. 2021 May; 12:617365.
doi: 10.3389/fimmu.2021.617365.

Immune Modulation Plus Tumor Ablation: Adjuvants and Antibodies to Prime and Boost Anti-Tumor Immunity In Situ

Renske J E van den Bijgaart 1 Fabian Schuurmans 1 Jurgen J Fütterer 2 Marcel Verheij 1 Lenneke A M Cornelissen 1 Gosse J Adema 1 
  • PMID: 33936033
  •     142 References
  •     4 citations


In situ tumor ablation techniques, like radiotherapy, cryo- and heat-based thermal ablation are successfully applied in oncology for local destruction of tumor masses. Although diverse in technology and mechanism of inducing cell death, ablative techniques share one key feature: they generate tumor debris which remains in situ. This tumor debris functions as an unbiased source of tumor antigens available to the immune system and has led to the concept of in situ cancer vaccination. Most studies, however, report generally modest tumor-directed immune responses following local tumor ablation as stand-alone treatment. Tumors have evolved mechanisms to create an immunosuppressive tumor microenvironment (TME), parts of which may admix with the antigen depot. Provision of immune stimuli, as well as approaches that counteract the immunosuppressive TME, have shown to be key to boost ablation-induced anti-tumor immunity. Recent advances in protein engineering have yielded novel multifunctional antibody formats. These multifunctional antibodies can provide a combination of distinct effector functions or allow for delivery of immunomodulators specifically to the relevant locations, thereby mitigating potential toxic side effects. This review provides an update on immune activation strategies that have been tested to act in concert with tumor debris to achieve in situ cancer vaccination. We further provide a rationale for multifunctional antibody formats to be applied together with in situ ablation to boost anti-tumor immunity for local and systemic tumor control.

Keywords: combination therapy; immune activation; in situ cancer vaccination; multifunctional antibodies; tumor ablation.

