Evidence map›Paper›PMID 39417106›Full record

ArticlemedRxiv : the preprint server for health sciences2024

Characterization of cell states in biliary tract cancers identifies mechanisms of therapeutic resistance in a phase II trial of DKN-01/nivolumab.

Ryan J Park, Milan Parikh, Leon Pappas, Moshe Sade-Feldman, Anupriya S Kulkarni, Lynn Bi, Thomas J LaSalle, Aralee Galway, Caroline Kuhlman, Lawrence S Blaszkowsky and 14 more

Registry-linked trialAbstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in medRxiv : the preprint server for health sciences, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT04057365 (A Single Arm Phase II Study of the Combination of DKN-01 and Nivolumab in Previously Treated Patients With Advanced Biliary Tract Cancer), which is not on this map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT04057365 phase2terminatednot on this map

A Single Arm Phase II Study of the Combination of DKN-01 and Nivolumab in Previously Treated Patients With Advanced Biliary Tract Cancer (BTC)

TypeinterventionalSponsorMassachusetts General HospitalRan2019 to 2022Enrolled15ConditionsBiliary Tract CancerArmsNivolumab, DKN-01
3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

24 authors.

Ryan J ParkDepartment of Radiation Oncology, Massachusetts General Hospital, Boston, MA.
Milan ParikhBroad Institute of MIT and Harvard, Cambridge, MA.
Leon PappasDepartment of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Moshe Sade-FeldmanBroad Institute of MIT and Harvard, Cambridge, MA.
Anupriya S KulkarniDepartment of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Lynn BiBroad Institute of MIT and Harvard, Cambridge, MA.
Thomas J LaSalleBroad Institute of MIT and Harvard, Cambridge, MA.
Aralee GalwayDepartment of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Caroline KuhlmanDepartment of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Lawrence S BlaszkowskyDepartment of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Jeffrey A MeyerhardtDepartment of Medical Oncology, Dana Farber Cancer Institute, Boston, MA.
Peter C EnzingerDepartment of Medical Oncology, Dana Farber Cancer Institute, Boston, MA.
Leah BillerDepartment of Medical Oncology, Dana Farber Cancer Institute, Boston, MA.
Jill N AllenDepartment of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Michael H KageyLeap Therapeutics, Inc., Cambridge, MA.
Jason BaumLeap Therapeutics, Inc., Cambridge, MA.
Cynthia SirardLeap Therapeutics, Inc., Cambridge, MA.
Dan G DudaDepartment of Radiation Oncology, Massachusetts General Hospital, Boston, MA.
Andrew X ZhuDepartment of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Thomas A AbramsDepartment of Medical Oncology, Dana Farber Cancer Institute, Boston, MA.
Nir HacohenBroad Institute of MIT and Harvard, Cambridge, MA.
David T TingDepartment of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Arnav MehtaBroad Institute of MIT and Harvard, Cambridge, MA.
Lipika GoyalDepartment of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

Funding

Dana Farber/Harvard Cancer Consortium Career Development Program in Clinical OncologyK12CA087723 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI David Tsai Ting · 2002 to 2026
$17.9M
A Phase II and Biomarker Study of Dual VEGF/PD-L1 Blockade in Neoadjuvant Setting in Resectable HCC PatientsR01CA260872 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI AMIN, HESHAM M, DUDA, DAN GABRIEL · 2021 to 2025
$3.0M
Multiplexed time domain fluorescence tomography of tumor biomarkers during immunotherapyR01CA260857 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI Dan Gabriel Duda, Anand T.N. Kumar · 2021 to 2026
$2.7M
Vascularized tumor explants for drug testingR01CA247441 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI MUNN, LANCE L. · 2021 to 2025
$1.9M
NCI NIH HHS K12 CA087723NCI NIH HHS R01 CA247441NCI NIH HHS R01 CA260857NCI NIH HHS R01 CA260872
6 · The paper itself

Abstract

Biliary tract cancers demonstrate profound therapeutic resistance, and broadly effective therapies for refractory disease are lacking. We conducted a single-arm, second-line phase II trial combining DKN-01, a humanized monoclonal antibody targeting Dickkopf-1 (DKK-1), and nivolumab to treat patients with advanced biliary tract cancer (NCT04057365). No objective responses were seen. To identify mechanisms of treatment failure, we analyzed paired pre-treatment and on-treatment biopsies using scRNA-seq and constructed a detailed molecular classification of malignant and immune cells. We annotated five biliary tract cancer malignant cell states: classical, basal, mesenchymal, neural-like, and endothelial-like. Neural-like and endothelial-like states, which drive therapeutic resistance in other cancers, have not previously been described in BTC. Malignant cell states co-varied with distinct immune cell states, revealing diverse mechanisms of myeloid and T-cell mediated immune suppression, including M2 myeloid and terminally exhausted T cell programs that were induced by DKN-01/nivolumab. Here, we provide the first systematic classification of functionally annotated cell states in biliary tract cancer and provide new insight into resistance mechanisms to an immunotherapy combination that can inform the next generation of trials.

Identifiers

PMID39417106
PMCPMC11483019

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.