Activation of TLR9 by direct injection of unmethylated CpG nucleotides into a tumor can induce a therapeutic immune response; however, Tregs eventually inhibit the antitumor immune response and thereby limit the power of cancer immunotherapies. In tumor-bearing mice, we found that Tregs within the tumor preferentially express the cell surface markers CTLA-4 and OX40. We show that intratumoral coinjection of anti–CTLA-4 and anti-OX40 together with CpG depleted tumor-infiltrating Tregs. This in situ immunomodulation, which was performed with low doses of antibodies in a single tumor, generated a systemic antitumor immune response that eradicated disseminated disease in mice. Further, this treatment modality was effective against established CNS lymphoma with leptomeningeal metastases, sites that are usually considered to be tumor cell sanctuaries in the context of conventional systemic therapy. These results demonstrate that antitumor immune effectors elicited by local immunomodulation can eradicate tumor cells at distant sites. We propose that, rather than using mAbs to target cancer cells systemically, mAbs could be used to target the tumor infiltrative immune cells locally, thereby eliciting a systemic immune response.
Aurélien Marabelle, Holbrook Kohrt, Idit Sagiv-Barfi, Bahareh Ajami, Robert C. Axtell, Gang Zhou, Ranjani Rajapaksa, Michael R. Green, James Torchia, Joshua Brody, Richard Luong, Michael D. Rosenblum, Lawrence Steinman, Hyam I. Levitsky, Victor Tse, Ronald Levy
Title and authors | Publication | Year |
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CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small cell lung cancer
Kipp Weiskopf, Nadine Jahchan, peter Schnorr, Sandra Cristea, Aaron Ring, Roy Maute, Anne Volkmer, Jens-Peter Volkmer, Jie Liu, Jing Shan Lim, Dian Yang, Garrett Seitz, Thuyen Nguyen, Di Wu, Kevin Jude, Heather Guerston, Amira Barkal, Francesca Trapani, Julie George, John Poirier, Eric Gardner, Linde Miles, Elisa de Stanchina, Shane Lofgren, Hannes Vogel, monte winslow, Caroline Dive, Roman Thomas, Charles Rudin, Matt van de Rijn, Ravindra Majeti, K. Christopher Garcia, Irving L. Weissman, Julien Sage |
Journal of Clinical Investigation | 2016 |
Blocking Indolamine-2,3-Dioxygenase Rebound Immune Suppression Boosts Antitumor Effects of Radio-Immunotherapy in Murine Models and Spontaneous Canine Malignancies
AM Monjazeb, MS Kent, SK Grossenbacher, C Mall, AE Zamora, A Mirsoian, M Chen, A Kol, SL Shiao, A Reddy, JR Perks, WT Culp, EE Sparger, RJ Canter, GD Sckisel, WJ Murphy |
Clinical cancer research | 2016 |
CTLA-4 limits anti-CD20-mediated tumor regression
Z Ren, J Guo, J Liao, Y Luan, Z Liu, Z Sun, X Liu, Y Liang, H Peng, YX Fu |
Clinical cancer research | 2016 |
Understanding Immune Cells in Tertiary Lymphoid Organ Development: It Is All Starting to Come Together
GW Jones, DG Hill, SA Jones |
Frontiers in immunology | 2016 |
Intratumoral Immunization by p19Arf and Interferon-β Gene Transfer in a Heterotopic Mouse Model of Lung Carcinoma
JP Catani, RF Medrano, A Hunger, PD Valle, S Adjemian, DB Zanatta, G Kroemer, E Costanzi-Strauss, BE Strauss |
Translational oncology | 2016 |
Combinatorial approach to cancer immunotherapy: strength in numbers
AE Vilgelm, DB Johnson, A Richmond |
Journal of leukocyte biology | 2016 |
Serum-resistant CpG-STAT3 decoy for targeting survival and immune checkpoint signaling in acute myeloid leukemia
Q Zhang, DM Hossain, P Duttagupta, D Moreira, X Zhao, H Won, R Buettner, S Nechaev, M Majka, B Zhang, Q Cai, P Swiderski, YH Kuo, S Forman, G Marcucci, M Kortylewski |
Blood | 2016 |
Immunomodulatory antibodies for the treatment of lymphoma: Report on the CALYM Workshop
R Houot, P Gaulard, R Schreiber, I Mellman, O Lambotte, PG Coulie, T Fest, A Korman, R Levy, M Shipp, K Tarte, H Kohrt, A Marabelle, S Ansell, H Watier, A Elsas, A Balakumaran, FA Vargas, SA Quezada, G Salles, D Olive |
OncoImmunology | 2016 |
Enhancing the safety of antibody-based immunomodulatory cancer therapy without compromising therapeutic benefit: Can we have our cake and eat it too?
JM Ryan, JS Wasser, AJ Adler, AT Vella |
Expert Opinion on Biological Therapy | 2016 |
TLR-activated plasmacytoid dendritic cells inhibit breast cancer cell growth in vitro and in vivo
J Wu, S Li, Y Yang, S Zhu, M Zhang, Y Qiao, YJ Liu, J Chen |
Oncotarget | 2016 |
The oncolytic peptide LTX-315 overcomes resistance of cancers to immunotherapy with CTLA4 checkpoint blockade
T Yamazaki, JM Pitt, M Vétizou, A Marabelle, C Flores, Ø Rekdal, G Kroemer, L Zitvogel |
Cell Death and Differentiation | 2016 |
Inflammation-Triggered Cancer Immunotherapy by Programmed Delivery of CpG and Anti-PD1 Antibody
C Wang, W Sun, G Wright, AZ Wang, Z Gu |
Advanced Materials | 2016 |
Strategies for designing synthetic immune agonists
TY Wu |
Immunology | 2016 |
Systemic delivery of chTNT-3/CpG immunoconjugates for immunotherapy in murine solid tumor models
JK Jang, LA Khawli, DC Canter, P Hu, TH Zhu, BW Wu, TE Angell, Z Li, AL Epstein |
Cancer Immunology, Immunotherapy | 2016 |
OX40+ Regulatory T Cells in Cutaneous Squamous Cell Carcinoma Suppress Effector T-Cell Responses and Associate with Metastatic Potential
C Lai, S August, A Albibas, R Behar, SY Cho, ME Polak, J Theaker, AS MacLeod, RR French, MJ Glennie, A Al-Shamkhani, E Healy |
Clinical cancer research | 2016 |
Transcriptional Landscape of Human Tissue Lymphocytes Unveils Uniqueness of Tumor-Infiltrating T Regulatory Cells
M De Simone, A Arrigoni, G Rossetti, P Gruarin, V Ranzani, C Politano, RJ Bonnal, E Provasi, ML Sarnicola, I Panzeri, M Moro, M Crosti, S Mazzara, V Vaira, S Bosari, A Palleschi, L Santambrogio, G Bovo, N Zucchini, M Totis, L Gianotti, G Cesana, RA Perego, N Maroni, AP Ceretti, E Opocher, R De Francesco, J Geginat, HG Stunnenberg, S Abrignani, M Pagani |
Immunity | 2016 |
Nutrients and the microenvironment to feed a T cell army
MO Johnson, PJ Siska, DC Contreras, JC Rathmell |
Seminars in Immunology | 2016 |
Tumor-directed immunotherapy can generate tumor-specific T cell responses through localized co-stimulation
P Ellmark, SM Mangsbo, C Furebring, P Norlén, TH Tötterman |
Cancer Immunology, Immunotherapy | 2016 |