Low-dose targeted radionuclide therapy renders immunologically cold tumors responsive to immune checkpoint blockade

Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works..

Molecular and cellular effects of radiotherapy on tumor microenvironment (TME) can help prime and propagate antitumor immunity. We hypothesized that delivering radiation to all tumor sites could augment response to immunotherapies. We tested an approach to enhance response to immune checkpoint inhibitors (ICIs) by using targeted radionuclide therapy (TRT) to deliver radiation semiselectively to tumors. NM600, an alkylphosphocholine analog that preferentially accumulates in most tumor types, chelates a radioisotope and semiselectively delivers it to the TME for therapeutic or diagnostic applications. Using serial 86Y-NM600 positron emission tomography (PET) imaging, we estimated the dosimetry of 90Y-NM600 in immunologically cold syngeneic murine models that do not respond to ICIs alone. We observed strong therapeutic efficacy and reported optimal dose (2.5 to 5 gray) and sequence for 90Y-NM600 in combination with ICIs. After combined treatment, 45 to 66% of mice exhibited complete response and tumor-specific T cell memory, compared to 0% with 90Y-NM600 or ICI alone. This required expression of STING in tumor cells. Combined TRT and ICI activated production of proinflammatory cytokines in the TME, promoted tumor infiltration by and clonal expansion of CD8+ T cells, and reduced metastases. In mice bearing multiple tumors, combining TRT with moderate-dose (12 gray) external beam radiotherapy (EBRT) targeting a single tumor augmented response to ICIs compared to combination of ICIs with either TRT or EBRT alone. The safety of TRT was confirmed in a companion canine study. Low-dose TRT represents a translatable approach to promote response to ICIs for many tumor types, regardless of location.

Medienart:

E-Artikel

Erscheinungsjahr:

2021

Erschienen:

2021

Enthalten in:

Zur Gesamtaufnahme - volume:13

Enthalten in:

Science translational medicine - 13(2021), 602 vom: 14. Juli

Sprache:

Englisch

Beteiligte Personen:

Patel, Ravi B [VerfasserIn]
Hernandez, Reinier [VerfasserIn]
Carlson, Peter [VerfasserIn]
Grudzinski, Joseph [VerfasserIn]
Bates, Amber M [VerfasserIn]
Jagodinsky, Justin C [VerfasserIn]
Erbe, Amy [VerfasserIn]
Marsh, Ian R [VerfasserIn]
Arthur, Ian [VerfasserIn]
Aluicio-Sarduy, Eduardo [VerfasserIn]
Sriramaneni, Raghava N [VerfasserIn]
Jin, Won Jong [VerfasserIn]
Massey, Christopher [VerfasserIn]
Rakhmilevich, Alexander L [VerfasserIn]
Vail, David [VerfasserIn]
Engle, Johnathan W [VerfasserIn]
Le, Trang [VerfasserIn]
Kim, KyungMann [VerfasserIn]
Bednarz, Bryan [VerfasserIn]
Sondel, Paul M [VerfasserIn]
Weichert, Jamey [VerfasserIn]
Morris, Zachary S [VerfasserIn]

Links:

Volltext

Themen:

Immune Checkpoint Inhibitors
Journal Article
Radioisotopes
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Tpt1 protein, mouse
Tumor Protein, Translationally-Controlled 1

Anmerkungen:

Date Completed 06.08.2021

Date Revised 04.12.2021

published: Print

Citation Status MEDLINE

doi:

10.1126/scitranslmed.abb3631

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM328073431