Clinical immunotherapy in pancreatic cancer

1.

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2020) GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Ca-a Cancer J Clin 71(2021):209–249. https://doi.org/10.3322/caac.21660

2.

Conroy T, Hammel P, Hebbar M, Ben Abdelghani M, Wei AC, Raoul JL, Chone L, Francois E, Artru P, Biagi JJ, Lecomte T, Assenat E, Faroux R, Ychou M, Volet J, Sauvanet A, Breysacher G, Di Fiore F, Cripps C, Kavan P, Texereau P, Bouhier-Leporrier K, Khemissa-Akouz F, Legoux JL, Juzyna B, Gourgou S, O’Callaghan CJ, Jouffroy-Zeller C, Rat P, Malka D, Castan F, Bachet JB, G. Canadian Canc Trials, G.I.P.G. Unicanc (2018) FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. New Engl J Med 379:2395–2406. https://doi.org/10.1056/NEJMoa1809775

3.

Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardiere C, Bennouna J, Bachet JB, Khemissa-Akouz F, Pere-Verge D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M, U. Grp Tumeurs Digestives, P. Intergrp (2011) FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. New Engl J Med 364:1817–1825. https://doi.org/10.1056/NEJMoa1011923CrossRefPubMed

4.

Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF (2013) Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 369:1691–1703.CrossRef

5.

Sinn M, Bahra M, Liersch T, Gellert K, Messmann H, Bechstein W, Waldschmidt D, Jacobasch L, Wilhelm M, Rau BM, Grützmann R, Weinmann A, Maschmeyer G, Pelzer U, Stieler JM, Striefler JK, Ghadimi M, Bischoff S, Dörken B, Oettle H, Riess H (2017) CONKO-005: Adjuvant chemotherapy with gemcitabine plus erlotinib versus gemcitabine alone in patients after r0 resection of pancreatic cancer: a multicenter randomized phase III trial. J Clin Oncol Official J Am Soc Clin Oncol 35:3330–3337.CrossRef

6.

Carreau NA, Pavlick AC (2019) Nivolumab and ipilimumab: immunotherapy for treatment of malignant melanoma. Future Oncol (London, England) 15:349–358.CrossRef

7.

Zhang Q, Vignali DAA (2016) Co-stimulatory and co-inhibitory pathways in autoimmunity. Immunity 44:1034–1051.PubMedPubMedCentralCrossRef

8.

Chen L, Flies DB (2013) Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol 13:227–242.PubMedPubMedCentralCrossRef

9.

Keir ME, Liang SC, Guleria I, Latchman YE, Qipo A, Albacker LA, Koulmanda M, Freeman GJ, Sayegh MH, Sharpe AH (2006) Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med 203:883–895PubMedPubMedCentralCrossRef

10.

Keir ME, Butte MJ, Freeman GJ, Sharpe AH (2008) PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26:677–704.PubMedPubMedCentralCrossRef

11.

Fife BT, Pauken KE, Eagar TN, Obu T, Wu J, Tang Q, Azuma M, Krummel MF, Bluestone JA (2009) Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. Nat Immunol 10:1185–1192.PubMedPubMedCentralCrossRef

12.

Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12:252–264.PubMedPubMedCentralCrossRef

13.

Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E, Chen L (2002) Tumor-associated B7–H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 8:793–800PubMedCrossRef

14.

Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N (2002) Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A 99:12293–12297PubMedPubMedCentralCrossRef

15.

Wei SC, Duffy CR, Allison JP (2018) Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov 8:1069–1086.PubMedCrossRef

16.

Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, Bellmunt J, Burris HA, Petrylak DP, Teng S-L, Shen X, Boyd Z, Hegde PS, Chen DS, Vogelzang NJ (2014) MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515:558–562. https://doi.org/10.1038/nature13904PubMedCrossRef

17.

Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, Iwai Y, Long AJ, Brown JA, Nunes R, Greenfield EA, Bourque K, Boussiotis VA, Carter LL, Carreno BM, Malenkovich N, Nishimura H, Okazaki T, Honjo T, Sharpe AH, Freeman GJ (2001) PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2:261–268PubMedCrossRef

18.

Djureinovic D, Wang M, Kluger HM (2021) Agonistic CD40 antibodies in cancer treatment Cancers 13. https://doi.org/10.3390/cancers13061302

19.

Vonderheide RH (2020) CD40 agonist antibodies in cancer immunotherapy. In: Klotman ME (ed) Annual review of medicine 71:47–58

20.

Beatty GL, Chiorean EG, Fishman MP, Saboury B, Teitelbaum UR, Sun WJ, Huhn RD, Song WR, Li DG, Sharp LL, Torigian DA, O’Dwyer PJ, Vonderheide RH (2011) CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 331:1612–1616. https://doi.org/10.1126/science.1198443PubMedPubMedCentralCrossRef

21.

Herbst RS, Arkenau H-T, Santana-Davila R, Calvo E, Paz-Ares L, Cassier PA, Bendell J, Penel N, Krebs MG, Martin-Liberal J, Isambert N, Soriano A, Wermke M, Cultrera J, Gao L, Widau RC, Mi G, Jin J, Ferry D, Fuchs CS, Petrylak DP, Chau I (2019) Ramucirumab plus pembrolizumab in patients with previously treated advanced non-small-cell lung cancer, gastro-oesophageal cancer, or urothelial carcinomas (JVDF): a multicohort, non-randomised, open-label, phase 1a/b trial. Lancet Oncol 20:1109–1123. https://doi.org/10.1016/S1470-2045(19)30458-9PubMedCrossRef

22.

Topalian SL, Drake CG, Pardoll DM (2015) Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27:450–461. https://doi.org/10.1016/j.ccell.2015.03.001PubMedPubMedCentralCrossRef

23.

Sharpe AH, Pauken KE (2018) The diverse functions of the PD1 inhibitory pathway. Nat Rev Immunol 18:153–167. https://doi.org/10.1038/nri.2017.108PubMedCrossRef

24.

Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, Weber JS, Joshua AM, Hwu W-J, Gangadhar TC, Patnaik A, Dronca R, Zarour H, Joseph RW, Boasberg P, Chmielowski B, Mateus C, Postow MA, Gergich K, Elassaiss-Schaap J, Li XN, Iannone R, Ebbinghaus SW, Kang SP, Daud A (2014) Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet (London, England) 384:1109–1117. https://doi.org/10.1016/S0140-6736(14)60958-2PubMedCrossRef

25.

Patnaik A, Kang SP, Rasco D, Papadopoulos KP, Elassaiss-Schaap J, Beeram M, Drengler R, Chen C, Smith L, Espino G, Gergich K, Delgado L, Daud A, Lindia JA, Li XN, Pierce RH, Yearley JH, Wu D, Laterza O, Lehnert M, Iannone R, Tolcher AW (2015) Phase I study of pembrolizumab (MK-3475; Anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. Clin Cancer Res 21:4286–4293. https://doi.org/10.1158/1078-0432.CCR-14-2607PubMedCrossRef

26.

Brahmer JR, Tykodi SS, Chow LQM, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen SM, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366:2455–2465. https://doi.org/10.1056/NEJMoa1200694PubMedPubMedCentralCrossRef

27.

Mizugaki H, Yamamoto N, Murakami H, Kenmotsu H, Fujiwara Y, Ishida Y, Kawakami T, Takahashi T (2016) Phase I dose-finding study of monotherapy with atezolizumab, an engineered immunoglobulin monoclonal antibody targeting PD-L1, Japanese patients with advanced solid tumors. Invest New Drugs 34:596–603. https://doi.org/10.1007/s10637-016-0371-6 PubMedPubMedCentralCrossRef

28.

Royal RE, Levy C, Turner K, Mathur A, Hughes M, Kammula US, Sherry RM, Topalian SL, Yang JC, Lowy I, Rosenberg SA (2010) Phase 2 trial of single agent ipilimumab (Anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother 33:828–833. https://doi.org/10.1097/CJI.0b013e3181eec14c PubMedPubMedCentralCrossRef

29.

Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hogg D, Hill A, Marquez-Rodas I, Haanen J, Guidoboni M, Maio M, Schoffski P, Carlino MS, Lebbe C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bastholt L, Rizzo JI, Balogh A, Moshyk A, Hodi FS, Wolchok JD (2019) Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 381:1535–1546. https://doi.org/10.1056/NEJMoa1910836PubMedCrossRef

30.

Motzer R, Rini BI, McDermott DF, Frontera OA, Hammers HJ, Carducci MA, Salman P, Escudier B, Beuselinck B, Amin A, Porta C, George S, Neiman V, Bracarda S, Tykodi SS, Barthelemy P, Leibowitz-Amit R, Plimack ER, Oosting SF, Redman B, Melichar B, Powles T, Nathan P, Oudard S, Pook D, Choueiri TK, Donskov F, Grimm MO, Gurney H, Heng DYC, Kollmannsberger CK, Harrison MR, Tamita Y, Duran I, Grunwold V, McHenry MB, Mekan S, Tannir NM, CheckMate I (2019) Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol 20:1370–1385. https://doi.org/10.1016/s1470-2045(19)30413-9 PubMedPubMedCentralCrossRef

31.

O’Reilly EM, Oh DY, Dhani N, Renouf DJ, Lee MA, Sun WJ, Fisher G, Hezel A, Chang SC, Vlahovic G, Takahashi O, Yang Y, Fitts D, Philip PA (2019) Durvalumab with or without tremelimumab for patients with metastatic pancreatic ductal adenocarcinoma: a phase 2 randomized clinical trial. Jama Oncol 5:1431–1438. https://doi.org/10.1001/jamaoncol.2019.1588PubMedPubMedCentralCrossRef

32.

Klein O, Kee D, Markman B, Michael M, Underhill C, Carlino MS, Jackett L, Lum C, Scott C, Nagrial A, Behren A, So JY, Palmer J, Cebon J (2020) Immunotherapy of ipilimumab and nivolumab in patients with advanced neuroendocrine tumors: a subgroup analysis of the CA209-538 clinical trial for rare cancers. Clin Cancer Res 26:4454–4459. https://doi.org/10.1158/1078-0432.Ccr-20-0621 PubMedCrossRef

33.

