should be available soon to most clinicians who treat patients, Miklos said.
The materials needed to perform the assay are commercially available, and his group is already sharing their fluorochrome panels with other CAR-T centers to enable on-site evaluation for future clinical trials.
“Most of the companies in the CAR-T business are now employing this technology,” Miklos told Healio.
The assay provides actionable data to optimize treatment, Miklos said. If a patient is found to have a CD19 density below 3,000 molecules per cell, he said he would advise another treatment strategy be recommended.
"We are fortunate many different targeted therapies are becoming available, both in terms of monoclonal antibodies and CAR-T,” he said.
For more information:
David B. Miklos, MD, PhD, can be reached at dmiklos@stanford.edu.
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