Journal Article
. 2016 Sep; 5(7):e1186323.
doi: 10.1080/2162402X.2016.1186323.

Immunomodulatory antibodies for the treatment of lymphoma: Report on the CALYM Workshop

Roch Houot 1 Philippe Gaulard 2 Robert Schreiber 3 Ira Mellman 4 Olivier Lambotte 5 Pierre G Coulie 6 Thierry Fest 7 Alan Korman 8 Ronald Levy 9 Margaret Shipp 10 Karin Tarte 7 Holbrook Kohrt 11 Aurélien Marabelle 12 Stephen Ansell 13 Hervé Watier 14 Andrea van Elsas 15 Arun Balakumaran 16 Frederick Arce Vargas 17 Sergio A Quezada 17 Gilles Salles 18 Daniel Olive 19 
  • PMID: 27622041
  •     74 References
  •     2 citations


In November 2015, the CALYM Carnot Institute held a 2-d workshop to discuss the current and future development of immunomodulatory antibodies for the treatment of lymphoma. Highlights from the workshop are presented in this article.

Keywords: Immunomodulation; immunotherapy; lymphoma; programmed cell death 1 ligand 1; programmed cell death 1 receptor.

Radiotherapy increases the permissiveness of established mammary tumors to rejection by immunomodulatory antibodies.
Inge Verbrugge, Jim Hagekyriakou, +8 authors, Nicole M Haynes.
Cancer Res, 2012 May 10; 72(13). PMID: 22570253
Highly Cited.
Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells.
Mark J Selby, John J Engelhardt, +4 authors, Alan J Korman.
Cancer Immunol Res, 2014 Apr 30; 1(1). PMID: 24777248
Highly Cited.
The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma.
Kerry J Savage, Stefano Monti, +19 authors, Margaret A Shipp.
Blood, 2003 Aug 23; 102(12). PMID: 12933571
Highly Cited.
Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma.
Michael R Green, Stefano Monti, +9 authors, Margaret A Shipp.
Blood, 2010 Jul 16; 116(17). PMID: 20628145    Free PMC article.
Highly Cited.
Human Vγ9Vδ2 T cells specifically recognize and kill acute myeloid leukemic blasts.
Julie Gertner-Dardenne, Remy Castellano, +7 authors, Daniel Olive.
J Immunol, 2012 Apr 03; 188(9). PMID: 22467661
Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial.
Jonathan E Rosenberg, Jean Hoffman-Censits, +28 authors, Robert Dreicer.
Lancet, 2016 Mar 10; 387(10031). PMID: 26952546    Free PMC article.
Highly Cited.
Targeting immune effector cells to promote antibody-induced cytotoxicity in cancer immunotherapy.
Roch Houot, Holbrook E Kohrt, Aurélien Marabelle, Ronald Levy.
Trends Immunol, 2011 Sep 13; 32(11). PMID: 21907000
A mutated intron sequence codes for an antigenic peptide recognized by cytolytic T lymphocytes on a human melanoma.
P G Coulie, F Lehmann, +4 authors, T Boon.
Proc Natl Acad Sci U S A, 1995 Aug 15; 92(17). PMID: 7644523    Free PMC article.
Highly Cited.
Anti-ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti-PD-1 or anti-CD137 mAb therapy.
John Stagg, Sherene Loi, +5 authors, Mark J Smyth.
Proc Natl Acad Sci U S A, 2011 Apr 13; 108(17). PMID: 21482773    Free PMC article.
Highly Cited.
Genetic basis of PD-L1 overexpression in diffuse large B-cell lymphomas.
Konstantinos Georgiou, Longyun Chen, +22 authors, Qiang Pan-Hammarström.
Blood, 2016 Apr 01; 127(24). PMID: 27030389
Highly Cited.
Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates.
Julie R Brahmer, Charles G Drake, +17 authors, Suzanne L Topalian.
J Clin Oncol, 2010 Jun 03; 28(19). PMID: 20516446    Free PMC article.
Highly Cited.
The co-receptor BTLA negatively regulates human Vγ9Vδ2 T-cell proliferation: a potential way of immune escape for lymphoma cells.
Julie Gertner-Dardenne, Cyril Fauriat, +6 authors, Daniel Olive.