Blazer M, Wu C, Goldberg RM, Phillips G, Schmidt C, Muscarella P, Wuthrick E, Williams TM, Reardon J, Ellison EC, Bloomston M, Bekaii-Saab T (2015) Neoadjuvant modified (m) FOLFIRINOX for locally advanced unresectable (LAPC) and borderline resectable (BRPC) adenocarcinoma of the pancreas. Ann Surg Oncol 22:1153–1159. https://doi.org/10.1245/s10434-014-4225-1 PubMedCrossRef

34.

Nevala-Plagemann C, Hidalgo M, Garrido-Laguna I (2020) From state-of-the-art treatments to novel therapies for advanced-stage pancreatic cancer. Nat Rev Clin Oncol 17:108–123. https://doi.org/10.1038/s41571-019-0281-6 PubMedCrossRef

35.

Ramanathan RK, McDonough S, Philip PA, Hingorani SR, Lacy J, Kortmansky JS, Thumar J, Chiorean EG, Shields AF, Behl D, Mehan PT, Gaur R, Seery T, Guthrie K, Hochster HS (2019) Phase IB/II randomized study of FOLFIRINOX plus pegylated recombinant human hyaluronidase versus FOLFIRINOX alone in patients with metastatic pancreatic adenocarcinoma: SWOG S1313. J Clin Oncol 37:1062. https://doi.org/10.1200/jco.18.01295CrossRefPubMedPubMedCentral

36.

Springfeld C, Jäger D, Büchler MW, Strobel O, Hackert T, Palmer DH, Neoptolemos JP (1983) Chemotherapy for pancreatic cancer, Presse Medicale (Paris. France 48(2019):e159–e174. https://doi.org/10.1016/j.lpm.2019.02.025

37.

Ueno M, Morizane C, Ikeda M, Sudo K, Hirashima Y, Kuroda M, Fukuyama Y, Okusaka T, Furuse J (2022) A phase II study of nivolumab in combination with modified FOLFIRINOX for metastatic pancreatic cancer. J Clin Oncol 40:553. https://doi.org/10.1200/JCO.2022.40.4_suppl.553CrossRef

38.

Lambert A, Gavoille C, Conroy T (2017) Current status on the place of FOLFIRINOX in metastatic pancreatic cancer and future directions. Ther Adv Gastroenterol 10:631–645. https://doi.org/10.1177/1756283x17713879 CrossRef

39.

Kang H, Jo JH, Lee HS, Chung MJ, Bang S, Park SW, Song SY, Park JY (2018) Comparison of efficacy and safety between standard-dose and modified-dose FOLFIRINOX as a first-line treatment of pancreatic cancer. World J Gastrointest Oncol 10:421–430. https://doi.org/10.4251/wjgo.v10.i11.421PubMedPubMedCentralCrossRef

40.

Chen YW, Guo CX, Bai XL, Gao SL, Shen Y, Zhang M, Wu J, Que RS, Li X, Liang TB, Wu J (2022) Randomized phase II trial of neoadjuvant chemotherapy with modified FOLFIRINOX versus modified FOLFIRINOX and PD-1 antibody for borderline resectable and locally advanced pancreatic cancer (the CISPD-4 study). J Clin Oncol 40:562. https://doi.org/10.1200/JCO.2022.40.4_suppl.562CrossRef

41.

Weiss GJ, Blaydorn L, Beck J, Bornemann-Kolatzki K, Urnovitz H, Schutz E, Khemka V (2018) Phase Ib/II study of gemcitabine, nab-paclitaxel, and pembrolizumab in metastatic pancreatic adenocarcinoma. Invest New Drugs 36:96–102. https://doi.org/10.1007/s10637-017-0525-1PubMedCrossRef

42.

Cui JJ, Yang HY, Hu J, Yao JY, Wang Y, Liang YY, Wang YC, Jiao F, Zhang XF, Zhang X, Han T, Mao TB, Xia Q, Xiao XY, Wang LW (2021) Anti-PD-1 antibody combined with albumin-bound paclitaxel and gemcitabine (AG) as first-line therapy and Anti-PD-1 monotherapy as maintenance in metastatic pancreatic ductal adenocarcinoma (PDAC). J Clin Oncol 39:e16218. https://doi.org/10.1200/JCO.2021.39.15_suppl.e16218CrossRef

43.

Borazanci EH, Jameson GS, Borad MJ, Ramanathan RK, Korn RL, Caldwell L, Ansaldo K, Hendrickson K, Marceau K, Von Hoff DD (2018) A phase II pilot trial of nivolumab (N) plus albumin bound paclitaxel (AP) plus paricalcitol (P) plus cisplatin (C) plus gemcitabine (G) (NAPPCG) in patients with previously untreated metastatic pancreatic ductal adenocarcinoma (PDAC). J Clin Oncol 36:358. https://doi.org/10.1200/JCO.2018.36.4_suppl.358CrossRef

44.

Shui L, Cheng K, Li XF, Shui PX, Li SS, Peng Y, Li J, Guo FZ, Yi C, Cao D (2020) Durable response and good tolerance to the triple combination of toripalimab, gemcitabine, and nab-paclitaxel in a patient with metastatic pancreatic ductal adenocarcinoma. Front Immunol 11:1127. https://doi.org/10.3389/fimmu.2020.01127PubMedPubMedCentralCrossRef

45.

Aglietta M, Barone C, Sawyer MB, Moore MJ, Miller WH, Bagala C, Colombi F, Cagnazzo C, Gioeni L, Wang E, Huang B, Fly KD, Leone F (2014) A phase I dose escalation trial of tremelimumab (CP-675,206) in combination with gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer. Ann Oncol 25:1750–1755. https://doi.org/10.1093/annonc/mdu205PubMedCrossRef

46.

Kamath SD, Kalyan A, Kircher S, Nimeiri H, Fought AJ, Benson A, Mulcahy M (2020) Ipilimumab and gemcitabine for advanced pancreatic cancer: a phase Ib study. Oncologist 25:E808–E815. https://doi.org/10.1634/theoncologist.2019-0473PubMedCrossRef

47.

Zhang H, Dai Z, Wu W, Wang Z, Zhang N, Zhang L, Zeng W-J, Liu Z, Cheng Q (2021) Regulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in cancer. J Exp Clin Cancer Res CR 40:184. https://doi.org/10.1186/s13046-021-01987-7PubMedCrossRef

48.

Renouf DJ, Dhani NC, Kavan P, Jonker DJ, Wei ACC, Hsu T, Tang PA, Graham B, Gallinaro L, Hasan T, Li WW, Hart K, Tu DS, O’Callaghan CJ (2018) The Canadian Cancer Trials Group PA 7 trial: results from the safety run in of a randomized phase II study of gemcitabine (GEM) and nab-paclitaxel (Nab-P) versus GEM, nab-P, durvalumab (D), and tremelimumab (T) as first-line therapy in metastatic pancreatic ductal adenocarcinoma (mPDAC). J Clin Oncol 36:349. https://doi.org/10.1200/JCO.2018.36.4_suppl.349CrossRef

49.

Burris HA, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol Official J Am Soc Clin Oncol 15:2403–2413CrossRef

50.

O’Hara MH, O’Reilly EM, Varadhachary G, Wolff RA, Wainberg ZA, Ko AH, Fisher G, Rahma O, Lyman JP, Cabanski CR, Mick R, Gherardini PF, Kitch LJ, Xu JY, Samuel T, Karakunnel J, Fairchild J, Bucktrout S, LaVallee TM, Selinsky C, Till JE, Carpenter EL, Alanio C, Byrne KT, Chen RO, Trifan OC, Dugan U, Horak C, Hubbard-Lucey VM, Wherry EJ, Ibrahim R, Vonderheide RH (2021) CD40 agonistic monoclonal antibody APX005M (sotigalimab) and chemotherapy, with or without nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: an open-label, multicentre, phase 1b study. Lancet Oncol 22:118–131PubMedCrossRef

51.

O’Hara MH, O’Reilly EM, Wolff RA, Wainberg ZA, Ko AH, Rahma OE, Fisher GA, Lyman JP, Cabanski CR, Karakunnel JJ, Gherardini PF, Kitch LJ, Bucktrout S, Christopher E, Mick R, Chen R, Trifan OC, Salvador L, O’Donnell-Tormey J, Vonderheide RH (2021) Gemcitabine (Gem) and nab-paclitaxel (NP) ± nivolumab (nivo) ± CD40 agonistic monoclonal antibody APX005M (sotigalimab), in patients (Pts) with untreated metastatic pancreatic adenocarcinoma (mPDAC): Phase (Ph) 2 final results. J Clin Oncol 39:4019–4019. https://doi.org/10.1200/JCO.2021.39.15_suppl.4019CrossRef

52.

Padron LJ, Maurer DM, O’Hara MH, O’Reilly EM, Wolff RA, Wainberg ZA, Ko AH, Fisher G, Rahma O, Lyman JP, Cabanski CR, Yu JX, Pfeiffer SM, Spasic M, Xu JY, Gherardini PF, Karakunnel J, Mick R, Alanio C, Byrne KT, Hollmann TJ, Moore JS, Jones DD, Tognetti M, Chen RO, Yang XD, Salvador L, Wherry EJ, Dugan U, O’Donnell-Tormey J, Butterfield LH, Hubbard-Lucey VM, Ibrahim R, Fairchild J, Bucktrout S, LaVallee TM, Vonderheide RH (2022) Sotigalimab and/or nivolumab with chemotherapy in first-line metastatic pancreatic cancer: clinical and immunologic analyses from the randomized phase 2 PRINCE trial. Nat Med 9:1829. https://doi.org/10.1038/s41591-022-01829-9CrossRef

53.

Byrne KT, Betts CB, Mick R, Sivagnanam S, Bajor DL, Laheru DA, Chiorean EG, O’Hara MH, Liudahl SM, Newcomb C, Alanio C, Ferreira AP, Park BS, Ohtani T, Huffman AP, Vayrynen SA, Costa AD, Kaiser JC, Lacroix AM, Redlinger C, Stern M, Nowak JA, Wherry EJ, Cheever MA, Wolpin BM, Furth EE, Jaffee EM, Coussens LM, Vonderheide RH (2021) Neoadjuvant selicrelumab, an agonist CD40 antibody, induces changes in the tumor microenvironment in patients with resectable pancreatic cancer. Clin Cancer Res 27:4574–4586. https://doi.org/10.1158/1078-0432.Ccr-21-1047PubMedPubMedCentralCrossRef

54.

