Predicting the Response to CTLA-4 Blockade by Longitudinal Noninvasive Monitoring of CD8 T Cells

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2017 Jul 2

PMID 28666979

Citations 135

Authors

Mohammad Rashidian

Jessica R Ingram

Michael Dougan

Anushka Dongre

Katherine A Whang

Camille LeGall

Juan J Cragnolini

Brian Bierie

Monica Gostissa

James Gorman

Gijsbert M Grotenbreg

Atul Bhan

Robert A Weinberg

Hidde L Ploegh

Affiliations

Soon will be listed here.

Abstract

Immunotherapy using checkpoint-blocking antibodies against targets such as CTLA-4 and PD-1 can cure melanoma and non-small cell lung cancer in a subset of patients. The presence of CD8 T cells in the tumor correlates with improved survival. We show that immuno-positron emission tomography (immuno-PET) can visualize tumors by detecting infiltrating lymphocytes and, through longitudinal observation of individual animals, distinguish responding tumors from those that do not respond to therapy. We used Zr-labeled PEGylated single-domain antibody fragments (VHHs) specific for CD8 to track the presence of intratumoral CD8 T cells in the immunotherapy-susceptible B16 melanoma model in response to checkpoint blockade. A Zr-labeled PEGylated antiCD8 VHH detected thymus and secondary lymphoid structures as well as intratumoral CD8 T cells. Animals that responded to CTLA-4 therapy showed a homogeneous distribution of the anti-CD8 PET signal throughout the tumor, whereas more heterogeneous infiltration of CD8 T cells correlated with faster tumor growth and worse responses. To support the validity of these observations, we used two different transplantable breast cancer models, yielding results that conformed with predictions based on the antimelanoma response. It may thus be possible to use immuno-PET and monitor antitumor immune responses as a prognostic tool to predict patient responses to checkpoint therapies.

Citing Articles

CD45-PET is a robust, non-invasive tool for imaging inflammation.

Salehi Farid A, Rowley J, Allen H, Kruger I, Tavakolpour S, Neeley K Nature. 2025; 639(8053):214-224.

PMID: 39843738 DOI: 10.1038/s41586-024-08441-6.

Trends in nanobody radiotheranostics.

Long X, Cheng S, Lan X, Wei W, Jiang D Eur J Nucl Med Mol Imaging. 2025; .

PMID: 39800806 DOI: 10.1007/s00259-025-07077-6.

Human dose-escalation study of PET imaging CD8 T-cell infiltration in solid malignancies with [Ga]Ga -NODAGA-SNA006.

Wang Y, Zheng M, Zhao J, Wang C, Zhao S, Bian Y Eur J Nucl Med Mol Imaging. 2024; 52(4):1332-1344.

PMID: 39653817 DOI: 10.1007/s00259-024-06999-x.

Shortwave-Infrared-Emitting Nanoprobes for CD8 Targeting and In Vivo Imaging of Cytotoxic T Cells in Breast Cancer.

Shah J, Siebert J, Zhao X, He S, Riman R, Tan M Adv Nanobiomed Res. 2024; 4(2):2300092.

PMID: 39554690 PMC: 11566364. DOI: 10.1002/anbr.202300092.

Making the effect visible - OX40 targeting nanobodies for imaging of activated T cells.

Frecot D, Blaess S, Wagner T, Kaiser P, Traenkle B, Fandrich M Front Immunol. 2024; 15:1480091.

PMID: 39474429 PMC: 11518761. DOI: 10.3389/fimmu.2024.1480091.

References

Curran M, Montalvo W, Yagita H, Allison J . PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A. 2010; 107(9):4275-80. PMC: 2840093. DOI: 10.1073/pnas.0915174107. View

Vosjan M, Perk L, Visser G, Budde M, Jurek P, Kiefer G . Conjugation and radiolabeling of monoclonal antibodies with zirconium-89 for PET imaging using the bifunctional chelate p-isothiocyanatobenzyl-desferrioxamine. Nat Protoc. 2010; 5(4):739-43. DOI: 10.1038/nprot.2010.13. View

Chen I, Dorr B, Liu D . A general strategy for the evolution of bond-forming enzymes using yeast display. Proc Natl Acad Sci U S A. 2011; 108(28):11399-404. PMC: 3136257. DOI: 10.1073/pnas.1101046108. View

Li L, Turatti F, Crow D, Bading J, Anderson A, Poku E . Monodispersed DOTA-PEG-conjugated anti-TAG-72 diabody has low kidney uptake and high tumor-to-blood ratios resulting in improved 64Cu PET. J Nucl Med. 2010; 51(7):1139-46. PMC: 3247072. DOI: 10.2967/jnumed.109.074153. View

