276
Views
1
CrossRef citations to date
0
Altmetric
Review

Emerging antibody therapies for pancreatic adenocarcinoma: a review of recent phase 2 trials

ORCID Icon, , & ORCID Icon
Pages 103-129 | Received 04 Dec 2020, Accepted 16 Mar 2021, Published online: 12 Apr 2021

References

  • Ferlay J, Colombet M, Soerjomataram I, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer. 2019 April 15;144(8):1941–1953.
  • Rawla P, Sunkara T, Gaduputi V. Epidemiology of pancreatic cancer: global trends, etiology and risk factors. World J Oncol. 2019 February;10(1):10–27.
  • SEER Cancer Statistics Review, 1975–2017, National cancer institute. [Internet]. SEER web site. [ cited 2020 December 9]. Available from: https://seer.cancer.gov/csr/1975_2017/.
  • Pereira SP, Oldfield L, Ney A, et al. Early detection of pancreatic cancer. Lancet Gastroenterol Hepatol. 2020 July;5(7):698–710..
  • Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817–1825.
  • Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 October 31;369(18):1691–1703.
  • Wang-Gillam A, Li CP, Bodoky G, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016 February 6;387(10018):545–557.
  • Golan T, Hammel P, Reni M, et al. Maintenance olaparib for germline BRCA-Mutated metastatic pancreatic cancer. N Engl J Med. 2019 July 25;381(4):317–327.
  • Boyiadzis MM, Kirkwood JM, Marshall JL, et al. Significance and implications of FDA approval of pembrolizumab for biomarker-defined disease. J Immunother Cancer. 2018 May 14;6(1):35.
  • Pandol S, Edderkaoui M, Gukovsky I, et al. Desmoplasia of pancreatic ductal adenocarcinoma. Clin Gastroenterol Hepatol. 2009 November;7(11 Suppl):S44–7.
  • Bailey P, Chang DK, Nones K, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016 March 3;531(7592):47–52.
  • Felsenstein M, Hruban RH, Wood LD. New developments in the molecular mechanisms of pancreatic tumorigenesis. Adv Anat Pathol. 2018 March;25(2):131–142.
  • Abramson MA, Jazag A, Van Der Zee JA, et al. The molecular biology of pancreatic cancer. Gastrointest Cancer Res. 2007;1(4 Suppl 2):S7–s12.
  • Waddell N, Pajic M, Patch AM, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015 February 26;518(7540):495–501.
  • Fan Z, Fan K, Yang C, et al. Critical role of KRAS mutation in pancreatic ductal adenocarcinoma. Transl Cancer Res. 2018;7(6):1728–1736.
  • Ren B, Cui M, Yang G, et al. Tumor microenvironment participates in metastasis of pancreatic cancer. Mol Cancer. 2018 July 30;17(1):108.
  • Gaianigo N, Melisi D, Carbone CEMT. Treatment resistance in pancreatic cancer. Cancers (Basel). 2017 September 12;9(9):122.
  • Weniger M, Honselmann KC, Liss AS. The extracellular matrix and pancreatic cancer: a complex relationship. Cancers (Basel). 2018;10(9):316.
  • Von Ahrens D, Bhagat TD, Nagrath D, et al. The role of stromal cancer-associated fibroblasts in pancreatic cancer. J Hematol Oncol. 2017 March 28;10(1):76.
  • Kalluri R. The biology and function of fibroblasts in cancer. Nat Rev Cancer. 2016 August 23;16(9):582–598.
  • Rabinovich GA, Gabrilovich D, Sotomayor EM. Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol. 2007;25(1):267–296.
  • Vonderheide RH, Bayne LJ. Inflammatory networks and immune surveillance of pancreatic carcinoma. Curr Opin Immunol. 2013 April;25(2):200–205.
  • Orhan A, Vogelsang RP, Andersen MB, et al. The prognostic value of tumour-infiltrating lymphocytes in pancreatic cancer: a systematic review and meta-analysis. Eur J Cancer. 2020 June;132:71–84.
  • Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity. 2004 August;21(2):137–148.
  • Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011 March 25;331(6024):1565–1570.
  • Garbe AI, Vermeer B, Gamrekelashvili J, et al. Genetically induced pancreatic adenocarcinoma is highly immunogenic and causes spontaneous tumor-specific immune responses. Cancer Res. 2006 January 1;66(1):508–516.
  • Gnanamony M, Gondi CS. Chemoresistance in pancreatic cancer: emerging concepts. Oncol Lett. 2017 April;13(4):2507–2513.
  • Matsuoka T, Yashiro M. Molecular targets for the treatment of pancreatic cancer: clinical and experimental studies. World J Gastroenterol. 2016 January 14;22(2):776–789.
  • Oliveira-Cunha M, Newman WG, Siriwardena AK. Epidermal growth factor receptor in pancreatic cancer. Cancers (Basel). 2011 March 24;3(2):1513–1526.
  • Uegaki K, Nio Y, Inoue Y, et al. Clinicopathological significance of epidermal growth factor and its receptor in human pancreatic cancer. Anticancer Res. 1997;Sep-Oct;17(5b):3841–7.
  • Bloomston M, Bhardwaj A, Ellison EC, et al. Epidermal growth factor receptor expression in pancreatic carcinoma using tissue microarray technique. Dig Surg. 2006;23(1–2):74–79..