Holmgaard RB, Brachfeld A, Gasmi B, Jones DR, Mattar M, Doman T, Murphy M, Schaer D, Wolchok JD, Merghoub T (2016) Timing of CSF-1/CSF-1R signaling blockade is critical to improving responses to CTLA-4 based immunotherapy. Oncoimmunology 5:1151595. https://doi.org/10.1080/2162402x.2016.1151595CrossRef

55.

Zhu Y, Knolhoff BL, Meyer MA, Nywening TM, West BL, Luo JQ, Wang-Gillam A, Goedegebuure SP, Linehan DC, DeNardo DG (2014) CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Can Res 74:5057–5069. https://doi.org/10.1158/0008-5472.Can-13-3723CrossRef

56.

Razak ARA, Cleary JM, Moreno V, Boyer M, Aller EC, Edenfield W, Tie J, Harvey RD, Rutten A, Shah MA, Olszanski AJ, Jager D, Lakhani N, Ryan DP, Rasmussen E, Juan G, Wong HS, Soman N, Smit MAD, Nagorsen DKP (2020) Papadopoulos, Safety and efficacy of AMG 820, an anti-colony-stimulating factor 1 receptor antibody, in combination with pembrolizumab in adults with advanced solid tumors. J Immunother Cancer 8:6. https://doi.org/10.1136/jitc-2020-001006CrossRef

57.

Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, Kadel EE, Koeppen H, Astarita JL, Cubas R, Jhunjhunwala S, Banchereau R, Yang Y, Guan Y, Chalouni C, Ziai J, Şenbabaoğlu Y, Santoro S, Sheinson D, Hung J, Giltnane JM, Pierce AA, Mesh K, Lianoglou S, Riegler J, Carano RAD, Eriksson P, Höglund M, Somarriba L, Halligan DL, van der Heijden MS, Loriot Y, Rosenberg JE, Fong L, Mellman I, Chen DS, Green M, Derleth C, Fine GD, Hegde PS, Bourgon R, Powles T (2018) TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554:544–548. https://doi.org/10.1038/nature25501PubMedPubMedCentralCrossRef

58.

Derynck R, Zhang YE (2003) Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 425:577–584PubMedCrossRef

59.

Tauriello DVF, Palomo-Ponce S, Stork D, Berenguer-Llergo A, Badia-Ramentol J, Iglesias M, Sevillano M, Ibiza S, Cañellas A, Hernando-Momblona X, Byrom D, Matarin JA, Calon A, Rivas EI, Nebreda AR, Riera A, Attolini CS-O, Batlle E (2018) TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 554:538–543. https://doi.org/10.1038/nature25492PubMedCrossRef

60.

Herbertz S, Sawyer JS, Stauber AJ, Gueorguieva I, Driscoll KE, Estrem ST, Cleverly AL, Desaiah D, Guba SC, Benhadji KA, Slapak CA, Lahn MM (2015) Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway. Drug Des Dev Ther 9:4479–4499. https://doi.org/10.2147/dddt.S86621

61.

Melisi D, Garcia-Carbonero R, Macarulla T, Pezet D, Deplanque G, Fuchs M, Trojan J, Oettle H, Kozloff M, Cleverly A, Smith C, Estrem ST, Gueorguieva I, Lahn MMF, Blunt A, Benhadji KA, Tabernero J (2018) Galunisertib plus gemcitabine vs. gemcitabine for first-line treatment of patients with unresectable pancreatic cancer. Br J Cancer 119:1208–1214. https://doi.org/10.1038/s41416-018-0246-zCrossRefPubMedPubMedCentral

62.

Holmgaard RB, Schaer DA, Li YX, Castaneda SP, Murphy MY, Xu XH, Inigo I, Dobkin J, Manro JR, Iversen PW, Surguladze D, Hall GE, Novosiadly RD, Benhadji KA, Plowman GD, Kalos M, Driscoll KE (2018) Targeting the TGF beta pathway with galunisertib, a TGF beta RI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as monotherapy and in combination with checkpoint blockade. J Immunother Cancer 6:4. https://doi.org/10.1186/s40425-018-0356-4CrossRef

63.

Principe DR, Park A, Dorman MJ, Kumar S, Viswakarma N, Rubin J, Torres C, McKinney R, Munshi HG, Grippo PJ, Rana A (2019) TGF beta blockade augments PD-1 inhibition to promote T-cell-mediated regression of pancreatic cancer. Mol Cancer Ther 18:613–620. https://doi.org/10.1158/1535-7163.Mct-18-0850PubMedCrossRef

64.

Sow HS, Ren J, Camps M, Ossendorp F, ten Dijke P (2019) Combined inhibition of TGF—signaling and the PD-L1 immune checkpoint is differentially effective in tumor models. Cells 8:320. https://doi.org/10.3390/cells8040320PubMedPubMedCentralCrossRef

65.

Melisi D, Oh D, Hollebecque A, Calvo E, Varghese A, Borazanci E, Macarulla T, Merz V, Zecchetto C, Zhao YM, Gueorguieva I, Man M, Gandhi L, Estrem ST, Benhadji KA, Lanasa MC, Avsar E, Guba SC, Garcia-Carbonero R (2021) Safety and activity of the TGF beta receptor I kinase inhibitor galunisertib plus the anti-PD-L1 antibody durvalumab in metastatic pancreatic cancer. J Immunother Cancer 9:2068. https://doi.org/10.1136/jitc-2020-002068CrossRef

66.

Strauss J, Heery CR, Schlom J, Madan RA, Cao L, Kang ZG, Lamping E, Marte JL, Donahue RN, Grenga I, Cordes L, Christensen O, Mahnke L, Helwig C, Gulley JL (2018) Phase I trial of M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF beta. Adv Solid Tumors Clin Cancer Res 24:1287–1295. https://doi.org/10.1158/1078-0432.Ccr-17-2653CrossRef

67.

Seo Y, Baba H, Fukuda T, Takashima M, Sugimachi K (2000) High expression of vascular endothelial growth factor is associated with liver metastasis and a poor prognosis for patients with ductal pancreatic adenocarcinoma. Cancer 88:2239–2245PubMedCrossRef

68.

Halperin DM, Liu SY, Dasari A, Fogelman D, Bhosale P, Mahvash A, Estrella JS, Rubin L, Morani AC, Knafl M, Overeem TA, Fu SC, Solis LM, Cuentas EP, Verma A, Chen HL, Gite S, Subashchandrabose P, Dervin S, Schulze K, Darbonne WC, Yun C, Wistuba PAF II, Woodman SE, Yao JC (2022) Assessment of clinical response following atezolizumab and bevacizumab treatment in patients with neuroendocrine tumors a nonrandomized clinical trial. Jama Oncol. https://doi.org/10.1001/jamaoncol.2022.0212CrossRefPubMedPubMedCentral

69.

Ishida T, Ueda R (2006) CCR4 as a novel molecular target for immunotherapy of cancer. Cancer Sci 97:1139–1146. https://doi.org/10.1111/j.1349-7006.2006.00307.xPubMedCrossRef

70.

Kurose K, Ohue Y, Sato E, Yamauchi A, Eikawa S, Isobe M, Nishio Y, Uenaka A, Oka M, Nakayama E (2015) Increase in activated treg in TIL in lung cancer and in vitro depletion of treg by ADCC using an antihuman CCR4 mAb (KM2760). J Thorac Oncol 10:74–83. https://doi.org/10.1097/jto.0000000000000364PubMedCrossRef

71.

Kurose K, Ohue Y, Wada H, Iida S, Ishida T, Kojima T, Doi T, Suzuki S, Isobe M, Funakoshi T, Kakimi K, Nishikawa H, Udono H, Oka M, Ueda R, Nakayama E (2015) Phase Ia study of FoxP3(+) CD4 treg depletion by infusion of a humanized anti-CCR4 antibody, KW-0761. Cancer Patients Clin Cancer Res 21:4327–4336. https://doi.org/10.1158/1078-0432.Ccr-15-0357PubMedCrossRef

72.

Saito T, Kurose K, Kojima T, Funakoshi T, Sato E, Nishikawa H, Nakajima J, Seto Y, Kakimi K, Iida S, Doki Y, Oka M, Ueda R, Wada H (2021) Phase Ib study on the humanized anti-CCR4 antibody, KW-0761, in advanced solid tumors. Nagoya J Med Sci 83:827–840. https://doi.org/10.18999/nagjms.83.4.827PubMedPubMedCentral

73.

Zamarin D, Hamid O, Nayak-Kapoor A, Sahebjam S, Sznol M, Collaku A, Fox FE, Marshall MA, Hong DS (2020) y Mogamulizumab in combination with durvalumab or tremelimumab in patients with advanced solid tumors: a phase i study. Clin Cancer Res 26:4531–4541. https://doi.org/10.1158/1078-0432.Ccr-20-0328PubMedPubMedCentralCrossRef

74.

Bockorny B, Semenisty V, Macarulla T, Borazanci E, Wolpin BM, Stemmer SM, Golan T, Geva R, Borad MJ, Pedersen KS, Park JO, Ramirez RA, Abad DG, Feliu J, Munoz A, Ponz-Sarvise M, Peled A, Lustig TM, Bohana-Kashtan O, Shaw SM, Sorani E, Chaney M, Kadosh S, Haras AV, Von Hoff DD, Hidalgo M (2020) BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the COMBAT trial. Nat Med 26:878. https://doi.org/10.1038/s41591-020-0880-xCrossRefPubMed

75.

Bockorny B, Macarulla T, Semenisty V, Borazanci E, Feliu J, Ponz-Sarvise M, Abad DG, Oberstein P, Alistar A, Munoz A, Geva R, Guillen-Ponce C, Fernandez MS, Peled A, Chaney M, Gliko-Kabir I, Shemesh-Darvish L, Ickowicz D, Sorani E, Kadosh S, Vainstein-Haras A, Hidalgo M (2021) Motixafortide and pembrolizumab combined to nanoliposomal irinotecan, fluorouracil, and folinic acid in metastatic pancreatic cancer: the COMBAT/KEYNOTE-202 trial. Clin Cancer Res 27:5020–5027. https://doi.org/10.1158/1078-0432.Ccr-21-0929PubMedCrossRef

76.

Suarez-Carmona M, Williams A, Schreiber J, Hohmann N, Pruefer U, Krauss J, Jager D, Fromming A, Beyer D, Eulberg D, Jungelius JU, Baumann M, Mangasarian A, Halama N (2021) Combined inhibition of CXCL12 and PD-1 in MSS colorectal and pancreatic cancer: modulation of the microenvironment and clinical effects. J Immunother Cancer 9:2505. https://doi.org/10.1136/jitc-2021-002505CrossRef

77.

