Top

Published in:

Open Access 01-01-2017 | Review

Tumor-directed immunotherapy can generate tumor-specific T cell responses through localized co-stimulation

Authors: Peter Ellmark, Sara M. Mangsbo, Christina Furebring, Per Norlén, Thomas H. Tötterman

Published in: Cancer Immunology, Immunotherapy | Issue 1/2017

Abstract

The most important goals for the field of immuno-oncology are to improve the response rate and increase the number of tumor indications that respond to immunotherapy, without increasing adverse side effects. One approach to achieve these goals is to use tumor-directed immunotherapy, i.e., to focus the immune activation to the most relevant part of the immune system. This may improve anti-tumor efficacy as well as reduce immune-related adverse events. Tumor-directed immune activation can be achieved by local injections of immune modulators in the tumor area or by directing the immune modulator to the tumor using bispecific antibodies. In this review, we focus on therapies targeting checkpoint inhibitors and co-stimulatory receptors that can generate tumor-specific T cell responses through localized immune activation.

Ascierto PA (2015) Immunotherapies and novel combinations: the focus of advances in the treatment of melanoma. Cancer Immunol Immunother 64:271–274. doi:10.1007/s00262-014-1647-3 CrossRefPubMed

Hammerich L, Binder A, Brody JD (2015) In situ vaccination: cancer immunotherapy both personalized and off-the-shelf. Mol Oncol 9:1966–1981. doi:10.1016/j.molonc.2015.10.016 CrossRefPubMed

Pierce RH, Campbell JS, Pai SI, Brody JD, Kohrt HE (2015) In-situ tumor vaccination: bringing the fight to the tumor. Hum Vaccin Immunother 11:1901–1909. doi:10.1080/21645515.2015.1049779 CrossRefPubMedPubMedCentral

Wong KK, Li WA, Mooney DJ, Dranoff G (2016) Advances in therapeutic cancer vaccines. Adv Immunol 130:191–249. doi:10.1016/bs.ai.2015.12.001 CrossRefPubMed

Simpson TR, Li F, Montalvo-Ortiz W, Sepulveda MA, Bergerhoff K, Arce F, Roddie C, Henry JY, Yagita H, Wolchok JD, Peggs KS, Ravetch JV, Allison JP, Quezada SA (2013) Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J Exp Med 210:1695–1710. doi:10.1084/jem.20130579 CrossRefPubMedPubMedCentral

Romano E, Kusio-Kobialka M, Foukas PG, Baumgaertner P, Meyer C, Ballabeni P, Michielin O, Weide B, Romero P, Speiser DE (2015) Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients. Proc Natl Acad Sci 112:6140–6145. doi:10.1073/pnas.1417320112 CrossRefPubMedPubMedCentral

Sharma P, Allison JP (2015) Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 161:205–214. doi:10.1016/j.cell.2015.03.030 CrossRefPubMed

Sanmamed MF, Pastor F, Rodriguez A, Perez-Gracia JL, Rodriguez-Ruiz ME, Jure-Kunkel M, Melero I (2015) Agonists of co-stimulation in cancer immunotherapy directed against CD137, OX40, GITR, CD27, CD28, and ICOS. Semin Oncol 42:640–655. doi:10.1053/j.seminoncol.2015.05.014 CrossRefPubMed

Ellmark P, Mangsbo SM, Furebring C, Tötterman TH, Norlén P (2015) Kick-starting the cancer-immunity cycle by targeting CD40. Oncoimmunology 4:e1011484-1-3. doi:10.1080/2162402X.2015.1011484 CrossRef

10.

Vonderheide RH, Glennie MJ (2013) Agonistic CD40 antibodies and cancer therapy. Clin Cancer Res 19:1035–1043. doi:10.1158/1078-0432.CCR-12-2064 CrossRefPubMedPubMedCentral

11.

Sandin LC, Orlova A, Gustafsson E, Ellmark P, Tolmachev V, Tötterman TH, Mangsbo SM (2014) Locally delivered CD40 agonist antibody accumulates in secondary lymphoid organs and eradicates experimental disseminated bladder cancer. Cancer Immunol Res 2:80–90. doi:10.1158/2326-6066.CIR-13-0067 CrossRefPubMed

12.

van Mierlo GJ, den Boer AT, Medema JP, van der Voort EI, Fransen MF, Offringa R, Melief CJ, Toes RE (2002) CD40 stimulation leads to effective therapy of CD40⁻ tumors through induction of strong systemic cytotoxic T lymphocyte immunity. Proc Natl Acad Sci 99:5561–5566. doi:10.1073/pnas.082107699 CrossRefPubMedPubMedCentral

13.