  • Bruns CJ, Harbison MT, Davis DW, et al. Epidermal growth factor receptor blockade with C225 plus gemcitabine results in regression of human pancreatic carcinoma growing orthotopically in nude mice by antiangiogenic mechanisms. Clin Cancer Res. 2000 May;6(5):1936–1948.
  • Iqbal N, Iqbal N. Human Epidermal Growth Factor Receptor 2 (HER2) in cancers: overexpression and therapeutic implications. Mol Biol Int. 2014;2014:852748.
  • Safran H, Steinhoff M, Mangray S, et al. Overexpression of the HER-2/neu oncogene in pancreatic adenocarcinoma. Am J Clin Oncol. 2001 October;24(5):496–499..
  • Kimura K, Sawada T, Komatsu M, et al. Antitumor effect of trastuzumab for pancreatic cancer with high HER-2 expression and enhancement of effect by combined therapy with gemcitabine. Clin Cancer Res. 2006 August 15;12(16):4925–4932.
  • Faller BA, Burtness B. Treatment of pancreatic cancer with epidermal growth factor receptor-targeted therapy. Biologics. 2009;3:419–428.
  • Cascinu S, Berardi R, Labianca R, et al. Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, phase II trial. Lancet Oncol. 2008 January;9(1):39–44..
  • Philip PA, Benedetti J, Corless CL, et al. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: southwest oncology group-directed intergroup trial S0205. J Clin Oncol. 2010 August 1;28(22):3605–3610.
  • Burtness B, Powell M, Catalano P, et al. Randomized phase ii trial of irinotecan/docetaxel or irinotecan/docetaxel plus cetuximab for metastatic pancreatic cancer: an Eastern cooperative oncology group study. Am J Clin Oncol. 2016 August;39(4):340–345.
  • Ko AH, Youssoufian H, Gurtler J, et al. A phase II randomized study of cetuximab and bevacizumab alone or in combination with gemcitabine as first-line therapy for metastatic pancreatic adenocarcinoma. Invest New Drugs. 2012 August;30(4):1597–1606.
  • Forster T, Huettner FJ, Springfeld C, et al. Cetuximab in pancreatic cancer therapy: a systematic review and Meta-Analysis. Oncology. 2020;98(1):53–60.
  • Halfdanarson TR, Foster NR, Kim GP, et al. A phase ii randomized trial of panitumumab, erlotinib, and gemcitabine versus erlotinib and gemcitabine in patients with untreated, metastatic pancreatic adenocarcinoma: north central cancer treatment group trial N064B (Alliance). Oncologist. 2019 May;24(5):589–e160.
  • Schultheis B, Reuter D, Ebert MP, et al. Gemcitabine combined with the monoclonal antibody nimotuzumab is an active first-line regimen in KRAS wildtype patients with locally advanced or metastatic pancreatic cancer: a multicenter, randomized phase IIb study. Ann Oncol. 2017 October 1;28(10):2429–2435.
  • Assenat E, Mineur L, Mollevi C, et al. Phase II study evaluating the association of gemcitabine, trastuzumab, and erlotinib as first-line treatment in patients with metastatic pancreatic adenocarcinoma (GATE 1). J Clin Oncol. 2015;33(3_suppl):379.
  • Harder J, Ihorst G, Heinemann V, et al. Multicentre phase II trial of trastuzumab and capecitabine in patients with HER2 overexpressing metastatic pancreatic cancer. Br J Cancer. 2012 Mar 13;106(6):1033–1038.
  • Ogitani Y, Aida T, Hagihara K, et al. DS-8201a, A novel HER2-Targeting ADC with a novel DNA topoisomerase i inhibitor, demonstrates a promising antitumor efficacy with differentiation from T-DM1. Clin Cancer Res. 2016;22(20):5097–5108.
  • Harder J, Ihorst G, Heinemann V, et al. Multicentre phase II trial of trastuzumab and capecitabine in patients with HER2 overexpressing metastatic pancreatic cancer. Br J Cancer. 2012 [2012 March 01];106(6):1033–1038.
  • Rieder S, Michalski CW, Friess H, et al. Insulin-like growth factor signaling as a therapeutic target in pancreatic cancer. Anticancer Agents Med Chem. 2011 Jun;11(5):427–433..
  • Park JY, Lee JY, Zhang Y, et al. Targeting the insulin growth factor-1 receptor with fluorescent antibodies enables high resolution imaging of human pancreatic cancer in orthotopic mouse models. Oncotarget. 2016 Apr 5;7(14):18262–18268.
  • Camblin AJ, Pace EA, Adams S, et al. Dual inhibition of IGF-1R and ErbB3 enhances the activity of gemcitabine and Nab-Paclitaxel in preclinical models of pancreatic cancer. Clin Cancer Res. 2018;24(12):2873–2885.
  • Kindler HL, Richards DA, Garbo LE, et al. A randomized, placebo-controlled phase 2 study of ganitumab (AMG 479) or conatumumab (AMG 655) in combination with gemcitabine in patients with metastatic pancreatic cancer. Ann Oncol. 2012 Nov;23(11):2834–2842.