Feig C, Jones JO, Kraman M, Wells RJB, Deonarine A, Chan DS, Connell CM, Roberts EW, Zhao Q, Caballero OL, Teichmann SA, Janowitz T, Jodrell DI, Tuveson DA, Fearon DT (2013) Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci USA 110:20212–20217. https://doi.org/10.1073/pnas.1320318110PubMedPubMedCentralCrossRef

78.

Seo YD, Jiang XY, Sullivan KM, Jalikis FG, Smythe KS, Abbasi A, Vignali M, Park JO, Daniel SK, Pollack SM, Kim TS, Yeung R, Crispe IN, Pierce RH, Robins H, Pillarisetty VG (2019) Mobilization of CD8(+) T Cells via CXCR4 blockade facilitates PD-1 checkpoint therapy in human pancreatic cancer. Clin Cancer Res 25:3934–3945. https://doi.org/10.1158/1078-0432.Ccr-19-0081PubMedPubMedCentralCrossRef

79.

Peled A (2019) Combination of BL-8040, anti PD-1 and chemotherapy significantly reduced pancreatic tumor growth and changed the balance between CD4+/FOXP3+cells and CD8+cells in the tumor. J Immunother Cancer 7

80.

Pal Singh S, Dammeijer F, Hendriks RW (2018) Role of Bruton’s tyrosine kinase in B cells and malignancies. Mol Cancer 17:57. https://doi.org/10.1186/s12943-018-0779-zCrossRefPubMedPubMedCentral

81.

Wang M, Rule S, Zinzani PL, Goy A, Casasnovas O, Smith SD, Damaj G, Doorduijn J, Lamy T, Morschhauser F, Panizo C, Shah B, Davies A, Eek R, Dupuis J, Jacobsen E, Kater AP, Le Gouill S, Oberic L, Robak T, Covey T, Dua R, Hamdy A, Huang X, Izumi R, Patel P, Rothbaum W, Slatter JG, Jurczak W (2018) Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet (London, England) 391:659–667. https://doi.org/10.1016/S0140-6736(17)33108-2PubMedCrossRef

82.

Gunderson AJ, Kaneda MM, Tsujikawa T, Nguyen AV, Affara NI, Ruffell B, Gorjestani S, Liudahl SM, Truitt M, Olson P, Kim G, Hanahan D, Tempero MA, Sheppard B, Irving B, Chang BY, Varner JA, Coussens LM (2016) Bruton tyrosine kinase-dependent immune cell cross-talk drives pancreas cancer. Cancer Discov 6:270–285. https://doi.org/10.1158/2159-8290.CD-15-0827PubMedCrossRef

83.

Overman M, Javle M, Davis RE, Vats P, Kumar-Sinha C, Xiao LC, Mettu NB, Parra ER, Benson A, Lopez CD, Munugalavadla V, Patel P, Tao L, Neelapu S, Maitra A (2020) Randomized phase II study of the Bruton tyrosine kinase inhibitor acalabrutinib, alone or with pembrolizumab in patients with advanced pancreatic cancer. J Immunother Cancer 8:587. https://doi.org/10.1136/jitc-2020-000587CrossRef

84.

Shen G, Zheng F, Ren D, Du F, Dong Q, Wang Z, Zhao F, Ahmad R, Zhao J (2018) Anlotinib: a novel multi-targeting tyrosine kinase inhibitor in clinical development. J Hematol Oncol 11:120. https://doi.org/10.1186/s13045-018-0664-7PubMedPubMedCentralCrossRef

85.

Xie C, Wan X, Quan H, Zheng M, Fu L, Li Y, Lou L (2018) Preclinical characterization of anlotinib, a highly potent and selective vascular endothelial growth factor receptor-2 inhibitor. Cancer Sci 109:1207–1219. https://doi.org/10.1111/cas.13536PubMedPubMedCentralCrossRef

86.

Yuan M, Zhu ZZ, Mao W, Wang H, Qian H, Wu JG, Guo XL, Xu Q (2021) Anlotinib combined with anti-PD-1 antibodies therapy in patients with advanced refractory solid tumors: a single-center, observational, Prospective Study. Front Oncol 11:683502. https://doi.org/10.3389/fonc.2021.683502CrossRefPubMedPubMedCentral

87.

Patnaik A, Yap TA, Chung HC, de Miguel MJ, Bang YJ, Lin CC, Su WC, Italiano A, Chow KH, Szpurka AM, Yu DN, Zhao YM, Carlsen M, Schmidt S, Vangerow B, Gandhi L, Xu XJ, Bendell J (2021) Safety and Clinical activity of a new anti-PD-L1 antibody as monotherapy or combined with targeted therapy in advanced solid tumors: the PACT phase Ia/Ib trial. Clin Cancer Res 27:1267–1277. https://doi.org/10.1158/1078-0432.Ccr-20-2821PubMedCrossRef

88.

Rodon Ahnert J, Tan DS, Garrido-Laguna I, Harb W, Bessudo A, Beck JT, Rottey S, Bahary N, Kotecki N, Zhu Z, Deng S, Kowalski K, Wei C, Pathan N, Laliberte RJ, Messersmith WA (2023) Avelumab or talazoparib in combination with binimetinib in metastatic pancreatic ductal adenocarcinoma: dose-finding results from phase Ib of the JAVELIN PARP MEKi trial. ESMO Open 8:101584. https://doi.org/10.1016/j.esmoop.2023.101584CrossRefPubMedPubMedCentral

89.

Wang-Gillam A, Lim KH, McWilliams R, Suresh R, Lockhart AC, Brown A, Breden M, Belle JI, Herndon J, Bogner SJ, Pedersen K, Tan B, Boice N, Acharya A, Abdiannia M, Gao F, Yoon HH, Zhu M, Trikalinos NA, Ratner L, Aranha O, Hawkins WG, Herzog BH, DeNardo DG (2022) Defactinib, pembrolizumab, and gemcitabine in patients with advanced treatment refractory pancreatic cancer: a phase I dose escalation and expansion study. Clin Cancer Res 28:5254–5262. https://doi.org/10.1158/1078-0432.Ccr-22-0308PubMedPubMedCentralCrossRef

90.

Wu XH, Zhu JQ, Yin RT, Yang JX, Liu JH, Wang J, Wu LY, Liu ZL, Gao YN, Wang DB, Lou G, Yang HY, Zhou Q, Kong BH, Huang Y, Chen LP, Li GL, An RF, Wang K, Zhang Y, Yan XJ, Lu X, Lu WG, Hao M, Wang L, Cui H, Chen QH, Abulizi G, Huang XH, Tian XF, Wen H, Zhang C, Hou JM, Mirza MR (2021) Niraparib maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer using an individualized starting dose (NORA): a randomized, double-blind, placebo-controlled phase III trial(☆). Ann Oncol 32:512–521. https://doi.org/10.1016/j.annonc.2020.12.018PubMedCrossRef

91.

Reiss KA, Mick R, Teitelbaum U, O’Hara M, Schneider C, Massa R, Karasic T, Tondon R, Onyiah C, Gosselin MK, Donze A, Domchek SM, Vonderheide RH (2022) Niraparib plus nivolumab or niraparib plus ipilimumab in patients with platinum-sensitive advanced pancreatic cancer: a randomised, phase 1b/2 trial. Lancet Oncol 23:1009–1020. https://doi.org/10.1016/s1470-2045(22)00369-2PubMedPubMedCentralCrossRef

92.

Lemech C, Dredge K, Bampton D, Hammond E, Clouston A, Waterhouse NJ, Stanley AC, Leveque-El Mouttie L, Chojnowski GM, Haydon A, Pavlakis N, Burge M, Brown MP, Goldstein D (2023) Phase Ib open-label, multicenter study of pixatimod, an activator of TLR9, in combination with nivolumab in subjects with microsatellite-stable metastatic colorectal cancer, metastatic pancreatic ductal adenocarcinoma and other solid tumors. J Immunother Cancer 11:6136. https://doi.org/10.1136/jitc-2022-006136CrossRef

93.

Parikh AR, Szabolcs A, Allen JN, Clark JW, Wo JY, Raabe M, Thel H, Hoyos D, Mehta A, Arshad S, Lieb DJ, Drapek LC, Blaszkowsky LS, Giantonio BJ, Weekes CD, Zhu AX, Goyal L, Nipp RD, Dubois JS, Van Seventer EE, Foreman BE, Matlack LE, Ly L, Meurer JA, Hacohen N, Ryan DP, Yeap BY, Corcoran RB, Greenbaum BD, Ting DT, Hong TS (2021) Radiation therapy enhances immunotherapy response in microsatellite stable colorectal and pancreatic adenocarcinoma in a phase II trial. Nat Cancer 2:1124–1135. https://doi.org/10.1038/s43018-021-00269-7PubMedPubMedCentralCrossRef

94.

Xie C, Duffy AG, Brar G, Fioravanti S, Mabry-Hrones D, Walker M, Bonilla CM, Wood BJ, Citrin DE, Gil Ramirez EM, Escorcia FE, Redd B, Hernandez JM, Davis JL, Gasmi B, Kleiner D, Steinberg SM, Jones JC, Greten TF (2020) Immune checkpoint blockade in combination with stereotactic body radiotherapy in patients with metastatic pancreatic ductal adenocarcinoma. Clin Cancer Res 26:2318–2326. https://doi.org/10.1158/1078-0432.Ccr-19-3624PubMedPubMedCentralCrossRef

95.

Chen IM, Johansen JS, Theile S, Hjaltelin JX, Novitski SI, Brunak S, Hasselby JP, Willemoe GL, Lorentzen T, Madsen K, Jensen BV, Wilken EE, Geertsen P, Behrens C, Nolsoe C, Hermann KL, Svane IM, Nielsen D (2022) Randomized phase II study of nivolumab with or without ipilimumab combined with stereotactic body radiotherapy for refractory metastatic pancreatic cancer (CheckPAC). J Clin Oncol 40:3180–3189. https://doi.org/10.1200/jco.21.02511PubMedCrossRef

96.