Fransen MF, Sluijter M, Morreau H, Arens R, Melief CJ (2011) Local activation of CD8 T cells and systemic tumor eradication without toxicity via slow release and local delivery of agonistic CD40 antibody. Clin Cancer Res 17:2270–2280. doi:10.1158/1078-0432.CCR-10-2888 CrossRefPubMed

14.

Jackaman C, Lew AM, Zhan Y, Allan JE, Koloska B, Graham PT, Robinson BW, Nelson DJ (2008) Deliberately provoking local inflammation drives tumors to become their own protective vaccine site. Int Immunol 20:1467–1479. doi:10.1093/intimm/dxn104 CrossRefPubMed

15.

Mangsbo SM, Broos S, Fletcher E, Veitonmäki N, Furebring C, Dahlén E, Norlén P, Lindstedt M, Tötterman TH, Ellmark P (2015) The human agonistic CD40 antibody ADC-1013 eradicates bladder tumors and generates T-cell-dependent tumor immunity. Clin Cancer Res 21:1115–1126. doi:10.1158/1078-0432.CCR-14-0913 CrossRefPubMed

16.

Lindqvist C, Sandin LC, Fransson M, Loskog A (2009) Local AdCD40L gene therapy is effective for disseminated murine experimental cancer by breaking T-cell tolerance and inducing tumor cell growth inhibition. J Immunother 32:785–792. doi:10.1097/CJI.0b013e3181acea69 CrossRefPubMed

17.

Loskog A, Björkland A, Brown MP, Korsgren O, Malmström PU, Tötterman TH (2001) Potent antitumor effects of CD154 transduced tumor cells in experimental bladder cancer. J Urol 166:1093–1097. doi:10.1016/S0022-5347(05)65928-9 CrossRefPubMed

18.

Tuve S, Chen BM, Liu Y, Cheng TL, Touré P, Sow PS, Feng Q, Kiviat N, Strauss R, Ni S, Li ZY, Roffler SR (2007) Lieber A (2007) Combination of tumor site-located CTL-associated antigen-4 blockade and systemic regulatory T-cell depletion induces tumor-destructive immune responses. Cancer Res 67:5929–5939. doi:10.1158/0008-5472.CAN-06-4296 CrossRefPubMed

19.

Fransen MF, van der Sluis TC, Ossendorp F, Arens R, Melief CJ (2013) Controlled local delivery of CTLA-4 blocking antibody induces CD8⁺ T-cell-dependent tumor eradication and decreases risk of toxic side effects. Clin Cancer Res 19:5381–5389. doi:10.1158/1078-0432.CCR-12-0781 CrossRefPubMed

20.

Sandin LC, Eriksson F, Ellmark P, Loskog AS, Tötterman TH, Mangsbo SM (2014) Local CTLA4 blockade effectively restrains experimental pancreatic adenocarcinoma growth in vivo. Oncoimmunology 3:e27614-1-8. doi:10.4161/onci.27614

21.

Michot JM, Bigenwald C, Champiat S, Collins M, Carbonnel F, Postel-Vinay S, Berdelou A, Varga A, Bahleda R, Hollebecque A, Massard C, Fuerea A, Ribrag V, Gazzah A, Armand JP, Amellal N, Angevin E, Noel N, Boutros C, Mateus C, Robert C, Soria JC, Marabelle A, Lambotte O (2016) Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer 54:139–148. doi:10.1016/j.ejca.2015.11.016 CrossRefPubMed

22.

Marabelle A, Kohrt H, Sagiv-Barfi I, Ajami B, Axtell RC, Zhou G, Rajapaksa R, Green MR, Torchia J, Brody J, Luong R, Rosenblum MD, Steinman L, Levitsky HI, Tse V, Levy R (2013) Depleting tumor-specific Tregs at a single site eradicates disseminated tumors. J Clin Invest 123:2447–2463. doi:10.1172/JCI64859 CrossRefPubMedPubMedCentral

23.

Palazón A, Martínez-Forero I, Teijeira A, Morales-Kastresana A, Alfaro C, Sanmamed MF, Perez-Gracia JL, Peñuelas I, Hervás-Stubbs S, Rouzaut A, de Landázuri MO, Jure-Kunkel M, Aragonés J, Melero I (2012) The HIF-1α hypoxia response in tumor-infiltrating T lymphocytes induces functional CD137 (4-1BB) for immunotherapy. Cancer Discov 2:608–623. doi:10.1158/2159-8290.CD-11-0314 CrossRefPubMed

24.

Kim YH, Gratzinger D, Harrison C, Brody JD, Czerwinski DK, Ai WZ, Morales A, Abdulla F, Xing L, Navi D, Tibshirani RJ, Advani RH, Lingala B, Shah S, Hoppe RT, Levy R (2012) In situ vaccination against mycosis fungoides by intratumoral injection of a TLR9 agonist combined with radiation: a phase 1/2 study. Blood 119:355–363. doi:10.1182/blood-2011-05-355222 CrossRefPubMedPubMedCentral

25.