  • Philip PA, Goldman B, Ramanathan RK, et al. Dual blockade of epidermal growth factor receptor and insulin-like growth factor receptor-1 signaling in metastatic pancreatic cancer: phase Ib and randomized phase II trial of gemcitabine, erlotinib, and cixutumumab versus gemcitabine plus erlotinib (SWOG S0727). Cancer. 2014 Oct 1;120(19):2980–2985.
  • Abdel-Wahab R, Varadhachary GR, Bhosale PR, et al. Randomized, phase I/II study of gemcitabine plus IGF-1R antagonist (MK-0646) versus gemcitabine plus erlotinib with and without MK-0646 for advanced pancreatic adenocarcinoma. J Hematol Oncol. 2018 May 30;11(1):71.
  • Fuchs CS, Azevedo S, Okusaka T, et al. A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. Ann Oncol. 2015 May;26(5):921–927.
  • Kundranda M, Gracian AC, Zafar SF, et al. Randomized, double-blind, placebo-controlled phase II study of istiratumab (MM-141) plus nab-paclitaxel and gemcitabine versus nab-paclitaxel and gemcitabine in front-line metastatic pancreatic cancer (CARRIE). Ann Oncol. 2020 Jan;31(1):79–87.
  • Ozawa F, Friess H, Kleeff J, et al. Effects and expression of TRAIL and its apoptosis-promoting receptors in human pancreatic cancer. Cancer Lett. 2001 Feb 10;163(1):71–81.
  • Derosier LC, Vickers SM, Zinn KR, et al. TRA-8 anti-DR5 monoclonal antibody and gemcitabine induce apoptosis and inhibit radiologically validated orthotopic pancreatic tumor growth. Mol Cancer Ther. 2007 Dec;6(12 Pt 1):3198–3207.
  • Dubuisson A, Micheau O. Antibodies and derivatives targeting DR4 and DR5 for cancer therapy. Antibodies (Basel). 2017 October 25;6(4):4.
  • Forero-Torres A, Infante JR, Waterhouse D, et al. Phase 2, multicenter, open-label study of tigatuzumab (CS-1008), a humanized monoclonal antibody targeting death receptor 5, in combination with gemcitabine in chemotherapy-naive patients with unresectable or metastatic pancreatic cancer. Cancer Med. 2013 December;2(6):925–932.
  • Ratain MJ, Doi T, De Jonge MJ, et al. Phase 1, first-in-human study of TRAIL receptor agonist fusion protein ABBV-621. Am Soc Clin Oncol. 2019;37(15_suppl):3013..
  • Argani P, Iacobuzio-Donahue C, Ryu B, et al. Mesothelin is overexpressed in the vast majority of ductal adenocarcinomas of the pancreas: identification of a new pancreatic cancer marker by serial analysis of gene expression (SAGE). Clin Cancer Res. 2001 Dec;7(12):3862–3868.
  • Zheng C, Jia W, Tang Y, et al. Mesothelin regulates growth and apoptosis in pancreatic cancer cells through p53-dependent and -independent signal pathway. J Exp Clin Cancer Res. 2012 Oct 3;31(1):84.
  • Baldo P, Cecco S. Amatuximab and novel agents targeting mesothelin for solid tumors. Onco Targets Ther. 2017;10:5337–5353.
  • Hassan R, Ebel W, Routhier EL, et al. Preclinical evaluation of MORAb-009, a chimeric antibody targeting tumor-associated mesothelin. Cancer Immun. 2007 Dec 19;7:20.
  • Hassan R, Thomas A, Alewine C, et al. Mesothelin Immunotherapy for cancer: ready for prime time? J Clin Oncol. 2016 Dec;34(34):4171–4179.
  • Hassan R, Bullock S, Premkumar A, et al. Phase I study of SS1P, a recombinant anti-mesothelin immunotoxin given as a bolus I.V. infusion to patients with mesothelin-expressing mesothelioma, ovarian, and pancreatic cancers. Clin Cancer Res. 2007 September 1;13(17):5144–5149.
  • Sahin U, Koslowski M, Dhaene K, et al. Claudin-18 splice variant 2 is a pan-cancer target suitable for therapeutic antibody development. Clin Cancer Res. 2008 December 1;14(23):7624–7634.
  • Tanaka M, Shibahara J, Fukushima N, et al. Claudin-18 is an early-stage marker of pancreatic carcinogenesis. J Histochem Cytochem. 2011 October;59(10):942–952.
  • Wöll S, Schlitter AM, Dhaene K, et al. Claudin 18.2 is a target for IMAB362 antibody in pancreatic neoplasms. Int J Cancer. 2014 February 1;134(3):731–739.
  • Ӧ T, Mitnacht-Kraus R, Wöll S, et al. Characterization of zolbetuximab in pancreatic cancer models. Oncoimmunology. 2019;8(1):e1523096.
  • Park W, O’Reilly EM, Furuse J, et al. Phase II, open-label, randomized study of first-line zolbetuximab plus gemcitabine and nab-paclitaxel (GN) in Claudin 18.2–positive metastatic pancreatic cancer (mPC). Am Soc Clin Oncol. 2020;38(15_suppl): TPS4667-TPS4667.
  • Engle DD, Tiriac H, Rivera KD, et al., The glycan CA19-9 promotes pancreatitis and pancreatic cancer in mice. Science (New York, NY). 364(6446): 1156–1162. 2019.