Zhu XF, Cao YS, Liu WY, Ju XP, Zhao XZ, Jiang LG, Ye YS, Jin G, Zhang HJ (2021) Stereotactic body radiotherapy plus pembrolizumab and trametinib versus stereotactic body radiotherapy plus gemcitabine for locally recurrent pancreatic cancer after surgical resection: an open-label, randomised, controlled, phase 2 trial. Lancet Oncol 22:1093–1102. https://doi.org/10.1016/s1470-2045(21)00286-2PubMedCrossRef

97.

Chen IM, Donia M, Chamberlain CA, Jensen AWP, Draghi A, Theile S, Madsen K, Hasselby JP, Toxværd A, Høgdall E, Lorentzen T, Wilken EE, Geertsen P, Svane IM, Johansen JS, Nielsen D (2023) Phase 2 study of ipilimumab, nivolumab, and tocilizumab combined with stereotactic body radiotherapy in patients with refractory pancreatic cancer (TRIPLE-R). Eur J Cancer 180:125–133. https://doi.org/10.1016/j.ejca.2022.11.035PubMedCrossRef

98.

Fukuhara H, Ino Y, Todo T (2016) Oncolytic virus therapy: A new era of cancer treatment at dawn. Cancer Sci 107:1373–1379. https://doi.org/10.1111/cas.13027PubMedPubMedCentralCrossRef

99.

Eissa IR, Bustos-Villalobos I, Ichinose T, Matsumura S, Naoe Y, Miyajima N, Morimoto D, Mukoyama N, Zhiwen W, Tanaka M, Hasegawa H, Sumigama S, Aleksic B, Kodera Y, Kasuya H (2018) The current status and future prospects of oncolytic viruses in clinical trials against melanoma, glioma, pancreatic, and breast cancers. Cancers 10:356. https://doi.org/10.3390/cancers10100356CrossRefPubMedPubMedCentral

100.

Mahalingam D, Wilkinson GA, Eng KH, Fields P, Raber P, Moseley JL, Cheetham K, Coffey M, Nuovo G, Kalinski P, Zhang B, Arora SP, Fountzilas C (2020) Pembrolizumab in combination with the oncolytic virus pelareorep and chemotherapy in patients with advanced pancreatic adenocarcinoma: a phase Ib study. Clin Cancer Res 26:71–81. https://doi.org/10.1158/1078-0432.Ccr-19-2078PubMedCrossRef

101.

Hajda J, Leuchs B, Angelova AL, Frehtman V, Rommelaere J, Mertens M, Pilz M, Kieser M, Krebs O, Dahm M, Huber B, Engeland CE, Mavratzas A, Hohmann N, Schreiber J, Jäger D, Halama N, Sedlaczek O, Gaida MM, Daniel V, Springfeld C, Ungerechts G (2021) Phase 2 trial of oncolytic h-1 parvovirus therapy shows safety and signs of immune system activation in patients with metastatic pancreatic ductal adenocarcinoma. Clin Cancer Res 27:5546–5556. https://doi.org/10.1158/1078-0432.Ccr-21-1020PubMedCrossRef

102.

Hegde A, Jayaprakash P, Couillault CA, Piha-Paul S, Karp D, Rodon J, Pant S, Fu SQ, Dumbrava EE, Yap TA, Subbiah V, Bhosale P, Coarfa C, Higgins JP, Williams ET, Wilson TF, Lim J, Meric-Bernstam F, Sumner E, Zain H, Nguyen D, Nguyen LM, Rajapakshe K, Curran MA, Hong DS (2021) A phase I dose-escalation study to evaluate the safety and tolerability of evofosfamide in combination with ipilimumab in advanced solid malignancies. Clin Cancer Res 27:3050–3060. ttps://doi.org/10.1158/1078-0432.Ccr-20-4118PubMedPubMedCentralCrossRef

103.

Khan SM, Nazzal M, Zelenock G, Qu W, Aplin B, Baldawi M, Arishi A, Stoller J (2015) A nationwide comparison of early outcomes after carotid endarterectomy and carotid artery stenting. J Vasc Surg 62:819–820. https://doi.org/10.1016/j.jvs.2015.06.147CrossRef

104.

Khan S, Ebeling MC, Chauhan N, Thompson PA, Gara RK, Ganju A, Yallapu MM, Behrman SW, Zhao H, Zafar N, Singh MM, Jaggi M, Chauhan SC (2015) Ormeloxifene suppresses desmoplasia and enhances sensitivity of gemcitabine in pancreatic cancer. Can Res 75:2292–2304. https://doi.org/10.1158/0008-5472.CAN-14-2397CrossRef

105.

Martin RCG, Kwon D, Chalikonda S, Sellers M, Kotz E, Scoggins C, McMasters KM, Watkins K (2015) Treatment of 200 locally advanced (stage III) pancreatic adenocarcinoma patients with irreversible electroporation: safety and efficacy. Ann Surg 262:1441. https://doi.org/10.1097/SLA.0000000000001441CrossRef

106.

Holland MM, Bhutiani N, Kruse EJ, Weiss MJ, Christein JD, White RR, Huang K-W, Martin RCG (2019) A prospective, multi-institution assessment of irreversible electroporation for treatment of locally advanced pancreatic adenocarcinoma: initial outcomes from the AHPBA pancreatic registry. HPB (Oxford) 21:1024–1031. https://doi.org/10.1016/j.hpb.2018.12.004PubMedCrossRef

107.

O’Neill C, Hayat T, Hamm J, Healey M, Zheng QQ, Li Y, Martin RC (2020) A phase 1b trial of concurrent immunotherapy and irreversible electroporation in the treatment of locally advanced pancreatic adenocarcinoma. Surgery 168:610–616. https://doi.org/10.1016/j.surg.2020.04.057PubMedCrossRef

108.

Kohler G, Milstein C (1975) Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256:495–497. https://doi.org/10.1038/256495a0PubMedCrossRef

109.

Boland AJ, O’Kane AA, Buick R, Longley DB, Scott CJ (2021) Antibody therapy in pancreatic cancer: mAb-ye we’re onto something? Biochim Biophys Acta Rev Cancer 1876:188557. https://doi.org/10.1016/j.bbcan.2021.188557PubMedCrossRef

110.

Zahavi D, Weiner L (2020) Monoclonal antibodies in cancer therapy. Antibodies 9:34. https://doi.org/10.3390/antib9030034CrossRefPubMedPubMedCentral

111.

Kunjiappan S, Pavadai P, Vellaichamy S, Pandian SRK, Ravishankar V, Palanisamy P, Govindaraj S, Srinivasan G, Premanand A, Sankaranarayanan M, Theivendren P (2021) Surface receptor-mediated targeted drug delivery systems for enhanced cancer treatment: a state-of-the-art review. Drug Dev Res 82:309–340. https://doi.org/10.1002/ddr.21758PubMedCrossRef

112.

Halfdanarson TR, Foster NR, Kim GP, Meyers JP, Smyrk TC, McCullough AE, Ames MM, Jaffe JP, Alberts SR (2019) 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 24:589. https://doi.org/10.1634/theoncologist.2018-0878CrossRefPubMedPubMedCentral

113.

Liermann J, Munter M, Naumann P, Abdollahi A, Krempien R, Debus J (2022) Cetuximab, gemcitabine and radiotherapy in locally advanced pancreatic cancer: long-term results of the randomized controlled phase II PARC trial, Clinical and Translational. Radiat Oncol 34:15–22. https://doi.org/10.1016/j.ctro.2022.03.003

114.

Assenat E, Mineur L, Mollevi C, Lopez-Crapez E, Lombard-Bohas C, Samalin E, Portales F, Walter T, de Forges H, Dupuy M, Boissiere-Michot F, Ho-Pun-Cheung A, Ychou M, Mazard T (2021) PhaseIIstudy evaluating the association of gemcitabine, trastuzumab and erlotinib as first-line treatment in patients with metastatic pancreatic adenocarcinoma (GATE1). Int J Cancer 148:682–691. https://doi.org/10.1002/ijc.33225PubMedCrossRef

115.

Kindler HL, Richards DA, Garbo LE, Garon EB, Stephenson JJ, Rocha-Lima CM, Safran H, Chan D, Kocs DM, Galimi F, McGreivy J, Bray SL, Hei Y, Feigal EG, Loh E, Fuchs CS (2012) 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 23:2834–2842. https://doi.org/10.1093/annonc/mds142PubMedCrossRef

116.

Forero-Torres A, Infante JR, Waterhouse D, Wong L, Vickers S, Arrowsmith E, He AR, Hart L, Trent D, Wade J, Jin XP, Wang Q, Austin T, Rosen M, Beckman R, von Roemeling R, Greenberg J, Saleh M (2013) 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 2:925–932. https://doi.org/10.1002/cam4.137PubMedPubMedCentralCrossRef

117.

Hassan R, Alewine C, Mian I, Spreafico A, Siu LL, Gomez-Roca C, Delord JP, Italiano A, Lassen U, Soria JC, Bahleda R, Thomas A, Steinberg SM, Peer CJ, Figg WD, Niederfellner G, Naegelen VM, Pastan I (2020) Phase 1 study of the immunotoxin LMB-100 in patients with mesothelioma and other solid tumors expressing mesothelin. Cancer 126:4936–4947. https://doi.org/10.1002/cncr.33145PubMedCrossRef

118.

Hassan R, Blumenschein GR, Moore KN, Santin AD, Kindler HL, Nemunaitis JJ, Seward SM, Thomas A, Kim SK, Rajagopalan P, Walter AO, Laurent D, Childs BH, Sarapa N, Elbi C, Bendell JC (2020) First-in-human, multicenter, phase i dose-escalation and expansion study of anti-mesothelin antibody-drug conjugate anetumab ravtansine in advanced or metastatic solid tumors. J Clin Oncol 38:1824. https://doi.org/10.1200/jco.19.02085CrossRefPubMedPubMedCentral

119.

Berlin JD, Feng Y, Catalano P, Abbruzzese JL, Philip PA, McWilliams RR, Lowy AM, Benson A, Blackstock AW (2018) An intergroup randomized phase II study of bevacizumab or cetuximab in combination with gemcitabine and in combination with chemoradiation in patients with resected pancreatic carcinoma: a trial of the ECOG-ACRIN cancer research group (E2204). Oncology 94:39–46. https://doi.org/10.1159/000480295PubMedCrossRef

120.