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Clin Cancer Res, 2011 Oct 27; 17(21). PMID: 22028490    Free PMC article.
Dendritic Cells but Not Macrophages Sense Tumor Mitochondrial DNA for Cross-priming through Signal Regulatory Protein α Signaling.
Meng Michelle Xu, Yang Pu, +9 authors, Yang-Xin Fu.
Immunity, 2017 Aug 13; 47(2). PMID: 28801234    Free PMC article.
Highly Cited.
IL-10 elicits IFNγ-dependent tumor immune surveillance.
John B Mumm, Jan Emmerich, +28 authors, Martin Oft.
Cancer Cell, 2011 Dec 17; 20(6). PMID: 22172723
Highly Cited.
Immune adjuvant efficacy of CpG oligonucleotide in cancer treatment is founded specifically upon TLR9 function in plasmacytoid dendritic cells.
Stefan Nierkens, Martijn H den Brok, +9 authors, Edith M Janssen.
Cancer Res, 2011 Jul 27; 71(20). PMID: 21788345    Free PMC article.
High-Intensity Focused Ultrasound (HIFU) Triggers Immune Sensitization of Refractory Murine Neuroblastoma to Checkpoint Inhibitor Therapy.
Avinash Eranki, Priya Srinivasan, +11 authors, Peter C W Kim.
Clin Cancer Res, 2019 Oct 17; 26(5). PMID: 31615935    Free PMC article.
Blockade of ErbB2 and PD-L1 using a bispecific antibody to improve targeted anti-ErbB2 therapy.
Deepak Mittal, Dipti Vijayan, +5 authors, Mark J Smyth.
Oncoimmunology, 2019 Oct 28; 8(11). PMID: 31646095    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.
Radiotherapy and CD40 Activation Separately Augment Immunity to Checkpoint Blockade in Cancer.
Andrew J Rech, Hannah Dada, +4 authors, Robert H Vonderheide.
Cancer Res, 2018 May 31; 78(15). PMID: 29844122    Free PMC article.
PD-1 Blockade Boosts Radiofrequency Ablation-Elicited Adaptive Immune Responses against Tumor.
Liangrong Shi, Lujun Chen, +10 authors, Jingting Jiang.
Clin Cancer Res, 2016 Mar 05; 22(5). PMID: 26933175    Free PMC article.
In vivo MR guided boiling histotripsy in a mouse tumor model evaluated by MRI and histopathology.
Martijn Hoogenboom, Dylan Eikelenboom, +7 authors, Arend Heerschap.
NMR Biomed, 2016 Apr 12; 29(6). PMID: 27061290
Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade.
Simon J Dovedi, Amy L Adlard, +11 authors, Tim M Illidge.
Cancer Res, 2014 Oct 03; 74(19). PMID: 25274032
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Sialic Acid Blockade Suppresses Tumor Growth by Enhancing T-cell-Mediated Tumor Immunity.
Christian Büll, Thomas J Boltje, +9 authors, Gosse J Adema.
Cancer Res, 2018 Apr 29; 78(13). PMID: 29703719
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Cryotherapy with concurrent CpG oligonucleotide treatment controls local tumor recurrence and modulates HER2/neu immunity.
Jesse J Veenstra, Heather M Gibson, +4 authors, Wei-Zen Wei.
Cancer Res, 2014 Aug 06; 74(19). PMID: 25092895    Free PMC article.
Tumor abolition and antitumor immunostimulation by physico-chemical tumor ablation.
Yona Keisari.
Front Biosci (Landmark Ed), 2016 Nov 05; 22(2). PMID: 27814617
TLR7 and TLR8 as targets in cancer therapy.
M P Schön, M Schön.
Oncogene, 2008 Jan 08; 27(2). PMID: 18176600
Anti-OX40 monoclonal antibody therapy in combination with radiotherapy results in therapeutic antitumor immunity to murine lung cancer.
Hiroshi Yokouchi, Koichi Yamazaki, +6 authors, Masaharu Nishimura.
Cancer Sci, 2008 Jan 19; 99(2). PMID: 18201271
Combined TLR and CD40 triggering induces potent CD8+ T cell expansion with variable dependence on type I IFN.
Cory L Ahonen, Christie L Doxsee, +6 authors, Ross M Kedl.
J Exp Med, 2004 Mar 10; 199(6). PMID: 15007094    Free PMC article.
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A Novel TGFβ Trap Blocks Chemotherapeutics-Induced TGFβ1 Signaling and Enhances Their Anticancer Activity in Gynecologic Cancers.
Haiyan Zhu, Xiang Gu, +9 authors, Xueqiong Zhu.
Clin Cancer Res, 2018 Mar 20; 24(12). PMID: 29549162    Free PMC article.
Impact of MR-guided boiling histotripsy in distinct murine tumor models.
Martijn Hoogenboom, Dylan C Eikelenboom, +5 authors, Gosse J Adema.
Ultrason Sonochem, 2017 Jun 22; 38. PMID: 28633808
Radiation biology in the context of changing patterns of radiotherapy.
David Murray, William H McBride, Jeffrey L Schwartz.
Radiat Res, 2014 Jul 17; 182(3). PMID: 25029108
OX40 triggering blocks suppression by regulatory T cells and facilitates tumor rejection.
Silvia Piconese, Barbara Valzasina, Mario P Colombo.
J Exp Med, 2008 Mar 26; 205(4). PMID: 18362171    Free PMC article.
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The role of the TGF-β family in wound healing, burns and scarring: a review.
Jack W Penn, Adriaan O Grobbelaar, Kerstin J Rolfe.
Int J Burns Trauma, 2012 Aug 29; 2(1). PMID: 22928164    Free PMC article.
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CD137/OX40 Bispecific Antibody Induces Potent Antitumor Activity that Is Dependent on Target Coengagement.
Miguel Gaspar, John Pravin, +6 authors, Neil Brewis.