Goldstein MJ, Varghese B, Brody JD, Rajapaksa R, Kohrt H, Czerwinski DK, Levy S, Levy RA (2011) CpG-loaded tumor cell vaccine induces antitumor CD4⁺ T cells that are effective in adoptive therapy for large and established tumors. Blood 117:118–127. doi:10.1182/blood-2010-06-288456 CrossRefPubMedPubMedCentral

26.

Malmström PU, Loskog AS, Lindqvist CA, Mangsbo SM, Fransson M, Wanders A, Gårdmark T, Tötterman TH (2010) AdCD40L immunogene therapy for bladder carcinoma—the first phase I/IIa trial. Clin Cancer Res 16:3279–3287. doi:10.1158/1078-0432.CCR-10-0385 CrossRefPubMed

27.

von Euler H, Sadeghi A, Carlsson B, Rivera P, Loskog A, Segall T, Korsgren O, Tötterman TH (2008) Efficient adenovector CD40 ligand immunotherapy of canine malignant melanoma. J Immunother 31:377–384. doi:10.1097/CJI.0b013e31816a812d CrossRef

28.

Westberg S, Sadeghi A, Svensson E, Segall T, Dimopoulou M, Korsgren O, Hemminki A, Loskog AS, Tötterman TH, von Euler H (2013) Treatment efficacy and immune stimulation by AdCD40L gene therapy of spontaneous canine malignant melanoma. J Immunother 36:350–358. doi:10.1097/CJI.0b013e31829d8a1b CrossRefPubMed

29.

Loskog A, Maleka A, Mangsbo S, Svensson E, Lundberg C, Nilsson A, Krause J, Agnarsdóttir M, Sundin A, Ahlström H, Tötterman TH, Ullenhag G (2016) Immunostimulatory AdCD40L gene therapy combined with low-dose cyclophosphamide in metastatic melanoma patients. Br J Cancer 114:872–880. doi:10.1038/bjc.2016.42 CrossRefPubMed

30.

Hemminki A (2014) Oncolytic immunotherapy: where are we clinically? Scientifica (Cairo) 2014:862925. doi:10.1155/2014/862925

31.

Broos S, Sandin LC, Apel J, Tötterman TH, Akagi T, Akashi M, Borrebaeck CA, Ellmark P, Lindstedt M (2012) Synergistic augmentation of CD40-mediated activation of antigen-presenting cells by amphiphilic poly(γ-glutamic acid) nanoparticles. Biomaterials 33:6230–6239. doi:10.1016/j.biomaterials.2012.05.011 CrossRefPubMed

32.

Fransen MF, Cordfunke RA, Sluijter M, van Steenbergen MJ, Drijfhout JW, Ossendorp F, Hennink WE, Melief CJ (2014) Effectiveness of slow-release systems in CD40 agonistic antibody immunotherapy of cancer. Vaccine 32:1654–1660. doi:10.1016/j.vaccine.2014.01.056 CrossRefPubMed

33.

McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, Saini SK, Jamal-Hanjani M, Wilson GA, Birkbak NJ, Hiley CT, Watkins TB, Shafi S, Murugaesu N, Mitter R, Akarca AU, Linares J, Marafioti T, Henry JY, Van Allen EM, Miao D, Schilling B, Schadendorf D, Garraway LA, Makarov V, Rizvi NA, Snyder A, Hellmann MD, Merghoub T, Wolchok JD, Shukla SA, Wu CJ, Peggs KS, Chan TA, Hadrup SR, Quezada SA, Swanton C (2016) Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351:1463–1469. doi:10.1126/science.aaf1490 CrossRefPubMedPubMedCentral

34.

Kiefer JD, Neri D (2016) Immunocytokines and bispecific antibodies: two complementary strategies for the selective activation of immune cells at the tumor site. Immunol Rev 270:178–192. doi:10.1111/imr.12391 CrossRefPubMedPubMedCentral

35.

Neri D, Sondel PM (2016) Immunocytokines for cancer treatment: past, present and future. Curr Opin Immunol 40:96–102. doi:10.1016/j.coi.2016.03.006 CrossRefPubMedPubMedCentral

36.

Sondel PM, Gillies SD (2012) Current and potential uses of immunocytokines as cancer immunotherapy. Antibodies 1:149–171. doi:10.3390/antib1020149 CrossRefPubMedPubMedCentral

37.

Danielli R, Patuzzo R, Ruffini PA, Maurichi A, Giovannoni L, Elia G, Neri D, Santinami M (2015) Armed antibodies for cancer treatment: a promising tool in a changing era. Cancer Immunol Immunother 64:113–121. doi:10.1007/s00262-014-1621-0 CrossRefPubMed

38.