Sen S, Kato S, Agarwal R, Piha-Paul S, Hess K, Karp D, Janku F, Fu SQ, Naing A, Pant S, Falchook G, Tang C, Wu XF, Ye YQ, Tsimberidou A, Subbiah V, Kurzrock R, Byers L, Westin S, Lim J, Bean S, Bass A, Nguyen L, Meric-Bernstam F, Hong D (2018) Phase I study of nab-paclitaxel, gemcitabine, and bevacizumab in patients with advanced cancers. Br J Cancer 118:1419–1424. https://doi.org/10.1038/s41416-018-0068-zPubMedPubMedCentralCrossRef

121.

Sahai V, Saif MW, Kalyan A, Philip PA, Rocha-Lima CM, Ocean A, Ondovik MS, Simeone DM, Banerjee S, Bhore R, Louis CU, Picozzi V (2019) A phase I/II open-label multicenter single-arm study of FABLOx (metronomic 5-fluorouracil plus nab-paclitaxel, bevacizumab, leucovorin, and oxaliplatin) in patients with metastatic pancreatic cancer. J Pancreatic Cancer 5:35–42. https://doi.org/10.1089/pancan.2019.0012CrossRef

122.

Lutz ER, Wu AA, Bigelow E, Sharma R, Mo G, Soares K, Solt S, Dorman A, Wamwea A, Yager A, Laheru D, Wolfgang CL, Wang J, Hruban RH, Anders RA, Jaffee EM, Zheng L (2014) Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation. Cancer Immunol Res 2:616–631. https://doi.org/10.1158/2326-6066.CIR-14-0027PubMedPubMedCentralCrossRef

123.

Zheng L, Ding D, Edil BH, Judkins C, Durham JN, Thomas DL, Bever KM, Mo GL, Solt SE, Hoare JA, Bhattacharya R, Zhu QF, Osipov A, Onner B, Purtell KA, Cai HY, Parkinson R, Hacker-Prietz A, Herman JM, Le DT, Azad NS, De Jesus-Acosta AMC, Blair AB, Kim V, Soares KC, Manos L, Cameron JL, Makary MA, Weiss MJ, Schulick RD, He J, Wolfgang CL, Thompson ED, Anders RA, Sugar E, Jaffee EM, Laheru DA (2021) Vaccine-induced intratumoral lymphoid aggregates correlate with survival following treatment with a neoadjuvant and adjuvant vaccine in patients with resectable pancreatic adenocarcinoma. Clin Cancer Res 27:1278–1286. https://doi.org/10.1158/1078-0432.Ccr-20-2974PubMedCrossRef

124.

Le DT, Wang-Gillam A, Picozzi V, Greten TF, Crocenzi T, Springett G, Morse M, Zeh H, Cohen D, Fine RL, Onners B, Uram JN, Laheru DA, Lutz ER, Solt S, Murphy AL, Skoble J, Lemmens E, Grous J, Dubensky T, Brockstedt DG, Jaffee EM (2015) Safety and survival with gvax pancreas prime and listeria monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J Clin Oncol 33:1325. https://doi.org/10.1200/jco.2014.57.4244CrossRefPubMedPubMedCentral

125.

Le DT, Picozzi VJ, Ko AH, Wainberg ZA, Kindler H, Wang-Gillam A, Oberstein P, Morse MA, Zeh HJ, Weekes C, Reid T, Borazanci E, Crocenzi T, LoConte NK, Musher B, Laheru D, Murphy A, Whiting C, Nair N, Enstrom A, Ferber S, Brockstedt DG, Jaffee EM (2019) Results from a phase iib, randomized, multicenter study of GVAX pancreas and CRS-207 compared with chemotherapy in adults with previously treated metastatic pancreatic adenocarcinoma (ECLIPSE Study). Clin Cancer Res 25:5493–5502. https://doi.org/10.1158/1078-0432.Ccr-18-2992PubMedPubMedCentralCrossRef

126.

Nair N, Chen SY, Lemmens E, Chang S, Le DT, Jaffee EM, Murphy A, Whiting C, Muller T, Brockstedt DG (2020) Single-cell immune competency signatures associate with survival in phase II GVAX and CRS-207 randomized studies in patients with metastatic pancreatic cancer. Cancer Immunol Res 8:609–617. https://doi.org/10.1158/2326-6066.Cir-19-0650PubMedPubMedCentralCrossRef

127.

Soares KC, Rucki AA, Wu AA, Olino K, Xiao Q, Chai Y, Wamwea A, Bigelow E, Lutz E, Liu LD, Yao S, Anders RA, Laheru D, Wolfgang CL, Edil BH, Schulick RD, Jaffee EM, Zheng L (2015) PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T-cell infiltration into pancreatic tumors. J Immunother 38:1–11PubMedPubMedCentralCrossRef

128.

Le DT, Lutz E, Uram JN, Sugar EA, Onners B, Solt S, Zheng L, Diaz LA, Donehower RC, Jaffee EM, Laheru DA (1997) Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer, Journal of Immunotherapy (Hagerstown. MD 36(2013):382–389. https://doi.org/10.1097/CJI.0b013e31829fb7a2

129.

Tsujikawa T, Crocenzi T, Durham JN, Sugar EA, Wu AA, Onners B, Nauroth JM, Anders RA, Fertig EJ, Laheru DA, Reiss K, Vonderheide RH, Ko AH, Tempero MA, Fisher GA, Considine M, Danilova L, Brockstedt DG, Coussens LM, Jaffee EM, Le DT (2020) Evaluation of cyclophosphamide/GVAX pancreas followed by listeria-mesothelin (CRS-207) with or without nivolumab in patients with pancreatic. Clin Cancer Res 26:3578–3588. https://doi.org/10.1158/1078-0432.Ccr-19-3978PubMedPubMedCentralCrossRef

130.

Heumann T, Judkins C, Li K, Lim SJ, Hoare J, Parkinson R, Cao H, Zhang T, Gai J, Celiker B, Zhu Q, McPhaul T, Durham J, Purtell K, Klein R, Laheru D, De Jesus-Acosta A, Le DT, Narang A, Anders R, Burkhart R, Burns W, Soares K, Wolfgang C, Thompson E, Jaffee E, Wang H, He J, Zheng L (2023) A platform trial of neoadjuvant and adjuvant antitumor vaccination alone or in combination with PD-1 antagonist and CD137 agonist antibodies in patients with resectable pancreatic adenocarcinoma. Nat Commun 14:3650. https://doi.org/10.1038/s41467-023-39196-9PubMedPubMedCentralCrossRef

131.

Wu AA, Bever KM, Ho WJ, Fertig EJ, Niu N, Zheng L, Parkinson RM, Durham JN, Onners B, Ferguson AK, Wilt C, Ko AH, Wang-Gillam A, Laheru DA, Anders RA, Thompson ED, Sugar EA, Jaffee EM, Le DT (2020) A phase II study of allogeneic GM-CSF-transfected pancreatic tumor vaccine (GVAX) with ipilimumab as maintenance treatment for metastatic pancreatic cancer. Clin Cancer Res 26:5129–5139. https://doi.org/10.1158/1078-0432.Ccr-20-1025PubMedPubMedCentralCrossRef

132.

Gao T, Cen Q, Lei H (2020) A review on development of MUC1-based cancer vaccine. Biomed Pharmacother 132. https://doi.org/10.1016/j.biopha.2020.110888

133.

Hollingsworth MA, Swanson BJ (2004) Mucins in cancer: protection and control of the cell surface. Nat Rev Cancer 4:45–60PubMedCrossRef

134.

Nath S, Mukherjee P (2014) MUC1: a multifaceted oncoprotein with a key role in cancer progression. Trends Mol Med 20:332–342. https://doi.org/10.1016/j.molmed.2014.02.007PubMedPubMedCentralCrossRef

135.

Rong Y, Qin X, Jin D, Lou W, Wu L, Wang D, Wu W, Ni X, Mao Z, Kuang T, Zang YQ, Qin X (2012) A phase I pilot trial of MUC1-peptide-pulsed dendritic cells in the treatment of advanced pancreatic cancer. Clin Exp Med 12:173–180. https://doi.org/10.1007/s10238-011-0159-0PubMedCrossRef

136.

Lau SP, Klaase L, Vink M, Dumas J, Bezemer K, van Krimpen A, van der Breggen R, Wismans LV, Doukas M, de Koning W, Stubbs AP, Mustafa DAM, Vroman H, Stadhouders R, Nunes JB, Stingl C, de Miranda NFCC, Luider TM, van der Burg SH, Aerts JG, van Eijck CHJ (1990) Autologous dendritic cells pulsed with allogeneic tumour cell lysate induce tumour-reactive T-cell responses in patients with pancreatic cancer: a phase I study. Eur J Cancer (Oxford, England) 169(2022):20–31. https://doi.org/10.1016/j.ejca.2022.03.015

137.

Hirooka Y, Kawashima H, Ohno E, Ishikawa T, Kamigaki T, Goto S, Takahara M, Goto H (2018) Comprehensive immunotherapy combined with intratumoral injection of zoledronate-pulsed dendritic cells, intravenous adoptive activated T lymphocyte and gemcitabine in unresectable locally advanced pancreatic carcinoma: a phase I/II trial. Oncotarget 9:2838–2847. https://doi.org/10.18632/oncotarget.2297PubMedCrossRef

138.

Kimura Y, Tsukada J, Tomoda T, Takahashi H, Imai K, Shimamura K, Sunamura M, Yonemitsu Y, Shimodaira S, Koido S, Homma S, Okamoto M (2012) Clinical and immunologic evaluation of dendritic cell-based immunotherapy in combination with gemcitabine and/or S-1 in patients with advanced pancreatic carcinoma. Pancreas 41:195–205. https://doi.org/10.1097/MPA.0b013e31822398c6PubMedCrossRef

139.

Mehrotra S, Britten CD, Chin S, Garrett-Mayer E, Cloud CA, Li M, Scurti G, Salem ML, Nelson MH, Thomas MB, Paulos CM, Salazar AM, Nishimura MI, Rubinstein MP, Li Z, Cole DJ (2017) Vaccination with poly(IC:LC) and peptide-pulsed autologous dendritic cells in patients with pancreatic cancer. J Hematol Oncol 10:82. https://doi.org/10.1186/s13045-017-0459-2PubMedPubMedCentralCrossRef

140.