  • Ragupathi G, Wu X, Livingston P, et al. Abstract A73: antitumor activity of MVT-5873, a monoclonal antibody targeting sialyl Lewisa, alone and in combination with gemcitabine/nab-paclitaxel in a BxPC3 human pancreatic cancer xenograft model. Cancer Res. 2016;76(24 Supplement):A73–A73.
  • O’Reilly EM, Wang JS-Z, Yu KH, et al. Single agent HuMab-5B1 (MVT-5873), a monoclonal antibody targeting sLea, in patients with pancreatic cancer and other CA19-9 positive malignancies. J Clin Oncol. 2017 [2017 May 20];35(15_suppl):4110.
  • O’Reilly EM, Wang JS-Z, Yu KH, et al. Abstract LB-B25: preliminary phase I data comparing HuMab-5B1 (MVT-5873), a monoclonal antibody targeting sLea, as a single agent and in combination with first line nab-paclitaxel and gemcitabine in patients with CA19-9 positive pancreatic cancer. Mol Cancer Ther. 2018;17(1Supplement):LB-B25-LB-B25.
  • Abel EV, Kim EJ, Wu J, et al. The Notch pathway is important in maintaining the cancer stem cell population in pancreatic cancer. PLoS One. 2014;9(3):e91983.
  • Yabuuchi S, Pai SG, Campbell NR, et al. Notch signaling pathway targeted therapy suppresses tumor progression and metastatic spread in pancreatic cancer. Cancer Lett. 2013 Jul 10;335(1):41–51.
  • Shih IM, Wang TL. Notch signaling, gamma-secretase inhibitors, and cancer therapy. Cancer Res. 2007 Mar 1;67(5):1879–1882.
  • Yen WC, Fischer MM, Axelrod F, et al. Targeting Notch signaling with a Notch2/Notch3 antagonist (tarextumab) inhibits tumor growth and decreases tumor-initiating cell frequency. Clin Cancer Res. 2015 May 1;21(9):2084–2095.
  • Wan-Ching Yen MF, Lewicki J, Gurney A, et al. The combination of gemcitabine/nab-paclitaxel with an anti-DLL4 monoclonal antibody demcizumab produces synergistic growth inhibition, delays tumor recurrence and reduces tumorigenicity of tumor initiating cells in pancreatic cancer. Gastrointest Cancer Symp 2014 Jan 22; REDWOOD CITY, California. GlobeNewswire: GlobeNewswire 2014.
  • Cook N, Basu B, Smith DM, et al. A phase I trial of the γ-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma. Br J Cancer. 2018 Mar 20;118(6):793–801.
  • Hu ZI, Bendell JC, Bullock A, et al. A randomized phase II trial of nab-paclitaxel and gemcitabine with tarextumab or placebo in patients with untreated metastatic pancreatic cancer. Cancer Med. 2019;8(11):5148–5157..
  • Cubillo Gracian A, Dean A, Muñoz A, et al. 620PD - YOSEMITE: a 3 arm double-blind randomized phase 2 study of gemcitabine, paclitaxel protein-bound particles for injectable suspension, and placebo (GAP) versus gemcitabine, paclitaxel protein-bound particles for injectable suspension and either 1 or 2 truncated courses of demcizumab (GAD). Ann Oncol. 2017 [2017 September 01];28:v211.
  • Ram Makena M, Gatla H, Verlekar D, et al. Wnt/β-Catenin signaling: the culprit in pancreatic carcinogenesis and therapeutic resistance. Int J Mol Sci. 2019 Aug 30;20(17):17.
  • Gurney A, Axelrod F, Bond CJ, et al. Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors. Proceedings of the National Academy of Sciences of the United States of America. 2012 2012/July//;109( 29):11717–11722.
  • Davis SL, Cardin DB, Shahda S, et al. A phase 1b dose escalation study of Wnt pathway inhibitor vantictumab in combination with nab-paclitaxel and gemcitabine in patients with previously untreated metastatic pancreatic cancer. Invest New Drugs. 2020 Jun;38(3):821–830.
  • Dotan E, Cardin DB, Lenz H-J, et al. Phase Ib study of wnt inhibitor ipafricept with gemcitabine and nab-paclitaxel in patients with previously untreated stage IV pancreatic cancer. In Clinical cancer research. 2020.
  • Ko AH, Chiorean EG, Kwak EL, et al. Final results of a phase Ib dose-escalation study of PRI-724, a CBP/beta-catenin modulator, plus gemcitabine (GEM) in patients with advanced pancreatic adenocarcinoma (APC) as second-line therapy after FOLFIRINOX or FOLFOX. J Clin Oncol. 2016;34(15_suppl):e15721–e15721.
  • Longo V, Brunetti O, Gnoni A, et al. Angiogenesis in pancreatic ductal adenocarcinoma: a controversial issue. Oncotarget. 2016 Sep 6;7(36):58649–58658.
  • Craven KE, Gore J, Korc M. Overview of pre-clinical and clinical studies targeting angiogenesis in pancreatic ductal adenocarcinoma. Cancer Lett. 2016 Oct 10;381(1):201–210.
  • Bruns CJ, Shrader M, Harbison MT, et al. Effect of the vascular endothelial growth factor receptor-2 antibody DC101 plus gemcitabine on growth, metastasis and angiogenesis of human pancreatic cancer growing orthotopically in nude mice. Int J Cancer. 2002 Nov 10;102(2):101–108.
