Olivier Lantz

Noninvasive Multicancer Detection Using DNA Hypomethylation of LINE-1 Retrotransposons

Abstract Purpose: The detection of ctDNA, which allows noninvasive tumor molecular profiling and disease follow-up, promises optimal and individualized management of patients with cancer. However, detecting small fractions of tumor DNA released when the tumor burden is reduced remains a challenge. Experimental Design: We implemented a new, highly sensitive strategy to detect bp resolution methylation patterns from plasma DNA and assessed the potential of hypomethylation of long interspersed nuclear element-1 retrotransposons as a noninvasive multicancer detection biomarker. The Detection of Long Interspersed Nuclear Element Altered Methylation ON plasma DNA method targets 30 to 40,000 young long interspersed nuclear element-1 retrotransposons scattered throughout the genome, covering about 100,000 CpG sites and is based on a reference-free analysis pipeline. Results: Resulting machine learning–based classifiers showed powerful correct classification rates discriminating healthy and tumor plasmas from six types of cancers (colorectal, breast, lung, ovarian, and gastric cancers and uveal melanoma, including localized stages) in two independent cohorts (AUC = 88%–100%, N = 747). The Detection of Long Interspersed Nuclear Element Altered Methylation ON plasma DNA method can also be used to perform copy number alteration analysis that improves cancer detection. Conclusions: This should lead to the development of more efficient noninvasive diagnostic tests adapted to all patients with cancer, based on the universality of these factors. See related commentary by Szymanski et al., p. 1179

Nivolumab plus chemoradiotherapy in locally-advanced cervical cancer: the NICOL phase 1 trial

AbstractConcurrent chemoradiotherapy (CRT) with blockade of the PD-1 pathway may enhance immune-mediated tumor control through increased phagocytosis, cell death, and antigen presentation. The NiCOL phase 1 trial (NCT03298893) is designed to determine the safety/tolerance profile and the recommended phase-II dose of nivolumab with and following concurrent CRT in 16 women with locally advanced cervical cancer. Secondary endpoints include objective response rate (ORR), progression free survival (PFS), disease free survival, and immune correlates of response. Three patients experience grade 3 dose-limiting toxicities. The pre-specified endpoints are met, and overall response rate is 93.8% [95%CI: 69.8–99.8%] with a 2-year PFS of 75% [95% CI: 56.5–99.5%]. Compared to patients with progressive disease (PD), progression-free (PF) subjects show a brisker stromal immune infiltrate, higher proximity of tumor-infiltrating CD3+ T cells to PD-L1+ tumor cells and of FOXP3+ T cells to proliferating CD11c+ myeloid cells. PF show higher baseline levels of PD-1 and ICOS-L on tumor-infiltrating EMRA CD4+ T cells and tumor-associated macrophages, respectively; PD instead, display enhanced PD-L1 expression on TAMs, higher peripheral frequencies of proliferating Tregs at baseline and higher PD-1 levels at week 6 post-treatment initiation on CD4 and CD8 T cell subsets. Concomitant nivolumab plus definitive CRT is safe and associated with encouraging PFS rates. Further validation in the subset of locally advanced cervical cancer displaying pre-existing, adaptive immune activation is warranted.

Nivolumab in Association With Radiotherapy and Cisplatin in Locally Advanced Cervical Cancers Followed by Adjuvant Nivolumab for up to 6 Months (NiCOL)

To date, the majority of clinical trials on checkpoint inhibitors have tested these agents as monotherapy, and the next logical step is to evaluate rational therapeutic associations. The aim of the NiCOL study is to assess the safety of nivolumab in association with chemoradiation therapy and to gain initial insight into its efficacy in association with the current standard of care, including chemoradiation.