Bassani-Sternberg M, Digklia A, Huber F, Wagner D, Sempoux C, Stevenson BJ, Thierry AC, Michaux J, Pak H, Racle J, Boudousquie C, Balint K, Coukos G, Gfeller D, Lluesma SM, Harari A, Demartines N, Kandalaft LE (2019) A phase Ib study of the combination of personalized autologous dendritic cell vaccine, aspirin, and standard of care adjuvant chemotherapy followed by nivolumab for resected pancreatic adenocarcinoma-a proof of antigen discovery feasibility in three patients. Front Immunol 10:1832. https://doi.org/10.3389/fimmu.2019.01832CrossRefPubMedPubMedCentral

141.

Chen Z, Zhang S, Han N, Jiang J, Xu Y, Ma D, Lu L, Guo X, Qiu M, Huang Q, Wang H, Mo F, Chen S, Yang L (2021) A neoantigen-based peptide vaccine for patients with advanced pancreatic cancer refractory to standard treatment. Front Immunol 12:691605. https://doi.org/10.3389/fimmu.2021.691605PubMedPubMedCentralCrossRef

142.

Koido S, Homma S, Okamoto M, Takakura K, Mori M, Yoshizaki S, Tsukinaga S, Odahara S, Koyama S, Imazu H, Uchiyama K, Kajihara M, Arakawa H, Misawa T, Toyama Y, Yanagisawa S, Ikegami M, Kan S, Hayashi K, Komita H, Kamata Y, Ito M, Ishidao T, Yusa S-I, Shimodaira S, Gong J, Sugiyama H, Ohkusa T, Tajiri H (2014) Treatment with chemotherapy and dendritic cells pulsed with multiple Wilms’ tumor 1 (WT1)-specific MHC class I/II-restricted epitopes for pancreatic cancer. Clin Cancer Res 20:4228–4239. https://doi.org/10.1158/1078-0432.CCR-14-0314PubMedCrossRef

143.

Koido S, Homma S, Okamoto M, Takakura K, Gong J, Sugiyama H, Ohkusa T, Tajiri H (2014) Chemoimmunotherapy targeting Wilms’ tumor 1 (WT1)-specific cytotoxic T lymphocyte and helper T cell responses for patients with pancreatic cancer. Oncoimmunology 3:e958950PubMedPubMedCentralCrossRef

144.

Yanagisawa R, Koizumi T, Koya T, Sano K, Koido S, Nagai K, Kobayashi M, Okamoto M, Sugiyama H, Shimodaira S (2018) WT1-pulsed dendritic cell vaccine combined with chemotherapy for resected pancreatic cancer in a phase I study. Anticancer Res 38:2217–2225PubMed

145.

Asahara S, Takeda K, Yamao K, Maguchi H, Yamaue H (2013) Phase I/II clinical trial using HLA-A24-restricted peptide vaccine derived from KIF20A for patients with advanced pancreatic cancer. J Transl Med 11:291. https://doi.org/10.1186/1479-5876-11-291PubMedPubMedCentralCrossRef

146.

Shima H, Tsurita G, Wada S, Hirohashi Y, Yasui H, Hayashi H, Miyakoshi T, Watanabe K, Murai A, Asanuma H, Tokita S, Kubo T, Nakatsugawa M, Kanaseki T, Tsukahara T, Nakae Y, Sugita O, Ito YM, Ota Y, Kimura Y, Kutomi G, Hirata K, Mizuguchi T, Imai K, Takemasa I, Sato N, Torigoe T (2019) Randomized phase II trial of survivin 2B peptide vaccination for patients with HLA-A24-positive pancreatic adenocarcinoma. Cancer Sci 110:2378–2385. https://doi.org/10.1111/cas.14106PubMedPubMedCentralCrossRef

147.

Miyazawa M, Katsuda M, Maguchi H, Katanuma A, Ishii H, Ozaka M, Yamao K, Imaoka H, Kawai M, Hirono S, Okada K-I, Yamaue H (2017) Phase II clinical trial using novel peptide cocktail vaccine as a postoperative adjuvant treatment for surgically resected pancreatic cancer patients. Int J Cancer 140:973–982. https://doi.org/10.1002/ijc.30510PubMedCrossRef

148.

Hardacre JM, Mulcahy M, Small W, Talamonti M, Obel J, Krishnamurthi S, Rocha-Lima CS, Safran H, Lenz H-J, Chiorean EG (2013) Addition of algenpantucel-L immunotherapy to standard adjuvant therapy for pancreatic cancer: a phase 2 study. J Gastrointest Surg Official J Soc Surg Aliment Tract 17:6. https://doi.org/10.1007/s11605-012-2064-6CrossRef

149.

Hewitt DB, Nissen N, Hatoum H, Musher B, Seng J, Coveler AL, Al-Rajabi R, Yeo CJ, Leiby B, Banks J, Balducci L, Vaccaro G, LoConte N, George TJ, Brenner W, Elquza E, Vahanian N, Rossi G, Kennedy E, Link C, Lavu H (2022) A phase 3 randomized clinical trial of chemotherapy with or without algenpantucel-L (hyperacute-pancreas) immunotherapy in subjects with borderline resectable or locally advanced unresectable pancreatic cancer. Ann Surg 275:45–53. https://doi.org/10.1097/SLA.0000000000004669PubMedCrossRef

150.

Vonderheide RH, Kraynyak KA, Shields AF, McRee AJ, Johnson JM, Sun W, Chintakuntlawar AV, Pawlicki J, Sylvester AJ, McMullan T, Samuels R, Kim JJ, Weiner D, Boyer JD, Morrow MP, Humeau L, Skolnik JM (2021) Phase 1 study of safety, tolerability and immunogenicity of the human telomerase (hTERT)-encoded DNA plasmids INO-1400 and INO-1401 with or without IL-12 DNA plasmid INO-9012 in adult patients with solid tumors. J Immunother Cancer 9:3019. https://doi.org/10.1136/jitc-2021-003019CrossRef

151.

Rojas LA, Sethna Z, Soares KC, Olcese C, Pang N, Patterson E, Lihm J, Ceglia N, Guasp P, Chu A, Yu R, Chandra AK, Waters T, Ruan J, Amisaki M, Zebboudj A, Odgerel Z, Payne G, Derhovanessian E, Müller F, Rhee I, Yadav M, Dobrin A, Sadelain M, Łuksza M, Cohen N, Tang L, Basturk O, Gönen M, Katz S, Do RK, Epstein AS, Momtaz P, Park W, Sugarman R, Varghese AM, Won E, Desai A, Wei AC, D’Angelica MI, Kingham TP, Mellman I, Merghoub T, Wolchok JD, Sahin U, Türeci Ö, Greenbaum BD, Jarnagin WR, Drebin J, O’Reilly EM, Balachandran VP (2023) Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature 618:144–150. https://doi.org/10.1038/s41586-023-06063-yPubMedPubMedCentralCrossRef

152.

Huff AL, Zaidi N (2023) Vaccine boosts T cells that target pancreatic tumours. Nature 618:37–38. https://doi.org/10.1038/d41586-023-01526-8PubMedCrossRef

153.

Depil S, Duchateau P, Grupp SA, Mufti G, Poirot L (2020) “Off-the-shelf” allogeneic CAR T cells: development and challenges. Nat Rev Drug Discov 19:185–199. https://doi.org/10.1038/s41573-019-0051-2PubMedCrossRef

154.

Ramos CA, Dotti G (2011) Chimeric antigen receptor (CAR)-engineered lymphocytes for cancer therapy. Expert Opin Biol Ther 11:855–873. https://doi.org/10.1517/14712598.2011.573476PubMedPubMedCentralCrossRef

155.

Glumac PM, LeBeau AM (2018) The role of CD133 in cancer: a concise review. Clin Transl Med 7:18. https://doi.org/10.1186/s40169-018-0198-1PubMedPubMedCentralCrossRef

156.

Wang Y, Chen M, Wu Z, Tong C, Dai H, Guo Y, Liu Y, Huang J, Lv H, Luo C, Feng K-C, Yang Q-M, Li X-L, Han W (2018) CD133-directed CAR T cells for advanced metastasis malignancies: A phase I trial. Oncoimmunology 7:e1440169. https://doi.org/10.1080/2162402X.2018.1440169PubMedPubMedCentralCrossRef

157.

Beatty GL, O’Hara MH, Lacey SF, Torigian DA, Nazimuddin F, Chen F, Kulikovskaya IM, Soulen MC, McGarvey M, Nelson AM, Gladney WL, Levine BL, Melenhorst JJ, Plesa G, June CH (2018) Activity of mesothelin-specific chimeric antigen receptor T cells against pancreatic carcinoma metastases in a phase 1 trial. Gastroenterology 155:29–32. https://doi.org/10.1053/j.gastro.2018.03.029PubMedCrossRef

158.

Haas AR, Tanyi JL, O’Hara MH, Gladney WL, Lacey SF, Torigian DA, Soulen MC, Tian L, McGarvey M, Nelson AM, Farabaugh CS, Moon E, Levine BL, Melenhorst JJ, Plesa G, June CH, Albelda SM, Beatty GL (2019) Phase I study of lentiviral-transduced chimeric antigen receptor-modified T Cells recognizing mesothelin in advanced solid cancers. Mol Therapy J Am Soc Gene Therapy 27:1919–1929. https://doi.org/10.1016/j.ymthe.2019.07.015CrossRef

159.

Feng K, Liu Y, Guo Y, Qiu J, Wu Z, Dai H, Yang Q, Wang Y, Han W (2018) Phase I study of chimeric antigen receptor modified T cells in treating HER2-positive advanced biliary tract cancers and pancreatic cancers. Protein Cell 9:838–847. https://doi.org/10.1007/s13238-017-0440-4PubMedCrossRef

160.

Liu Y, Guo Y, Wu Z, Feng K, Tong C, Wang Y, Dai H, Shi F, Yang Q, Han W (2020) Anti-EGFR chimeric antigen receptor-modified T cells in metastatic pancreatic carcinoma: a phase I clinical trial. Cytotherapy 22:573–580. https://doi.org/10.1016/j.jcyt.2020.04.088PubMedCrossRef

161.

Lum LG, Thakur A, Choi M, Deol A, Kondadasula V, Schalk D, Fields K, Dufrense M, Philip P, Dyson G, Aon HD, Shields AF (2020) Clinical and immune responses to anti-CD3 x anti-EGFR bispecific antibody armed activated T cells (EGFR BATs) in pancreatic cancer patients. Oncoimmunology 9:1773201. https://doi.org/10.1080/2162402x.2020.1773201PubMedPubMedCentralCrossRef

162.

