PET imaging to non-invasively study immune activation leading to antitumor responses with a 4-1BB agonistic antibody.
BACKGROUND
Molecular imaging with positron emission tomography (PET) may allow the non-invasive study of the pharmacodynamic effects of agonistic monoclonal antibodies (mAb) to 4-1BB (CD137). 4-1BB is a member of the tumor necrosis factor family expressed on activated T cells and other immune cells, and activating 4-1BB antibodies are being tested for the treatment of patients with advanced cancers.


METHODS
We studied the antitumor activity of 4-1BB mAb therapy using [(18) F]-labeled fluoro-2-deoxy-2-D-glucose ([(18) F]FDG) microPET scanning in a mouse model of colon cancer. Results of microPET imaging were correlated with morphological changes in tumors, draining lymph nodes as well as cell subset uptake of the metabolic PET tracer in vitro.


RESULTS
The administration of 4-1BB mAb to Balb/c mice induced reproducible CT26 tumor regressions and improved survival; complete tumor shrinkage was achieved in the majority of mice. There was markedly increased [(18) F]FDG signal at the tumor site and draining lymph nodes. In a metabolic probe in vitro uptake assay, there was an 8-fold increase in uptake of [(3)H]DDG in leukocytes extracted from tumors and draining lymph nodes of mice treated with 4-1BB mAb compared to untreated mice, supporting the in vivo PET data.


CONCLUSIONS
Increased uptake of [(18) F]FDG by PET scans visualizes 4-1BB agonistic antibody-induced antitumor immune responses and can be used as a pharmacodynamic readout to guide the development of this class of antibodies in the clinic.
Department of Medicine (Division of Hematology-Oncology) at David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, USA.
Helena
H
Escuin-Ordinas
Pfizer Worldwide Research and Development, Oncology Research Unit, San Diego, CA, USA.
Mark W
MW
Elliott
Department of Medicine (Division of Hematology-Oncology) at David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, USA.
Mohammad
M
Atefi
Pfizer Worldwide Research and Development, Oncology Research Unit, San Diego, CA, USA.
Michelle
M
Lee
Department of Medicine (Division of Hematology-Oncology) at David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, USA.
Charles
C
Ng
Ahmanson Translational Imaging Division, Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, USA.
Liu
L
Wei
Department of Surgery (Division of Surgical-Oncology), UCLA, Los Angeles, USA ; Jonsson Comprehensive Cancer Center (JCCC), Los Angeles, USA.
Begoña
B
Comin-Anduix
Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, USA.
Encarnacion
E
Montecino-Rodriguez
Department of Surgery (Division of Surgical-Oncology), UCLA, Los Angeles, USA.
Earl
E
Avramis
Ahmanson Translational Imaging Division, Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, USA ; Jonsson Comprehensive Cancer Center (JCCC), Los Angeles, USA.
Caius
C
Radu
Pfizer Worldwide Research and Development, Oncology Research Unit, San Diego, CA, USA ; Current address: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Dr., San Diego, CA 92121, USA.
Leslie L
LL
Sharp
Department of Medicine (Division of Hematology-Oncology) at David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, USA ; Ahmanson Translational Imaging Division, Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, USA ; Jonsson Comprehensive Cancer Center (JCCC), Los Angeles, USA ; Department of Medicine, Division of Hematology-Oncology, 11-934 Factor Building, Jonsson Comprehensive Cancer Center at UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095-1782, USA.
Antoni
A
Ribas
4-1BB; CD137; Colon cancer; Immune activating antibodies; PET imaging