  • Fukasawa M, Korc M. Vascular endothelial growth factor-trap suppresses tumorigenicity of multiple pancreatic cancer cell lines. Clin Cancer Res. 2004 May 15;10(10):3327–3332.
  • Kindler HL, Friberg G, Singh DA, et al. Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2005 Nov 1;23(31):8033–8040.
  • Kindler HL, Niedzwiecki D, Hollis D, et al. Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303). J Clin Oncol. 2010 Aug 1;28(22):3617–3622.
  • Van Cutsem E, Vervenne WL, Bennouna J, et al. Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol. 2009 May 1;27(13):2231–2237.
  • Shaib WL, O’Neil B, El-Rayes BF, et al. Phase II randomized, double-blind, study of mFOLFIRINOX plus ramucirumab versus mFOLFIRINOX plus placebo in advanced pancreatic cancer patients hcrn GI14-198. Am Soc Clin Oncol. 2019;37(4_suppl): TPS475-TPS475.
  • Bais C, Rabe C, Wild N, et al. Comprehensive reassessment of plasma VEGFA (pVEGFA) as a candidate predictive biomarker for bevacizumab (Bv) in 13 pivotal trials (seven indications). J Clin Oncol. 2014 [2014 May 20];32(15_suppl):3040.
  • Martin LK, Li X, Kleiber B, et al. VEGF remains an interesting target in advanced pancreas cancer (APCA): results of a multi-institutional phase II study of bevacizumab, gemcitabine, and infusional 5-fluorouracil in patients with APCA. Ann Oncol. 2012 [2012 December 01];23(11):2812–2820.
  • Li S, Xu HX, Wu CT, et al. Angiogenesis in pancreatic cancer: current research status and clinical implications. Angiogenesis. 2019 Feb;22(1):15–36.
  • Brennen WN, Isaacs JT, Denmeade SR. Rationale behind targeting fibroblast activation protein-expressing carcinoma-associated fibroblasts as a novel chemotherapeutic strategy. Mol Cancer Ther. 2012 Feb;11(2):257–266.
  • Elyada E, Bolisetty M, Laise P, et al. Cross-Species Single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting Cancer-Associated fibroblasts. Cancer Discov. 2019;9(8):1102–1123.
  • Kawase T, Yasui Y, Nishina S, et al. Fibroblast activation protein-α-expressing fibroblasts promote the progression of pancreatic ductal adenocarcinoma. BMC Gastroenterol. 2015 Sep;2(15):109.
  • Kraman M, Bambrough PJ, Arnold JN, et al. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science. 2010 Nov 5;330(6005):827–830.
  • Gunderson AJ, Yamazaki T, McCarty K, et al. Blockade of fibroblast activation protein in combination with radiation treatment in murine models of pancreatic adenocarcinoma. PLoS One. 2019;14(2):e0211117.
  • Zhao X, Fan W, Xu Z, et al. Inhibiting tumor necrosis factor-alpha diminishes desmoplasia and inflammation to overcome chemoresistance in pancreatic ductal adenocarcinoma. Oncotarget. 2016 Dec 6;7(49):81110–81122.
  • Neesse A, Frese KK, Bapiro TE, et al. CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer. Proc Natl Acad Sci U S A. 2013 Jul 23;110(30):12325–12330.
  • Bennewith KL, Huang X, Ham CM, et al. The role of tumor cell-derived connective tissue growth factor (CTGF/CCN2) in pancreatic tumor growth. Cancer Res. 2009 Feb 1;69(3):775–784.
  • Aikawa T, Gunn J, Spong SM, et al. Connective tissue growth factor-specific antibody attenuates tumor growth, metastasis, and angiogenesis in an orthotopic mouse model of pancreatic cancer. Mol Cancer Ther. 2006 5; May(5): 1108–1116.
  • Picozzi VJ, Pishvaian MJ, Mody K, et al., Effect of anti-CTGF human recombinant monoclonal antibody pamrevlumab on resectability and resection rate when combined with gemcitabine/nab-paclitaxel in phase 1/2 clinical study for the treatment of locally advanced pancreatic cancer patients. Am Soc Clin Oncol. 36(15_suppl): 4016. 2018.
  • Yao H, Zeng ZZ, Fay KS, et al. Role of α(5)β(1) Integrin Up-regulation in Radiation-Induced invasion by human pancreatic cancer cells. Transl Oncol. 2011 Oct;4(5):282–292.
  • Bhaskar V, Zhang D, Fox M, et al. A function blocking anti-mouse integrin alpha5beta1 antibody inhibits angiogenesis and impedes tumor growth in vivo. J Transl Med. 2007 Nov 27;5(1):61.
  • Bhaskar V, Fox M, Breinberg D, et al. Volociximab, a chimeric integrin alpha5beta1 antibody, inhibits the growth of VX2 tumors in rabbits. Invest New Drugs. 2008 Feb;26(1):7–12.
  • Evans T, Ramanathan RK, Yazji S, et al. Final results from cohort 1 of a phase II study of volociximab, an anti-α5β1 integrin antibody, in combination with gemcitabine (GEM) in patients (pts) with metastatic pancreatic cancer (MPC). J Clin Oncol. 2007;25(18_suppl):4549.
  • Razidlo GL, Burton KM, McNiven MA. Interleukin-6 promotes pancreatic cancer cell migration by rapidly activating the small GTPase CDC42. J Biol Chem. 2018 Jul 13;293(28):11143–11153.
