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Kidney Cancer Study Links Checkpoint Immunotherapy Responses to T Cell Features

NEW YORK – A UK-led team has uncovered immune cell features that appear to coincide with kidney cancer response to treatment that targets the PD-1 immune checkpoint.

"[I]n this prospective study, we reveal features of anti-PD-1 response and resistance in ccRCC," the researchers reported in Cancer Cell on Thursday. They noted that the study, led by co-senior and co-corresponding authors Samra Turajlic, an investigator at the Francis Crick Institute and the Royal Marsden NHS Foundation Trust, and Sergio Quezada, a researcher at the University College London Cancer Institute, flagged "tumor-specific T cells with cytotoxic features in ccRCC, which hold promise for development of adoptive cellular therapy for this cancer."

For a single-arm Phase II trial known as "a study of anti-PD-1 (nivolumab) therapy as pre- and post-operative therapy in metastatic renal cell cancer," the researchers used exome sequencing, RNA sequencing, T-cell receptor profiling, multiplex immunohistochemistry-immunofluorescence-based immune microenvironment testing, and flow cytometry to profile 115 fresh or archived tumor samples from 15 individuals with metastatic clear cell renal cell carcinoma, or ccRCC, enrolled between October 2015 and the spring of 2018.

The data lock for the current analysis came after a median of 12.5 months from baseline, they noted, though individual patients were followed for anywhere from 3.9 to 27.3 months. During that time, the average progression-free survival time was just over four months and overall survival came in at 22.2 months, on average, with six patients dying from progressive disease.

When the team analyzed tumors profiled before and after treatment with the anti-PD-1 compound nivolumab (Bristol Myers Squibb's Opdivo), it saw expanded TCR clone sets found at baseline — and the persistence of those clones — in five patients classified as nivolumab treatment "responders" compared to the 10 "non-responders."

Treatment responses also corresponded to enhanced immune infiltration and higher-than-usual levels of CD8+ T cells that boost immune-related granzyme B serine protease enzyme activity, the researchers noted, consistent with the T cell expansion and activation detected after nivolumab exposure using the available differential gene expression, immune profiling, and other data.

The authors also highlighted a relationship between levels of ccRCC-specific human endogenous retrovirus, or HERV, in tumors from cases that did not respond to the anti-PD-1 treatment, though they speculated that this relationship indirectly reflected tumor purity and immune infiltration levels.

"We show that HERVs frequently associated with T cell infiltration in bulk tumor biopsies … are highly expressed in immune cells," the authors wrote. "This offers a more parsimonious explanation for previously described associations to both T cell infiltration and [checkpoint inhibitor] response."

In contrast, the investigators did not detect ties between treatment response and molecular features in the tumor itself, such as single base changes in specific genes, small insertions or deletions, somatic copy number profiles, or tumor mutational burden, although one tumor was marked by especially high TMB levels traced back to DNA mismatch repair pathway defects.

"While the source of antigenic stimulus in ccRCC remains elusive, antigen-agnostic evaluation of TCR offered new and relevant insights into the impact of anti-PD-1 on T cell responses," the authors reported, noting that "the existence of a tumor-specific T cell response is supported by our findings of pre-existing, expanded CD8+ cell clones in responders, and the maintenance of these expanded CD8+ T cell clones characterizes response to nivolumab."

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