Kawai O, Ishii G, Kubota K, Murata Y, Naito Y, Mizuno T . Predominant infiltration of macrophages and CD8(+) T Cells in cancer nests is a significant predictor of survival in stage IV nonsmall cell lung cancer. Cancer. 2008; 113(6):1387-95. DOI: 10.1002/cncr.23712. View

Tavare R, Escuin-Ordinas H, Mok S, McCracken M, Zettlitz K, Salazar F . An Effective Immuno-PET Imaging Method to Monitor CD8-Dependent Responses to Immunotherapy. Cancer Res. 2015; 76(1):73-82. PMC: 4703530. DOI: 10.1158/0008-5472.CAN-15-1707. View

van Elssen C, Rashidian M, Vrbanac V, Wucherpfennig K, Habre Z, Sticht J . Noninvasive Imaging of Human Immune Responses in a Human Xenograft Model of Graft-Versus-Host Disease. J Nucl Med. 2017; 58(6):1003-1008. PMC: 5450362. DOI: 10.2967/jnumed.116.186007. View

McNamee E, Korns Johnson D, Homann D, Clambey E . Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function. Immunol Res. 2012; 55(1-3):58-70. PMC: 3919451. DOI: 10.1007/s12026-012-8349-8. View

Theile C, Witte M, Blom A, Kundrat L, Ploegh H, Guimaraes C . Site-specific N-terminal labeling of proteins using sortase-mediated reactions. Nat Protoc. 2013; 8(9):1800-7. PMC: 3941705. DOI: 10.1038/nprot.2013.102. View

10.

Vesely M, Kershaw M, Schreiber R, Smyth M . Natural innate and adaptive immunity to cancer. Annu Rev Immunol. 2011; 29:235-71. DOI: 10.1146/annurev-immunol-031210-101324. View

11.

Knowles S, Zettlitz K, Tavare R, Rochefort M, Salazar F, Stout D . Quantitative immunoPET of prostate cancer xenografts with 89Zr- and 124I-labeled anti-PSCA A11 minibody. J Nucl Med. 2014; 55(3):452-9. PMC: 4052832. DOI: 10.2967/jnumed.113.120873. View

12.

Sockolosky J, Dougan M, Ingram J, Ho C, Kauke M, Almo S . Durable antitumor responses to CD47 blockade require adaptive immune stimulation. Proc Natl Acad Sci U S A. 2016; 113(19):E2646-54. PMC: 4868409. DOI: 10.1073/pnas.1604268113. View

13.

Dranoff G, Jaffee E, Lazenby A, Golumbek P, Levitsky H, Brose K . Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci U S A. 1993; 90(8):3539-43. PMC: 46336. DOI: 10.1073/pnas.90.8.3539. View

14.

Pardon E, Laeremans T, Triest S, Rasmussen S, Wohlkonig A, Ruf A . A general protocol for the generation of Nanobodies for structural biology. Nat Protoc. 2014; 9(3):674-93. PMC: 4297639. DOI: 10.1038/nprot.2014.039. View

15.

Movahedi K, Guilliams M, Van den Bossche J, Van den Bergh R, Gysemans C, Beschin A . Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. Blood. 2008; 111(8):4233-44. DOI: 10.1182/blood-2007-07-099226. View

16.

McCracken M, Tavare R, Witte O, Wu A . Advances in PET Detection of the Antitumor T Cell Response. Adv Immunol. 2016; 131:187-231. PMC: 5880626. DOI: 10.1016/bs.ai.2016.02.004. View

17.

Dougan M, Dranoff G . Immune therapy for cancer. Annu Rev Immunol. 2008; 27:83-117. DOI: 10.1146/annurev.immunol.021908.132544. View

18.

Baumeister S, Freeman G, Dranoff G, Sharpe A . Coinhibitory Pathways in Immunotherapy for Cancer. Annu Rev Immunol. 2016; 34:539-73. DOI: 10.1146/annurev-immunol-032414-112049. View

19.

Holzinger A, Barden M, Abken H . The growing world of CAR T cell trials: a systematic review. Cancer Immunol Immunother. 2016; 65(12):1433-1450. PMC: 11029082. DOI: 10.1007/s00262-016-1895-5. View

20.

DHuyvetter M, Xavier C, Caveliers V, Lahoutte T, Muyldermans S, Devoogdt N . Radiolabeled nanobodies as theranostic tools in targeted radionuclide therapy of cancer. Expert Opin Drug Deliv. 2014; 11(12):1939-54. PMC: 4245996. DOI: 10.1517/17425247.2014.941803. View