Blood, 2013 May 23; 122(6). PMID: 23692853
DC-SIGN-expressing macrophages trigger activation of mannosylated IgM B-cell receptor in follicular lymphoma.
Rada Amin, Frédéric Mourcin, +8 authors, Karin Tarte.
Blood, 2015 Aug 15; 126(16). PMID: 26272216    Free PMC article.
FcγRs Modulate the Anti-tumor Activity of Antibodies Targeting the PD-1/PD-L1 Axis.
Rony Dahan, Emanuela Sega, +3 authors, Jeffrey V Ravetch.
Cancer Cell, 2015 Sep 17; 28(3). PMID: 26373277
Highly Cited.
Immunological aspects of cancer chemotherapy.
Laurence Zitvogel, Lionel Apetoh, François Ghiringhelli, Guido Kroemer.
Nat Rev Immunol, 2007 Dec 22; 8(1). PMID: 18097448
Highly Cited. Review.
Mouse model recapitulating human Fcγ receptor structural and functional diversity.
Patrick Smith, David J DiLillo, +2 authors, Jeffrey V Ravetch.
Proc Natl Acad Sci U S A, 2012 Apr 05; 109(16). PMID: 22474370    Free PMC article.
Highly Cited.
MAP Kinase Inhibition Promotes T Cell and Anti-tumor Activity in Combination with PD-L1 Checkpoint Blockade.
Peter J R Ebert, Jeanne Cheung, +9 authors, Ira Mellman.
Immunity, 2016 Mar 06; 44(3). PMID: 26944201
Highly Cited.
Programmed cell death-1 inhibition in lymphoma.
Eliza A Hawkes, Andrew Grigg, Geoff Chong.
Lancet Oncol, 2015 May 07; 16(5). PMID: 25943068
Inducible tertiary lymphoid structures, autoimmunity, and exocrine dysfunction in a novel model of salivary gland inflammation in C57BL/6 mice.
Michele Bombardieri, Francesca Barone, +5 authors, Costantino Pitzalis.
J Immunol, 2012 Sep 04; 189(7). PMID: 22942425    Free PMC article.
Comprehensive Analysis of the Therapeutic IgG4 Antibody Pembrolizumab: Hinge Modification Blocks Half Molecule Exchange In Vitro and In Vivo.
Xiaoyu Yang, Fengqiang Wang, +12 authors, Alexandre Ambrogelly.
J Pharm Sci, 2015 Aug 27; 104(12). PMID: 26308749
Phase I study of the humanized anti-CD40 monoclonal antibody dacetuzumab in refractory or recurrent non-Hodgkin's lymphoma.
Ranjana Advani, Andres Forero-Torres, +6 authors, Jonathan G Drachman.
J Clin Oncol, 2009 Jul 29; 27(26). PMID: 19636010
Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results of an international phase II trial.
Philippe Armand, Arnon Nagler, +21 authors, Leo I Gordon.
J Clin Oncol, 2013 Oct 16; 31(33). PMID: 24127452    Free PMC article.
Highly Cited.
Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy.
Michael R Green, Scott Rodig, +5 authors, Margaret A Shipp.
Clin Cancer Res, 2012 Jan 25; 18(6). PMID: 22271878    Free PMC article.
Highly Cited.
Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion.
Robert D Schreiber, Lloyd J Old, Mark J Smyth.
Science, 2011 Mar 26; 331(6024). PMID: 21436444
Highly Cited. Review.
Characterization of intratumoral follicular helper T cells in follicular lymphoma: role in the survival of malignant B cells.
P Amé-Thomas, J Le Priol, +10 authors, K Tarte.
Leukemia, 2011 Oct 22; 26(5). PMID: 22015774    Free PMC article.
T-cell modulation combined with intratumoral CpG cures lymphoma in a mouse model without the need for chemotherapy.
Roch Houot, Ronald Levy.
Blood, 2008 Oct 23; 113(15). PMID: 18941113    Free PMC article.
PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma.
Stephen M Ansell, Alexander M Lesokhin, +16 authors, Philippe Armand.
N Engl J Med, 2014 Dec 09; 372(4). PMID: 25482239    Free PMC article.
Highly Cited.
Monoclonal antibodies against GARP/TGF-β1 complexes inhibit the immunosuppressive activity of human regulatory T cells in vivo.