  • Mace TA, Shakya R, Pitarresi JR, et al. IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer. Gut. 2018 Feb;67(2):320–332.
  • Angevin E, Tabernero J, Elez E, et al. A phase I/II, multiple-dose, dose-escalation study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with advanced solid tumors. Clin Cancer Res. 2014 April 15;20(8):2192–2204.
  • Sim GC, The RL. IL-2 cytokine family in cancer immunotherapy. Cytokine Growth Factor Rev. 2014 Aug;25(4):377–390.
  • Soerensen MM, Ros W, Rodriguez-Ruiz ME, et al. Safety, PK/ PD,and anti-tumor activity of RO6874281, an engineered variant of interleukin-2 (IL-2v) targeted to tumor-associated fibroblasts via binding to fibroblast activation protein (FAP). Am Soc Clin Oncol. 2018;36(15_suppl):e15155-e15155.
  • Boufraqech M, Zhang L, Nilubol N, et al. Lysyl Oxidase (LOX) transcriptionally regulates SNAI2 expression and TIMP4 secretion in human cancers. Clin Cancer Res. 2016 Sep 1;22(17):4491–4504.
  • Puente A, Fortea JI, Cabezas J, et al. LOXL2-A new target in antifibrogenic therapy? Int J Mol Sci. 2019 Apr 2;20(7):7.
  • Sion AM, Figg WD. Lysyl oxidase (LOX) and hypoxia-induced metastases. Cancer Biol Ther. 2006 Aug;5(8):909–911.
  • Park JS, Lee JH, Lee YS, et al. Emerging role of LOXL2 in the promotion of pancreas cancer metastasis. Oncotarget. 2016 July 5;7(27):42539–42552.
  • Miller BW, Morton JP, Pinese M, et al. Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy. EMBO Mol Med. 2015 Aug;7(8):1063–1076.
  • Tanaka N, Yamada S, Sonohara F, et al. Clinical implications of Lysyl Oxidase-Like protein 2 expression in pancreatic cancer. Sci Rep. 2018 Jun 29;8(1):9846.
  • Barry-Hamilton V, Spangler R, Marshall D, et al. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat Med. 2010 Sep;16(9):1009–1017.
  • Benson III AB, Wainberg ZA, Hecht JR, et al. A phase II randomized, Double-Blind, Placebo-Controlled study of simtuzumab or placebo in combination with gemcitabine for the first-line treatment of pancreatic adenocarcinoma. Oncologist. 2017;22(3):241–e15.
  • Kabacaoglu D, Ciecielski KJ, Ruess DA, et al. Immune checkpoint inhibition for pancreatic ductal adenocarcinoma: current limitations and future options. Front Immunol. 2018;9:1878.
  • Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug 19;363(8): 711–723.
  • Sandin LC, Eriksson F, Ellmark P, et al. Local CTLA4 blockade effectively restrains experimental pancreatic adenocarcinoma growth in vivo. Oncoimmunology. 2014 Jan 1;3(1):e27614.
  • Royal RE, Levy C, Turner K, et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother. 2010 Oct;33(8):828–833.
  • Kamath SD, Kalyan A, Kircher S, et al. Ipilimumab and gemcitabine for advanced pancreatic cancer: a phase Ib study. Oncologist. 2020 May;25(5):e808–e815.
  • Okudaira K, Hokari R, Tsuzuki Y, et al. Blockade of B7-H1 or B7-DC induces an anti-tumor effect in a mouse pancreatic cancer model. Int J Oncol. 2009 Oct;35(4):741–749.
  • Gao M, Lin M, Moffitt RA, et al. Direct therapeutic targeting of immune checkpoint PD-1 in pancreatic cancer. Br J Cancer. 2019 Jan;120(1):88–96.
  • Brahmer JR, Tykodi SS, Chow LQM, et al. Safety and activity of Anti–PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–2465.
  • Weiss GJ, Blaydorn L, Beck J, et al. Phase Ib/II study of gemcitabine, nab-paclitaxel, and pembrolizumab in metastatic pancreatic adenocarcinoma. Invest New Drugs. 2018 Feb;36(1):96–102..
  • O’Reilly EM, Oh DY, Dhani N, et al. Durvalumab with or without tremelimumab for patients with metastatic pancreatic ductal adenocarcinoma: a phase 2 randomized clinical trial. JAMA Oncol. 2019 Jul 18;5(10):1431–1438.
  • Vonderheide RH. Prospect of targeting the CD40 pathway for cancer therapy. Clin Cancer Res. 2007 Feb 15;13(4):1083–1088.
  • Eliopoulos AG, Davies C, Knox PG, et al. CD40 induces apoptosis in carcinoma cells through activation of cytotoxic ligands of the tumor necrosis factor superfamily. Mol Cell Biol. 2000 Aug;20(15):5503–5515.
  • Beatty GL, Chiorean EG, Fishman MP, et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science. 2011 Mar 25;331(6024):1612–1616.
  • O’Hara MH, O’Reilly EM, Rosemarie M, et al. Abstract CT004: a Phase Ib study of CD40 agonistic monoclonal antibody APX005M together with gemcitabine (Gem) and nab-paclitaxel (NP) with or without nivolumab (Nivo) in untreated metastatic ductal pancreatic adenocarcinoma (PDAC) patients. Cancer Res. 2019;79(13Supplement):CT004–CT004.
