Immunologic Biomarkers and Survival in Third-Generation CAR T-Cell Therapy

Key Points

  • Third-generation CAR T-cell therapy induced remission in 6 of 15 patients with CD19-positive B-cell malignancy and was generally found to be safe, with modest levels of toxicity.
  • High plasma levels of biomarkers of an immunostimulatory environment, including IL-12, DC-LAMP, TRAIL, and Fas ligand, before administering CAR T-cell therapy was associated with increased overall survival.

A phase I/IIa study investigating the safety and effectiveness of a third-generation CD19-specific chimeric antigen receptor (CAR) T-cell therapy in patients with lymphoma or leukemia has found that the treatment led to a complete response in 6 of the 15 patients in the study and that overall survival was associated with the patient’s immune status. The study by Lövgren et al (Abstract B156) was presented during the third CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science Into Survival held in Mainz/Frankfurt, Germany, on September 6–9, 2017.

Study Methodology and Findings

The researchers enrolled 15 patients with relapsed or refractory CD19-positive B-cell malignancy: 11 patients with lymphoma and 4 with leukemia. The patients received salvage chemotherapy during CAR T-cell manufacture, and 11 of the 15 patients were given low-dose cyclophosphamide/fludarabine-conditioning prior to CAR T-cell infusion. Tumor responses were followed by bone marrow/blood analysis and/or radiology, depending on the patient’s type of malignancy.

The patients were sampled for blood/plasma prior and at multiple time points after their CAR T-cell infusion. The presence of CAR T cells and immune cell subsets were analyzed in blood by quantitative polymerase chain reaction/flow cytometry, and soluble immunologic biomarkers were analyzed in plasma by a 233-analyte proteomic assay.

The researchers found that six patients, four with lymphoma and two with leukemia, had an initial complete response, which lasted for a median of 5 months. Four lymphoma patients who relapsed after experiencing a complete response to CAR T-cell therapy responded well to subsequent conventional therapy. In total, four patients are still alive.

The researchers’ findings show that in patient blood, CAR mRNA levels peaked at 1 week and could be detected up to 12 months after infusion, but there was no correlation between CAR levels and therapy outcome/survival. Regarding the immune status, high levels of monocytic myeloid-derived suppressive cells prior to treatment correlated with decreased overall survival and increased levels of monocytic myeloid-derived suppressive cells after treatment preceded treatment failure. In plasma, high levels of myeloid activation markers, such as IL-12 and DC-LAMP, or lymphocyte effector markers, such as TRAIL and Fas ligand, prior to treatment correlated with increased overall survival. In addition, high levels of immunosuppressive factors, such as programmed cell death ligand 1 and 2 (PD-L1/PD-L2), after treatment correlated to decreased overall survival.

“Third-generation CD19-targeting CAR T-cell therapy has modest toxicity and can induce remission in patients with B-cell malignancy. The immune status of the patient affects the treatment outcome, which should be considered when developing new CAR T-cell treatment protocols, for example, by combining CAR T cells with other immunomodulatory therapies,” concluded the study authors.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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