Julia Cuende, Stéphanie Liénart, +15 authors, Sophie Lucas.
Sci Transl Med, 2015 Apr 24; 7(284). PMID: 25904740
Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK.
Idit Sagiv-Barfi, Holbrook E K Kohrt, +3 authors, Ronald Levy.
Proc Natl Acad Sci U S A, 2015 Mar 03; 112(9). PMID: 25730880    Free PMC article.
Highly Cited.
In situ vaccination with a TLR9 agonist induces systemic lymphoma regression: a phase I/II study.
Joshua D Brody, Weiyun Z Ai, +10 authors, Ronald Levy.
J Clin Oncol, 2010 Aug 11; 28(28). PMID: 20697067    Free PMC article.
Highly Cited.
The blockade of immune checkpoints in cancer immunotherapy.
Drew M Pardoll.
Nat Rev Cancer, 2012 Mar 23; 12(4). PMID: 22437870    Free PMC article.
Highly Cited. Review.
Characteristics and management of immunerelated adverse effects associated with ipilimumab, a new immunotherapy for metastatic melanoma.
Stephanie Andrews, Rita Holden.
Cancer Manag Res, 2012 Oct 11; 4. PMID: 23049279    Free PMC article.
Improved survival with ipilimumab in patients with metastatic melanoma.
F Stephen Hodi, Steven J O'Day, +26 authors, Walter J Urba.
N Engl J Med, 2010 Jun 08; 363(8). PMID: 20525992    Free PMC article.
Highly Cited.
Contrasting frequencies of antitumor and anti-vaccine T cells in metastases of a melanoma patient vaccinated with a MAGE tumor antigen.
Christophe Lurquin, Bernard Lethé, +5 authors, Thierry Boon.
J Exp Med, 2005 Jan 20; 201(2). PMID: 15657294    Free PMC article.
Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma.
Omid Hamid, Caroline Robert, +23 authors, Antoni Ribas.
N Engl J Med, 2013 Jun 04; 369(2). PMID: 23724846    Free PMC article.
Highly Cited.
Innate and adaptive immune cells in the tumor microenvironment.
Thomas F Gajewski, Hans Schreiber, Yang-Xin Fu.
Nat Immunol, 2013 Sep 21; 14(10). PMID: 24048123    Free PMC article.
Highly Cited. Review.
Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.
Caroline Robert, Luc Thomas, +21 authors, Jedd D Wolchok.
N Engl J Med, 2011 Jun 07; 364(26). PMID: 21639810
Highly Cited.
NFkappaB activity, function, and target-gene signatures in primary mediastinal large B-cell lymphoma and diffuse large B-cell lymphoma subtypes.
Friedrich Feuerhake, Jeffery L Kutok, +14 authors, Margaret A Shipp.
Blood, 2005 May 05; 106(4). PMID: 15870177
Expression of programmed cell death 1 ligand 2 (PD-L2) is a distinguishing feature of primary mediastinal (thymic) large B-cell lymphoma and associated with PDCD1LG2 copy gain.
Min Shi, Margaretha G M Roemer, +6 authors, Scott J Rodig.
Am J Surg Pathol, 2014 Jul 16; 38(12). PMID: 25025450    Free PMC article.
Targeting CD137 enhances the efficacy of cetuximab.
Holbrook E Kohrt, A Dimitrios Colevas, +20 authors, Ronald Levy.
J Clin Invest, 2014 May 20; 124(6). PMID: 24837434    Free PMC article.
Highly Cited.
Antigen spreading contributes to MAGE vaccination-induced regression of melanoma metastases.
Véronique Corbière, Jacques Chapiro, +7 authors, Pierre G Coulie.
Cancer Res, 2011 Jan 11; 71(4). PMID: 21216894
Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients.
F Stephen Hodi, Marcus Butler, +17 authors, Glenn Dranoff.
Proc Natl Acad Sci U S A, 2008 Feb 22; 105(8). PMID: 18287062    Free PMC article.
Highly Cited.
CD137 stimulation enhances the antilymphoma activity of anti-CD20 antibodies.
Holbrook E Kohrt, Roch Houot, +11 authors, Ronald Levy.
Blood, 2011 Jan 05; 117(8). PMID: 21193697    Free PMC article.
Highly Cited.
Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma.
