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16-07-2021 | Oncology | News | Article

Ex vivo tumor platform gives window to PD-1 blockade response

Author: Lynda Williams

medwireNews: A patient-derived tumor fragment (PDTF) platform has allowed close examination of the early immunologic responses to PD-1 blockade, revealing a relationship between immune cell reactivation and clinical response.

Daniela Thommen (Netherlands Cancer Institute, Amsterdam) and co-workers used the ex vivo technique to evaluate the cytokine, chemokine, and T-cell activation markers of 37 resected tumors from patients with non-small-cell lung cancer (NSCLC), breast cancer, ovarian cancer, renal cell carcinoma, or melanoma.

The majority (65%) of tumor tissues did not respond to ex vivo PD-1 blockade but 35% had “a clear increase in immune activity” on PD-1 inhibitor therapy; most of the responding PDTFs were derived from NSCLC or melanoma samples and two were from ovarian cancers, the researchers report in Nature Medicine.

Moreover, analysis of an additional cohort of 26 patients revealed a significant correlation between PDTF response to PD-1 blockade and the originating patient’s clinical response to PD-1 inhibitor treatment, they emphasize.

Only PDTFs that responded to PD-1 blockade had “detectable increases” in T-cell activation markers, but the researchers say that tumor-resident T cells in PDTFs that did not response to PD-1 inhibition could be activated by other means, indicating “that the PD-1–PD-L1 axis is not a critical signaling pathway that limits the physiological activity of this T cell pool.”

Flow cytometry showed that 10 of the PDTFs had less than 10% immune cells – none of these had responded to PD-1 blockade – but the remaining 27 PDTFs showed similar levels of immune cells regardless of response, albeit responding tumors had B-cell enrichment.

However, the presence of CD8+ T cells within the tumor tissue was associated with response to PD-1 blockade, with immune cell reactivation occurring in 12 of the 19 PDTFs with CD8+ infiltrated tumors versus just one of the seven tumors with CD8+ T cells only in the surrounding tissue.

“The strong correlation between ex vivo and clinical responses raises the question whether the PDTF platform could allow prospective assessment of individual patient responses to PD-1 blockade,” say Thommen et al.

“This may either entail the direct clinical application of the platform itself in addition to established biomarkers, such as PD-L1 or tumor mutational burden, or by deriving biomarkers (patterns) that can be measured using other less complex assay systems.”

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Nat Med 2021; doi: 10.1038/s41591-021-01398-3