Early predictive factors of failure in autologous CAR T-cell manufacturing and/or efficacy in hematologic malignancies

Abstract

Chimeric Antigen Receptor T-cells (CAR T-cells) therapies have shown significant benefits in the treatment of hematological malignancies, such as B-cell acute lymphoblastic leukemia (B-ALL) and B-cell lymphoma. Despite the therapeutic advances offered by these innovative treatments, failures are still observed in 15-40% of B-ALL and > 50% of B-cell lymphoma patients. Several hypotheses have emerged including CD19 negative or positive relapses, low CAR T-cell activation and/or expansion in vivo or T-cell exhaustion. To date, in European Union (EU), CAR T-cells granted with marketing authorization (MA) are autologous and are thus associated with a strong heterogeneity between products. Indeed, the manufacturing of a single batch requires cellular starting material collection by apheresis for each patient, with variable cellular composition, then challenging pharmaceutical companies to standardize as much as possible the production process. In addition, these cost and time-consuming therapies are associated with a risk of manufacturing failure reaching 25%. Thus, there is a growing need to identify early risk factors of unsuccessful production and/or therapeutic escape. Quality of the apheresis product, pathology progression as well as previous treatments have been reported as predictive factors of the variability in clinical response. The aim of this review is to report and discuss predictive factors that could help to anticipate the manufacturing success and clinical response.

Brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma in the United Kingdom: A real‐world intention‐to‐treat analysis

“…On UVA, MF was associated with features of disease burden, including LDH > ULN and circulating disease in the peripheral blood on the day of harvest. In the absence of detailed quantitative and qualitative analysis of the harvested material, 33 these findings are potentially suggestive of a disease‐associated qualitative T‐cell defect hampering cell expansion during manufacture. Wang et al have previously demonstrated that T‐cells in the MCL tumor microenvironment (TME) demonstrate decreased expression of activation markers with parallel increased expression of markers associated with exhaustion and senescence, 34 a well‐recognized phenomenon in cancer.…”

Harnessing the Transcriptional Signatures of CAR-T-Cells and Leukemia/Lymphoma Using Single-Cell Sequencing Technologies

“…Multiple factors are associated with CAR-T treatment responses, including the patient features, disease status, previous treatment, tumor characteristic, disease burden, cell starting materials, CAR-T product composition, and T-cell fitness [151,152] (Figure 2B). Here, we summarize recent single-cell studies that address the CAR-T-cell behaviors and their correlation to clinical therapeutic response.…”

Contemporary Approaches to Immunotherapy of Solid Tumors

“…Solutions to overcome these problems include developing a more rapid manufacturing process, using off-the-shelf allogeneic CAR-Ts, and decentralising the production of autologous CAR-Ts [ 145 , 181 , 182 , 183 , 184 , 185 ]. Thus, at present, there are still many obstacles limiting the application of CAR-T cell therapy in solid tumors.…”