Giao Q Phan, James C Yang, +14 authors, Steven A Rosenberg.
Proc Natl Acad Sci U S A, 2003 Jun 27; 100(14). PMID: 12826605    Free PMC article.
Highly Cited.
PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies.
Benjamin J Chen, Bjoern Chapuy, +8 authors, Scott J Rodig.
Clin Cancer Res, 2013 May 16; 19(13). PMID: 23674495    Free PMC article.
Highly Cited.
CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells.
Sergio A Quezada, Karl S Peggs, Michael A Curran, James P Allison.
J Clin Invest, 2006 Jun 17; 116(7). PMID: 16778987    Free PMC article.
Highly Cited.
OX40 engagement depletes intratumoral Tregs via activating FcγRs, leading to antitumor efficacy.
Yannick Bulliard, Rose Jolicoeur, +3 authors, Jennifer L Brogdon.
Immunol Cell Biol, 2014 Apr 16; 92(6). PMID: 24732076
Highly Cited.
Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial.
Jason R Westin, Fuliang Chu, +19 authors, Sattva S Neelapu.
Lancet Oncol, 2013 Dec 18; 15(1). PMID: 24332512    Free PMC article.
Highly Cited.
Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: a systematic review and meta-analysis.
Bin Shang, Yao Liu, Shu-juan Jiang, Yi Liu.
Sci Rep, 2015 Oct 16; 5. PMID: 26462617    Free PMC article.
Highly Cited. Systematic Review.
CTLA-4 blockade with ipilimumab: long-term follow-up of 177 patients with metastatic melanoma.
Peter A Prieto, James C Yang, +6 authors, Giao Q Phan.
Clin Cancer Res, 2012 Jan 25; 18(7). PMID: 22271879    Free PMC article.
Highly Cited.
High level of soluble programmed cell death ligand 1 in blood impacts overall survival in aggressive diffuse large B-Cell lymphoma: results from a French multicenter clinical trial.
D Rossille, M Gressier, +11 authors, Groupe Ouest-Est des Leucémies et Autres Maladies du Sang.
Leukemia, 2014 Apr 16; 28(12). PMID: 24732592
Highly Cited.
Targetable genetic features of primary testicular and primary central nervous system lymphomas.
Bjoern Chapuy, Margaretha G M Roemer, +28 authors, Margaret A Shipp.
Blood, 2015 Dec 25; 127(7). PMID: 26702065    Free PMC article.
Highly Cited.
The HVEM network: new directions in targeting novel costimulatory/co-inhibitory molecules for cancer therapy.
Christine Pasero, Daniel E Speiser, Laurent Derré, Daniel Olive.
Curr Opin Pharmacol, 2012 Mar 27; 12(4). PMID: 22445654
Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer.
Christina Twyman-Saint Victor, Andrew J Rech, +22 authors, Andy J Minn.
Nature, 2015 Mar 11; 520(7547). PMID: 25754329    Free PMC article.
Highly Cited.
New insights in the biology of Hodgkin lymphoma.
Ralf Küppers.
Hematology Am Soc Hematol Educ Program, 2012 Dec 13; 2012. PMID: 23233600
PD-L1 and PD-L2 Genetic Alterations Define Classical Hodgkin Lymphoma and Predict Outcome.
Margaretha G M Roemer, Ranjana H Advani, +14 authors, Margaret A Shipp.
J Clin Oncol, 2016 Apr 14; 34(23). PMID: 27069084    Free PMC article.
Highly Cited.
Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses.
R P Sutmuller, L M van Duivenvoorde, +6 authors, C J Melief.
J Exp Med, 2001 Sep 19; 194(6). PMID: 11560997    Free PMC article.
Highly Cited.
Antibody-Dependent Cellular Cytotoxicity Activity of a Novel Anti-PD-L1 Antibody Avelumab (MSB0010718C) on Human Tumor Cells.
Benjamin Boyerinas, Caroline Jochems, +4 authors, Jeffrey Schlom.
Cancer Immunol Res, 2015 May 28; 3(10). PMID: 26014098    Free PMC article.
Highly Cited.
Follicular lymphoma cell niche: identification of a preeminent IL-4-dependent T(FH)-B cell axis.
C Pangault, P Amé-Thomas, +11 authors, T Fest.