Yoshida GJ (2015) Metabolic reprogramming: the emerging concept and associated therapeutic strategies. J Exp Clin Cancer Res 34:1–10. doi:10.1186/s13046-015-0221-y CrossRef

39.

Vaughn DE, Bjorkman PJ (1998) Structural basis of pH-dependent antibody binding by the neonatal Fc receptor. Structure 6:63–73CrossRefPubMed

40.

Polu KR, Lowman HB (2014) Probody therapeutics for targeting antibodies to diseased tissue. Expert Opin Biol Ther 14:1049–1053. doi:10.1517/14712598.2014.920814 CrossRefPubMed

41.

Sanford M (2015) Blinatumomab: first global approval. Drugs 75:321–327. doi:10.1007/s40265-015-0356-3 CrossRefPubMed

42.

Zhukovsky EA, Morse RJ, Maus MV (2016) Bispecific antibodies and CARs: generalized immunotherapeutics harnessing T cell redirection. Curr Opin Immunol 40:24–35. doi:10.1016/j.coi.2016.02.006 CrossRefPubMed

43.

Wilson NS, Yang B, Yang A, Loeser S, Marsters S, Lawrence D, Li Y, Pitti R, Totpal K, Yee S, Ross S, Vernes JM, Lu Y, Adams C, Offringa R, Kelley B, Hymowitz S, Daniel D, Meng G, Ashkenazi A (2011) An Fcγ receptor-dependent mechanism drives antibody-mediated target-receptor signaling in cancer cells. Cancer Cell 19:101–113. doi:10.1016/j.ccr.2010.11.012 CrossRefPubMed

44.

Li F, Ravetch JV (2013) Antitumor activities of agonistic anti-TNFR antibodies require differential FcγRIIB coengagement in vivo. Proc Natl Acad Sci 110:19501–19506. doi:10.1073/pnas.1319502110 CrossRefPubMedPubMedCentral

45.

White AL, Chan HT, Roghanian A, French RR, Mockridge CI, Tutt AL, Dixon SV, Ajona D, Verbeek JS, Al-Shamkhani A, Cragg MS, Beers SA, Glennie MJ (2011) Interaction with FcγRIIB is critical for the agonistic activity of anti-CD40 monoclonal antibody. J Immunol 187:1754–1763. doi:10.4049/jimmunol.1101135 CrossRefPubMed

46.

French RR, Chan HT, Tutt AL, Glennie MJ (1999) CD40 antibody evokes a cytotoxic T-cell response that eradicates lymphoma and bypasses T-cell help. Nat Med 5:548–553. doi:10.1038/8426 CrossRefPubMed

47.

Melero I, Shuford WW, Newby SA, Aruffo A, Ledbetter JA, Hellström KE, Mittler RS, Chen L (1997) Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors. Nat Med 3:682–685CrossRefPubMed

48.

Müller D, Frey K, Kontermann RE (2008) A novel antibody-4-1BBL fusion protein for targeted costimulation in cancer immunotherapy. J Immunother 31:714–722. doi:10.1097/CJI.0b013e31818353e9 CrossRefPubMed

49.

Hornig N, Kermer V, Frey K, Diebolder P, Kontermann RE, Müller D (2012) Combination of a bispecific antibody and costimulatory antibody-ligand fusion proteins for targeted cancer immunotherapy. J Immunother 35:418–429. doi:10.1097/CJI.0b013e3182594387 CrossRefPubMed

Title: Tumor-directed immunotherapy can generate tumor-specific T cell responses through localized co-stimulation
Authors: Peter Ellmark
Sara M. Mangsbo
Christina Furebring
Per Norlén
Thomas H. Tötterman
Publication date: 01-01-2017
Publisher: Springer Berlin Heidelberg
Published in: Cancer Immunology, Immunotherapy / Issue 1/2017
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-016-1909-3

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2017

Efficacy and toxicity of rechallenge with combination immune checkpoint blockade in metastatic melanoma: a case series

Alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 1 can support immune responses toward tumors overexpressing ganglioside D3 in mice

Phase I–II study of lenalidomide and alemtuzumab in refractory chronic lymphocytic leukemia (CLL): effects on T cells and immune checkpoints

Heterogeneity of CD8+ tumor-infiltrating lymphocytes in non-small-cell lung cancer: impact on patient prognostic assessments and comparison of quantification by different sampling strategies

Increased PD-L1 and T-cell infiltration in the presence of HLA class I expression in metastatic high-grade osteosarcoma: a rationale for T-cell-based immunotherapy

Low-dose interleukin-2 impairs host anti-tumor immunity and inhibits therapeutic responses in a mouse model of melanoma

Keynote webinar | Spotlight on antibody–drug conjugates in cancer