  • Chen Q, Pu N, Yin H, et al. CD73 acts as a prognostic biomarker and promotes progression and immune escape in pancreatic cancer. J Cell Mol Med. 2020;24(15):8674–8686.
  • Zhou L, Jia S, Chen Y, et al. The distinct role of CD73 in the progression of pancreatic cancer. J Mol Med (Berl). 2019 Jun;97(6):803–815.
  • Chen Q, Pu N, Yin H, et al. CD73 acts as a prognostic biomarker and promotes progression and immune escape in pancreatic cancer. J Cell Mol Med. 2020 August;24(15):8674–8686.
  • Wang L, Tang S, Wang Y, et al. Ecto-5ʹ-nucleotidase (CD73) promotes tumor angiogenesis. Clin Exp Metastasis. 2013 June;30(5):671–680.
  • Tahkola K, Ahtiainen M, Kellokumpu I, et al. Virchows Arch. In: Prognostic impact of CD73 expression and its relationship to PD-L1 in patients with radically treated pancreatic cancer. Jul, 2020. 16.
  • Hay CM, Sult E, Huang Q, et al. Targeting CD73 in the tumor microenvironment with MEDI9447. Oncoimmunology. 2016 August;5(8):e1208875.
  • *Manji GA, Wainberg ZA, Krishnan K, et al. ARC-8: phase I/Ib study to evaluate safety and tolerability of AB680 + chemotherapy + zimberelimab (AB122) in patients with treatment-naive metastatic pancreatic adenocarcinoma (mPDAC). J Clin Oncol. 2021;39(3_suppl):404. 2021 January 20.
  • Chini EN, Chini CCS, Espindola Netto JM, et al. The pharmacology of CD38/NADase: an emerging target in cancer and diseases of aging. Trends Pharmacol Sci. 2018 April;39(4):424–436.
  • Malavasi F, Deaglio S, Funaro A, et al. Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology. Physiol Rev. 2008 July;88(3):841–886.
  • Zhang M, Yang J, Zhou J, et al. Prognostic Values of CD38+CD101+PD1+CD8+ T Cells in Pancreatic Cancer. Immunol Invest. 2019 [2019 July 04];48(5):466–479.
  • Johnston RJ, Comps-Agrar L, Hackney J, et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell. 2014 December 8;26(6):923–937.
  • Blake SJ, Dougall WC, Miles JJ, et al. Molecular pathways: targeting CD96 and TIGIT for cancer immunotherapy. Clin Cancer Res. 2016 November 1;22(21):5183–5188.
  • Blessin NC, Simon R, Kluth M, et al. Patterns of TIGIT expression in lymphatic tissue, inflammation, and cancer. Dis Markers. 2019;2019:5160565.
  • Chauvin JM, Pagliano O, Fourcade J, et al. TIGIT and PD-1 impair tumor antigen-specific CD8⁺ T cells in melanoma patients. J Clin Invest. 2015 May;125(5):2046–2058.
  • Ino Y, Yamazaki-Itoh R, Shimada K, et al. Immune cell infiltration as an indicator of the immune microenvironment of pancreatic cancer. Br J Cancer. 2013 March 5;108(4):914–923.
  • Kurahara H, Shinchi H, Mataki Y, et al. Significance of M2-polarized tumor-associated macrophage in pancreatic cancer. J Surg Res. 2011 May 15;167(2):e211–9.
  • Mollica Poeta V, Massara M, Capucetti A, et al. Chemokines and chemokine receptors: new targets for cancer immunotherapy. Front Immunol. 2019;10:379.
  • Vandercappellen J, Van Damme J, Struyf S. The role of CXC chemokines and their receptors in cancer. Cancer Lett. 2008 August 28;267(2):226–244.
  • Righetti A, Giulietti M, Šabanović B, et al. CXCL12 and its isoforms: different roles in pancreatic cancer? J Oncol. 2019;2019:9681698.
  • Singh S, Srivastava SK, Bhardwaj A, et al. CXCL12-CXCR4 signalling axis confers gemcitabine resistance to pancreatic cancer cells: a novel target for therapy. Br J Cancer. 2010 November 23;103(11):1671–1679.
  • Steele CW, Karim SA, Leach JDG, et al. CXCR2 inhibition profoundly suppresses metastases and augments immunotherapy in pancreatic ductal adenocarcinoma. Cancer Cell. 2016 June 13;29(6):832–845.
  • Yadav VN, Zamler D, Baker GJ, et al. CXCR4 increases in-vivo glioma perivascular invasion, and reduces radiation induced apoptosis: a genetic knockdown study. Oncotarget. 2016;7(50):50.
  • Safety and Efficacy Study of Ulocuplumab and Nivolumab in Subjects With Solid Tumors (CXCessoR4) [Internet]. 2018 [cited 9/30/2020]. Available from: https://clinicaltrials.gov/ct2/show/NCT02472977.
  • Bockorny B, Semenisty V, Macarulla T, et al. BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the COMBAT trial. Nat Med. 2020 June;26(6):878–885.
  • Nywening TM, Wang-Gillam A, Sanford DE, et al. Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial. Lancet Oncol. 2016 May;17(5):651–662.