Leukemia, 2010 Oct 15; 24(12). PMID: 20944673    Free PMC article.
Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer.
Julie Brahmer, Karen L Reckamp, +22 authors, David R Spigel.
N Engl J Med, 2015 Jun 02; 373(2). PMID: 26028407    Free PMC article.
Highly Cited.
Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens.
Matthew M Gubin, Xiuli Zhang, +24 authors, Robert D Schreiber.
Nature, 2014 Nov 28; 515(7528). PMID: 25428507    Free PMC article.
Highly Cited.
Drug of the year: programmed death-1 receptor/programmed death-1 ligand-1 receptor monoclonal antibodies.
Caroline Robert, Jean-Charles Soria, Alexander M M Eggermont.
Eur J Cancer, 2013 Aug 03; 49(14). PMID: 23907003
A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application.
Taku Okazaki, Shunsuke Chikuma, +2 authors, Tasuku Honjo.
Nat Immunol, 2013 Nov 19; 14(12). PMID: 24240160
Highly Cited. Review.
Pembrolizumab for the treatment of non-small-cell lung cancer.
Edward B Garon, Naiyer A Rizvi, +25 authors, KEYNOTE-001 Investigators.
N Engl J Med, 2015 Apr 22; 372(21). PMID: 25891174
Highly Cited.
Depletion of regulatory T cells by anti-GITR mAb as a novel mechanism for cancer immunotherapy.
David Coe, Shaima Begom, +3 authors, Jian-Guo Chai.
Cancer Immunol Immunother, 2010 May 19; 59(9). PMID: 20480365
Neoantigens in cancer immunotherapy.
Ton N Schumacher, Robert D Schreiber.
Science, 2015 Apr 04; 348(6230). PMID: 25838375
Highly Cited. Review.
Continuous cultures of fused cells secreting antibody of predefined specificity.
G Köhler, C Milstein.
Nature, 1975 Aug 07; 256(5517). PMID: 1172191
Highly Cited.
High frequency of antitumor T cells in the blood of melanoma patients before and after vaccination with tumor antigens.
Catherine Germeau, Wenbin Ma, +9 authors, Pierre G Coulie.
J Exp Med, 2005 Jan 20; 201(2). PMID: 15657293    Free PMC article.
Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial.
Louis Fehrenbacher, Alexander Spira, +16 authors, POPLAR Study Group.
Lancet, 2016 Mar 14; 387(10030). PMID: 26970723
Highly Cited.
CD10 delineates a subset of human IL-4 producing follicular helper T cells involved in the survival of follicular lymphoma B cells.
Patricia Amé-Thomas, Sylvia Hoeller, +8 authors, Karin Tarte.
Blood, 2015 Mar 04; 125(15). PMID: 25733581    Free PMC article.
Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma.
Tyler R Simpson, Fubin Li, +11 authors, Sergio A Quezada.
J Exp Med, 2013 Jul 31; 210(9). PMID: 23897981    Free PMC article.
Highly Cited.
High rate of TNFRSF14 gene alterations related to 1p36 region in de novo follicular lymphoma and impact on prognosis.
E Launay, C Pangault, +6 authors, T Fest.
Leukemia, 2011 Sep 24; 26(3). PMID: 21941365
Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer.
Holbrook E Kohrt, Roch Houot, +11 authors, Ronald Levy.
J Clin Invest, 2012 Feb 14; 122(3). PMID: 22326955    Free PMC article.
Highly Cited.
Depleting tumor-specific Tregs at a single site eradicates disseminated tumors.
Aurélien Marabelle, Holbrook Kohrt, +13 authors, Ronald Levy.
J Clin Invest, 2013 Jun 04; 123(6). PMID: 23728179    Free PMC article.
Highly Cited.
Trial Watch: Immunostimulatory monoclonal antibodies for oncological indications.
Mariona Cabo, Rienk Offringa, +3 authors, Lorenzo Galluzzi.
Oncoimmunology, 2017 Dec 07; 6(12). PMID: 29209572    Free PMC article.
Trial Watch: Oncolytic viro-immunotherapy of hematologic and solid tumors.
Jonathan G Pol, Sarah Lévesque, +12 authors, Lorenzo Galluzzi.
Oncoimmunology, 2018 Dec 14; 7(12). PMID: 30524901    Free PMC article.