Cancer Immunol Res, 2020 Apr 11; 8(6). PMID: 32273279
The CTLA-4 x OX40 bispecific antibody ATOR-1015 induces anti-tumor effects through tumor-directed immune activation.
Anne Månsson Kvarnhammar, Niina Veitonmäki, +16 authors, Peter Ellmark.
J Immunother Cancer, 2019 Apr 13; 7(1). PMID: 30975201    Free PMC article.
Stereotactic ablative body radiotherapy (SABR) combined with immunotherapy (L19-IL2) versus standard of care in stage IV NSCLC patients, ImmunoSABR: a multicentre, randomised controlled open-label phase II trial.
Relinde I Y Lieverse, Evert J Van Limbergen, +22 authors, Philippe Lambin.
BMC Cancer, 2020 Jun 17; 20(1). PMID: 32539805    Free PMC article.
Synergistic activation of macrophages via CD40 and TLR9 results in T cell independent antitumor effects.
Ilia N Buhtoiarov, Hillary D Lum, +2 authors, Alexander L Rakhmilevich.
J Immunol, 2005 Dec 21; 176(1). PMID: 16365423
The making of bispecific antibodies.
Ulrich Brinkmann, Roland E Kontermann.
MAbs, 2017 Jan 11; 9(2). PMID: 28071970    Free PMC article.
Highly Cited. Review.
Tumor ablation plus co-administration of CpG and saponin adjuvants affects IL-1 production and multifunctional T cell numbers in tumor draining lymph nodes.
Tonke K Raaijmakers, Renske J E van den Bijgaart, +7 authors, Gosse J Adema.
J Immunother Cancer, 2020 May 29; 8(1). PMID: 32461350    Free PMC article.
T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions.
S P Schoenberger, R E Toes, +2 authors, C J Melief.
Nature, 1998 Jun 12; 393(6684). PMID: 9624005
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Anti-CD47 antibody-mediated phagocytosis of cancer by macrophages primes an effective antitumor T-cell response.
Diane Tseng, Jens-Peter Volkmer, +8 authors, Irving L Weissman.
Proc Natl Acad Sci U S A, 2013 May 22; 110(27). PMID: 23690610    Free PMC article.
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Sialoglycans and Siglecs Can Shape the Tumor Immune Microenvironment.
Stephanie van de Wall, Kim C M Santegoets, +2 authors, Gosse J Adema.
Trends Immunol, 2020 Mar 07; 41(4). PMID: 32139317
Monocyte-Derived Dendritic Cells Dictate the Memory Differentiation of CD8+ T Cells During Acute Infection.
Kwang-Soo Shin, Insu Jeon, +11 authors, Chang-Yuil Kang.
Front Immunol, 2019 Sep 03; 10. PMID: 31474983    Free PMC article.
The immunocytokine L19-IL2: An interplay between radiotherapy and long-lasting systemic anti-tumour immune responses.
Nicolle H Rekers, Veronica Olivo Pimentel, +8 authors, Philippe Lambin.
Oncoimmunology, 2018 Apr 11; 7(4). PMID: 29632732    Free PMC article.
The paradoxical role of IL-10 in immunity and cancer.
Mark H Mannino, Ziwen Zhu, +3 authors, Yujiang Fang.
Cancer Lett, 2015 Jul 19; 367(2). PMID: 26188281
Highly Cited. Review.
Dendritic cells: tools and targets for antitumor vaccination.
Martijn H M G M den Brok, Stefan Nierkens, +2 authors, Gosse J Adema.
Expert Rev Vaccines, 2005 Oct 14; 4(5). PMID: 16221071
Strategies to improve radiotherapy with targeted drugs.
Adrian C Begg, Fiona A Stewart, Conchita Vens.
Nat Rev Cancer, 2011 Mar 25; 11(4). PMID: 21430696
Highly Cited. Review.
Bispecific antibodies: a mechanistic review of the pipeline.
Aran F Labrijn, Maarten L Janmaat, Janice M Reichert, Paul W H I Parren.
Nat Rev Drug Discov, 2019 Jun 09; 18(8). PMID: 31175342
Highly Cited. Review.
Combination of radiotherapy and suppression of Tregs enhances abscopal antitumor effect and inhibits metastasis in rectal cancer.
Dengbo Ji, Can Song, +6 authors, Jin Gu.
J Immunother Cancer, 2020 Oct 28; 8(2). PMID: 33106387    Free PMC article.
SIRPα-antibody fusion proteins stimulate phagocytosis and promote elimination of acute myeloid leukemia cells.
Laia Pascual Ponce, Nadja C Fenn, +5 authors, Karl-Peter Hopfner.
Oncotarget, 2017 Jan 07; 8(7). PMID: 28061465    Free PMC article.
Irreversible Electroporation and Nivolumab Combined with Intratumoral Administration of a Toll-Like Receptor Ligand, as a Means of In Vivo Vaccination for Metastatic Pancreatic Ductal Adenocarcinoma (PANFIRE-III). A Phase-I Study Protocol.
Bart Geboers, Florentine E F Timmer, +16 authors, On Behalf Of The Dutch Pancreatic Cancer Group.
Cancers (Basel), 2021 Aug 08; 13(15). PMID: 34359801    Free PMC article.
Clinical Applications and Anticancer Effects of Antimicrobial Peptides: From Bench to Bedside.
Ameneh Jafari, Amirhesam Babajani, +2 authors, Mostafa Rezaei-Tavirani.
Front Oncol, 2022 Mar 15; 12. PMID: 35280755    Free PMC article.
[Current Status and Progress of Thermal Ablation Combined with Immunotherapy for Lung Tumors].
Baodong Liu.
Zhongguo Fei Ai Za Zhi, 2022 Apr 29; 25(4). PMID: 35477191    Free PMC article.
How Compatible Are Immune Checkpoint Inhibitors and Thermal Ablation for Liver Metastases?
Yasunori Minami, Haruyuki Takaki, Koichiro Yamakado, Masatoshi Kudo.
Cancers (Basel), 2022 May 15; 14(9). PMID: 35565338    Free PMC article.