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Genetic biomarkers predict long-term OS for adoptive cell therapy in metastatic melanoma
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NATIONAL HARBOR, Md. — Certain genetic biomarkers predicted long-term overall survival for patients who received adoptive cell therapy with tumor infiltrating lymphocytes for metastatic melanoma, according to the results of a multicenter, retrospective study presented at Society for Immunotherapy of Cancer Annual Meeting.
Whole-exome sequencing of patients’ tumors revealed the overall long-term survival predictive value of certain genetic biomarkers but did not demonstrate an association between progression-free survival or response to treatment.
“Our lab is interested in adoptive cell therapy (ACT) of tumor infiltrating lymphocytes (TIL), which has a 40% to 50% response rate for metastatic melanoma across multiple centers worldwide,” Chantale Bernatchez, PhD, associate professor of melanoma medical oncology at The University of Texas MD Anderson Cancer Center, and one of the study’s co-authors, told Cell Therapy Next.
“The overall goal of this study was to identify mechanisms of response or resistance to therapy to guide further development of TIL ACT,” she added.
DNA extraction
The investigators used formalin-fixed, paraffin embedded tumor samples from 70 patients at MD Anderson Cancer Center (n = 61) and Moffitt Cancer Center (n = 9) who underwent ACT TIL for metastatic melanoma to evaluate genetic differences in response to therapy, PFS and OS. Patient samples underwent DNA extraction to determent whole exome sequencing and methylation profile.
Sixty-six patients had stage IV disease; 59 patients experienced disease progression after receiving ACT TIL.
Whole-exome sequencing of patients’ pretreated tumors showed that non-silent mutational burden (Cox-proportional hazards P = .07) and high neoantigen burden (Cox-proportional hazards P = .042) were associated with long-term OS but did not appear to be associated with PFS or response to treatment.
RNA extraction
Forty-two patients at MD Anderson underwent RNA sequencing of tumors. Forty of these patients had stage IV disease and 38 had disease progression after ACT TIL treatment.
RNA sequencing showed differences in genes enriched in patient response and OS to ACT TIL therapy.
“The prevalence of mutations did not differentiate responders. However, certain transcriptomic features were associated with response and survival,” Bernatchez said.
“To narrow down the list of candidate genes, we focused on the genes consistently enriched in patients with good or poor outcomes. Remarkably, the RNA expression of PDE1C, NGFR and RTKN2 was found to be enriched in patients with long overall survival, long progression-free survival, and response to TIL therapy (P < .003, pairwise Fisher exact test), while we found that gene expression of ELFN1-enriched in patients demonstrated short overall survival, short progression-free survival and lack of response to TIL therapy.”
A differential methylation pattern of the ELFN1 gene was found in both responders and nonresponders to TIL therapy, Bernatchez said.
“Mechanistic studies need to be performed to understand the contribution of these genes to the outcome of TIL therapy,” she added.
“The results of our study impact clinical practice by identifying routes of immune escape and novel biomarkers in TIL ACT that could be targeted for improved patient response,” Bernatchez concluded. – by Drew Amorosi
Reference:
Creasy C, et al. Abstract O5. Presented at: Society for Immunotherapy of Cancer Annual Meeting; Nov. 7-10, 2019; National Harbor, Md.
Disclosures: Bernatchez reports research funding from Iovance Biotherapeutics (not related to this study) and a scientific advisory board role with Myst Therapeutics.