  • Sadelain M, Rivière I, Brentjens R. Targeting tumours with genetically enhanced T lymphocytes. Nat Rev Cancer. 2003 January;3(1):35–45.
  • Eshhar Z, Waks T, Gross G, et al. Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proc Natl Acad Sci U S A. 1993 January 15;90(2):720–724.
  • Frigault MJ, Lee J, Basil MC, et al. Identification of chimeric antigen receptors that mediate constitutive or inducible proliferation of T cells. Cancer Immunol Res. 2015 April;3(4):356–367..
  • Akce M, Zaidi MY, Waller EK, et al. The Potential of CAR T Cell Therapy in Pancreatic Cancer. Front Immunol. 2018;9:2166.
  • Ho WJ, Jaffee EM, Zheng L. The tumour microenvironment in pancreatic cancer - clinical challenges and opportunities. Nat Rev Clin Oncol. 2020 September;17(9):527–540.
  • Chmielewski M, Hahn O, Rappl G, et al. T cells that target carcinoembryonic antigen eradicate orthotopic pancreatic carcinomas without inducing autoimmune colitis in mice. Gastroenterology. 2012 October;143(4):1095–107.e2.
  • Posey AD Jr., Schwab RD, Boesteanu AC, et al. Engineered CAR T Cells targeting the Cancer-Associated Tn-Glycoform of the membrane mucin MUC1 control adenocarcinoma. Immunity. 2016 June 21;44(6):1444–1454.
  • Kakarla S, Chow KK, Mata M, et al. Antitumor effects of chimeric receptor engineered human T cells directed to tumor stroma. Mol Ther. 2013 August;21(8):1611–1620.
  • Krishnamurthy A, Jimeno A. Bispecific antibodies for cancer therapy: a review. Pharmacol Ther. 2018 May;185:122–134.
  • Peipp M, Valerius T. Bispecific antibodies targeting cancer cells. Biochem Soc Trans. 2002 August;30(4):507–511.
  • Thakur A, Lum LG. Cancer therapy with bispecific antibodies: clinical experience. Curr Opin Mol Ther. 2010 June;12(3):340–349.
  • Beck A, Reichert JM. Antibody-drug conjugates: present and future. MAbs. 2014 January-February;6(1):15–17.
  • Chau CH, Steeg PS, Figg WD. Antibody-drug conjugates for cancer. Lancet. 2019August31;394(10200):793–804.
  • Cardillo TM, Govindan SV, Sharkey RM, et al. Sacituzumab Govitecan (IMMU-132), an Anti-Trop-2/SN-38 Antibody-Drug Conjugate: characterization and efficacy in pancreatic, gastric, and other cancers. Bioconjug Chem. 2015 May 20;26(5):919–931.
  • Andreev J, Thambi N, Perez Bay AE, et al. Bispecific antibodies and Antibody-Drug Conjugates (ADCs) bridging HER2 and prolactin receptor improve efficacy of HER2 ADCs. Mol Cancer Ther. 2017 April;16(4):681–693.
  • Lum LG, Le TM, Choi M, et al. Clinical and immune responses using anti-CD3 x anti-EGFR bispecific antibody armed T cells (BATs) for locally advanced or metastatic pancreatic cancer. Am Soc Clin Oncol. 2019;31(1):e75-e84..
  • Kimura K, Sawada T, Komatsu M, et al. Antitumor effect of trastuzumab for pancreatic cancer with high HER-2 expression and enhancement of effect by combined therapy with gemcitabine. Clin Cancer Res. 2006;12(16):4925–4932.
  • Adams C, Totpal K, Lawrence D, et al. Structural and functional analysis of the interaction between the agonistic monoclonal antibody Apomab and the proapoptotic receptor DR5. Cell Death Differ. 2008 April;15(4):751–761.
  • Cantargia announces pre-clinical results showing positive effects of. CAN04 combined with approved cancer therapies [Internet]. Cantargia. 2018. Available from: https://cantargia.com/en/press-releases/cantargia-announces-pre-clinical-results-showingpositiveeffects-of-can04combinedwith-approved-cancer-therapies
  • Gurney A, Axelrod F, Bond CJ, et al. Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors. Proc Natl Acad Sci U S A. 2012 July 17;109(29):11717–11722.
  • Reusch U, Sundaram M, Davol PA, et al. Anti-CD3 x anti-epidermal growth factor receptor (EGFR) bispecific antibody redirects T-cell cytolytic activity to EGFR-positive cancers in vitro and in an animal model. Clin Cancer Res. 2006 January 1;12(1):183–190.
  • Wente MN, Jain A, Kono E, et al. Prostate stem cell antigen is a putative target for immunotherapy in pancreatic cancer. Pancreas. 2005 August;31(2):119–125.
  • De Vries Schultink AHM, Doornbos RP, Bakker ABH, et al. Translational PK-PD modeling analysis of MCLA-128, a HER2/HER3 bispecific monoclonal antibody, to predict clinical efficacious exposure and dose. Invest New Drugs. 2018 December;36(6):1006–1015.
  • Han H, Ma J, Zhang K, et al. Bispecific anti‑CD3 x anti‑HER2 antibody mediates T cell cytolytic activity to HER2‑positive colorectal cancer in vitro and in vivo. Int J Oncol. 2014 [2014 December 01];45(6):2446–2454.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.