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Metastatic Prostate Cancer Features Linked to Immunotherapy Response, Despite Low TMB

NEW YORK – Metastatic prostate tumors with a low mutational burden may still respond to immune checkpoint blockade immunotherapy when they are marked by an interferon-gamma-related immune signature and enhanced CD8 T cell density, according to new work by a team from the University of Texas MD Anderson Cancer Center.

"We were encouraged to see that prostate cancers with a low mutational burden do in fact express neoantigens that elicit T-cell responses that lead to favorable clinical outcomes," co-senior and corresponding author Padmanee Sharma, a genitourinary medical oncology, immunotherapy, and immunology researcher at MD Anderson Cancer Center, said in a statement.

As part of a Phase II clinical trial of the anti-CTLA-4 drug ipilimumab (Bristol-Myer's Squibb's Yervoy), the researchers used exome sequencing and RNA sequencing to assess non-synonymous mutation and gene expression patterns in tumor and matched normal peripheral blood mononuclear cell (PBMC) samples from 29 individuals with metastatic, castration-resistant prostate cancer (mCRPC) who were treated with ipilimumab up to four times, with doses given three weeks apart, and followed for a median of 45.5 months.

Nine of the patients had particularly good responses to the drug, the authors noted. In that favorable outcome group, they saw post-treatment survival times spanning 33 months to four and a half years, with six patients surviving at the time when analyses for the study were done. In contrast, post-treatment survival times came in at between roughly two-and-a-half weeks and just over 10 months in the 10 mCRPC patients with poor treatment responses. Two patients withdrew from the trial after starting treatment, and 11 received the full four doses of the immune checkpoint drug.

As reported in Science Translational Medicine on Wednesday, the researchers tracked down immune-related expression signatures in tumors from mCRPC patients in the favorable outcome group, including antigen-specific T cell activity and an interferon-gamma response signature, which was subsequently confirmed with interferon-gamma enzyme-linked immunospot assay analyses.

Likewise, within-tumor CD8 T cells, levels were ramped up in the RNA-seq data from immunotherapy-responsive tumors — results the team validated with immunohistochemistry-based T cell staining. In contrast, the authors noted that "PD-L1 expression was detectable on the immune cells within the tumor microenvironment in both [favorable and unfavorable] patient cohorts."

In all but one of the favorable outcome cases, the investigators documented T cell responses targeting tumor antigens and neoantigens in blood samples — a pattern detected in just four of the 10 mCRPC patients in the unfavorable outcome group.

"Unlike melanoma or [non-small cell lung cancer], our data suggest that high TMB was not required for neoantigen detection or for the selection of patients with mCRPC who were likely to benefit from [immune checkpoint blockade]," the authors reported, noting that the study "provides data to support further testing of immunotherapy strategies in patients with metastatic prostate cancer."

On the somatic mutation side, meanwhile, the team saw relatively low somatic mutation burdens in the prostate tumors. Three patients had DNA repair-related gene mutations implicated in high TMB, including two patients with favorable ipilimumab responses and one patient in the poor outcome group. On the other hand, two mCRPC cases marked by particularly low TMB belonged to the ipilimumab-responsive group and had tumor features pointing to T cell neoantigen responses.

"Together, our results suggest that a particular subset of patients may benefit from [immune checkpoint blockade], despite having a relatively low TMB," the authors concluded. "Moreover, they also suggest that pretreatment tissue correlatives such as CD8 T cells and IFN-gamma response gene signature may improve patient selection for treatment with [immune checkpoint blockade], particularly for those cancers with low TMB."

"Our findings indicate that anti-CTLA-4 immune checkpoint therapy warrants additional studies in order to develop treatment strategies that may improve survival of patients with metastatic prostate cancer," Sharma said.