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Tumor Microenvironment Impacts CAR-T Outcomes for Large B-Cell Lymphoma

A pre-treatment TME with high levels of cytokines and chemokines was associated with complete response to axi-cel treatment.

Tumor microenvironment (TME) characteristics in large B-cell lymphoma (LBCL) are associated with clinical responses for CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy, potentially providing a basis for identification of biomarkers that could be used to optimize treatment, according to a study published in Nature Medicine.1

A retrospective analysis of 135 pre-treatment and post-treatment tumor biopsies from 51 patients treated with axicabtagene ciloleucel (axi-cel) in the ZUMA-1 (NCT02348216) phase 2 clinical trial of indicated that tumor-infiltrating T-cell density, quantified as “Immunoscore”, and the expression of a pre-defined immune gene panel referred to as “Immunosign 21” are associated with clinical response and overall survival. Furthermore, it was found that TMEs with higher levels of chemokines including CCL5 and CCL22, γ-chain receptor cytokines including IL-15, IL-7, and IL-21, and interferon-regulated molecules were associated with T-cell infiltration and activity markers. Pre-treatment TMEs with high levels of regulatory T-cells were also associated with reduced CAR-T therapy-related neurotoxicity and an association was noted between lower circulating levels of CAR T-cells and higher post-treatment TME T-cell exhaustion.

“CAR T-cell therapies are changing the standard of care in cancer treatment, and their expanded use increases the need for tools to help identify the patients most likely to benefit from them,” Jérôme Galon, PhD, research director at Inserm in France and senior vice president and scientific executive director at Veracyte, as well as lead author on the published paper, said in a statement regarding the paper’s publication.2 “The prognostic and predictive roles of the TME have been described for solid tumors, but the importance of TME for CAR T-cell therapy outcomes, and particularly in LBCL, has not previously been established. This study is the first to demonstrate this important clinical connection, and also confirms Immunoscore CR and Immunosign as one of the first pre-treatment TME biomarkers to be associated with prolonged survival following CAR T-cell therapy.”

A pre-treatment TME with high levels of cytokines and chemokines that favor T-cell involvement was specifically associated with complete response to axi-cel treatment, while a pre-treatment TME with high levels of PD-1+LAG-3+/– T-cells was specifically associated with overall response. It was also noted that immune features of the TME changed rapidly following treatment with axi-cel.

The investigators validated their findings from the ZUMA-1 data with independent data sets from treatment naïve and pre-treatment biopsies from participants in the on-going ZUMA-7 study (NCT03391466) and from patients receiving commercial axi-cel at Moffit Cancer Center whenever possible; however, clinical outcome information was only available for the ZUMA-1 data set. Further limitations mentioned by the investigators included the small sample size for relapse and paired subsets, their inability to include CAR-T probes, and their inability to investigate certain tumor cell intrinsic factors, including expression of death receptors, which other studies have indicated have an impact on predicting clinical outcomes.

“Finally, the broad deployment of immune responses after CAR-T infusion contrasts with the unexpected low frequency of detectable autologous CAR-T cells in the TME,” the investigators wrote, noting another limitation.1 “Reduced CAR expression on the membrane surface after antigen stimulation could occur through several mechanisms, hampering detection by IHC-based and RNA-based methods. Alternative approaches to detection of CAR T-cells in the TME are warranted before translating the results of this study to other cell therapy modalities.”

The investigators ultimately concluded that, pending validation of their results, CAR-T therapies such as axi-cel could provide greater clinical benefit if administered in earlier lines of treatment, during which TMEs typically have more favorable features and tumor burden is typically lower. Additionally, they recommended further studies exploring TME signature optimization in LBCL and other tumor types that could be treated with T-cell therapies.

REFERENCES
1. Scholler N, Perbost R, Locke FL, et al. Tumor immune contexture is a determinant of anti-CD19 CAR T cell efficacy in large B cell lymphoma. Nat Med. Published online August 29, 2022. doi.org/10.1038/s41591-022-01916-x
2. New data in Nature Medicine suggest pre-treatment tumor microenvironment can impact response for CAR T-cell therapy in patients with large B-cell lymphoma. News release. Veracyte, Inc. August 29, 2022. https://investor.veracyte.com/news-releases/news-release-details/new-data-nature-medicine-suggest-pre-treatment-tumor