Daher M, Rezvani K (2021) Outlook for new CAR-based therapies with a focus on CAR NK cells: what lies beyond CAR-engineered T cells in the race against cancer. Cancer Discov 11:45–58. https://doi.org/10.1158/2159-8290.CD-20-0556PubMedCrossRef

163.

Klichinsky M, Ruella M, Shestova O, Lu XM, Best A, Zeeman M, Schmierer M, Gabrusiewicz K, Anderson NR, Petty NE, Cummins KD, Shen F, Shan X, Veliz K, Blouch K, Yashiro-Ohtani Y, Kenderian SS, Kim MY, O’Connor RS, Wallace SR, Kozlowski MS, Marchione DM, Shestov M, Garcia BA, June CH, Gill S (2020) Human chimeric antigen receptor macrophages for cancer immunotherapy. Nat Biotechnol 38:947–953. https://doi.org/10.1038/s41587-020-0462-yPubMedPubMedCentralCrossRef

164.

Zheng L, Qin S, Si W, Wang A, Xing B, Gao R, Ren X, Wang L, Wu X, Zhang J, Wu N, Zhang N, Zheng H, Ouyang H, Chen K, Bu Z, Hu X, Ji J, Zhang Z (2021) Pan-cancer single-cell landscape of tumor-infiltrating T cells. Science 374:abe6474. https://doi.org/10.1126/science.abe6474CrossRefPubMed

165.

Han J, DePinho RA, Maitra A (2021) Single-cell RNA sequencing in pancreatic cancer. Nat Rev Gastroenterol Hepatol 18:451–452. https://doi.org/10.1038/s41575-021-00471-zPubMedPubMedCentralCrossRef

166.

Mahajan UM, Langhoff E, Goni E, Costello E, Greenhalf W, Halloran C, Ormanns S, Kruger S, Boeck S, Ribback S, Beyer G, Dombroswki F, Weiss FU, Neoptolemos JP, Werner J, D’Haese JG, Bazhin A, Peterhansl J, Pichlmeier S, Büchler MW, Kleeff J, Ganeh P, Sendler M, Palmer DH, Kohlmann T, Rad R, Regel I, Lerch MM, Mayerle J (2018) Immune cell and stromal signature associated with progression-free survival of patients with resected pancreatic ductal adenocarcinoma. Gastroenterology 155:1625-1639.e1622. https://doi.org/10.1053/j.gastro.2018.08.009PubMedCrossRef

167.

Sadozai H, Acharjee A, Eppenberger-Castori S, Gloor B, Gruber T, Schenk M, Karamitopoulou E (2021) Distinct stromal and immune features collectively contribute to long-term survival in pancreatic cancer. Front Immunol 12:643529. https://doi.org/10.3389/fimmu.2021.643529PubMedPubMedCentralCrossRef

168.

Wartenberg M, Cibin S, Zlobec I, Vassella E, Eppenberger-Castori S, Terracciano L, Eichmann MD, Worni M, Gloor B, Perren A, Karamitopoulou E (2018) Integrated genomic and immunophenotypic classification of pancreatic cancer reveals three distinct subtypes with prognostic/predictive significance. Clin Cancer Res 24:4444–4454. https://doi.org/10.1158/1078-0432.Ccr-17-3401PubMedCrossRef

169.

de Santiago I, Yau C, Heij L, Middleton MR, Markowetz F, Grabsch HI, Dustin ML, Sivakumar S (2019) Immunophenotypes of pancreatic ductal adenocarcinoma: meta-analysis of transcriptional subtypes. Int J Cancer 145:1125–1137. https://doi.org/10.1002/ijc.32186PubMedPubMedCentralCrossRef

170.

Montagne JM, Jaffee EM, Fertig EJ (2023) Multiomics empowers predictive pancreatic cancer immunotherapy. J Immunol 210:859–868. https://doi.org/10.4049/jimmunol.2200660PubMedCrossRef

171.

Ahmed J, Chard LS, Yuan M, Wang J, Howells A, Li Y, Li H, Zhang Z, Lu S, Gao D, Wang P, Chu Y, Al Yaghchi C, Schwartz J, Alusi G, Lemoine N, Wang Y (2020) A new oncolytic Vacciniavirus augments antitumor immune responses to prevent tumor recurrence and metastasis after surgery. J Immunother Cancer 8:415. https://doi.org/10.1136/jitc-2019-000415CrossRef

172.

Chen X, Ma H, Mo S, Zhang Y, Lu Z, Yu S, Chen J (2022) Analysis of the OX40/OX40L immunoregulatory axis combined with alternative immune checkpoint molecules in pancreatic ductal adenocarcinoma. Front Immunol 13:942154. https://doi.org/10.3389/fimmu.2022.942154PubMedPubMedCentralCrossRef

173.

Lau SP, van Montfoort N, Kinderman P, Lukkes M, Klaase L, van Nimwegen M, van Gulijk M, Dumas J, Mustafa DAM, Lievense SLA, Groeneveldt C, Stadhouders R, Li Y, Stubbs A, Marijt KA, Vroman H, van der Burg SH, Aerts J, van Hall T, Dammeijer F, van Eijck CHJ (2020) Dendritic cell vaccination and CD40-agonist combination therapy licenses T cell-dependent antitumor immunity in a pancreatic carcinoma murine model. J Immunother Cancer 8:772. https://doi.org/10.1136/jitc-2020-000772CrossRef

174.

Muth ST, Saung MT, Blair AB, Henderson MG, Thomas DL, Zheng L (2021) CD137 agonist-based combination immunotherapy enhances activated, effector memory T cells and prolongs survival in pancreatic adenocarcinoma. Cancer Lett 499:99–108. https://doi.org/10.1016/j.canlet.2020.11.041PubMedCrossRef

175.

Blair AB, Wang J, Davelaar J, Baker A, Li K, Niu N, Wang J, Shao Y, Funes V, Li P, Pachter JA, Maneval DC, Dezem F, Plummer J, Chan KS, Gong J, Hendifar AE, Pandol SJ, Burkhart R, Zhang Y, Zheng L, Osipov A (2022) Dual stromal targeting sensitizes pancreatic adenocarcinoma for anti-programmed cell death protein 1 therapy. Gastroenterology 163:1267-1280.e1267. https://doi.org/10.1053/j.gastro.2022.06.027PubMedCrossRef

176.

Xiao Z, Todd L, Huang L, Noguera-Ortega E, Lu Z, Huang L, Kopp M, Li Y, Pattada N, Zhong W, Guo W, Scholler J, Liousia M, Assenmacher CA, June CH, Albelda SM, Puré E (2023) Desmoplastic stroma restricts T cell extravasation and mediates immune exclusion and immunosuppression in solid tumors. Nat Commun 14:5110. https://doi.org/10.1038/s41467-023-40850-5PubMedPubMedCentralCrossRef

177.

Fujisawa T, Tsuchiya T, Kato M, Mizuide M, Takakura K, Nishimura M, Kutsumi H, Matsuda Y, Arai T, Ryozawa S, Itoi T, Isayama H, Saya H, Yahagi N (2023) STNM01, the RNA oligonucleotide targeting carbohydrate sulfotransferase 15, as second-line therapy for chemotherapy-refractory patients with unresectable pancreatic cancer: an open label, phase I/IIa trial. EClinical Medicine 55:101731. https://doi.org/10.1016/j.eclinm.2022.101731CrossRef

178.

Kinker GS, Vitiello GAF, Diniz AB, Cabral-Piccin MP, Pereira PHB, Carvalho MLR, Ferreira WAS, Chaves AS, Rondinelli A, Gusmão AF, Defelicibus A, Dos Santos GO, Nunes WA, Claro LCL, Bernardo TM, Nishio RT, Pacheco AM, Laus AC, Arantes L, Fleck JL, de Jesus VHF, de Moricz A, Weinlich R, Coimbra FJF, de Lima VCC, Medina TDS (2023) Mature tertiary lymphoid structures are key niches of tumour-specific immune responses in pancreatic ductal adenocarcinomas. Gut 72:1927–1941. https://doi.org/10.1136/gutjnl-2022-328697PubMedCrossRef

179.

Mirji G, Worth A, Bhat SA, El Sayed M, Kannan T, Goldman AR, Tang HY, Liu Q, Auslander N, Dang CV, Abdel-Mohsen M, Kossenkov A, Stanger BZ, Shinde RS (2022) The microbiome-derived metabolite TMAO drives immune activation and boosts responses to immune checkpoint blockade in pancreatic cancer. Sci Immunol 7:704. https://doi.org/10.1126/sciimmunol.abn0704CrossRef

180.

Riquelme E, Zhang Y, Zhang L, Montiel M, Zoltan M, Dong W, Quesada P, Sahin I, Chandra V, San Lucas A, Scheet P, Xu H, Hanash SM, Feng L, Burks JK, Do KA, Peterson CB, Nejman D, Tzeng CD, Kim MP, Sears CL, Ajami N, Petrosino J, Wood LD, Maitra A, Straussman R, Katz M, White JR, Jenq R, Wargo J, McAllister F (2019) Tumor microbiome diversity and composition influence pancreatic cancer outcomes. Cell 178:795–806. https://doi.org/10.1016/j.cell.2019.07.008CrossRefPubMedPubMedCentral

181.

Yu Q, Newsome RC, Beveridge M, Hernandez MC, Gharaibeh RZ, Jobin C, Thomas RM (2022) Intestinal microbiota modulates pancreatic carcinogenesis through intratumoral natural killer cells. Gut Microbes 14:2112881. https://doi.org/10.1080/19490976.2022.2112881PubMedPubMedCentralCrossRef

At a glance: The STEP trials

Springer Medicine

Clinical immunotherapy in pancreatic cancer

Abstract

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2024

A phase 2 study of AZD4635 in combination with durvalumab or oleclumab in patients with metastatic castration-resistant prostate cancer

Size selection of intrahepatic lesions for cryoablation contributes to abscopal effect and long-term survival in patients with liver metastatic melanoma receiving PD-1 blockade therapy

Neutrophils seeking new neighbors: radiotherapy affects the cellular framework and the spatial organization in a murine breast cancer model

Clinical evidence for efficacy of pembrolizumab in MSI-H and TMB-H advanced solid tumor: results from three cancer centers in China

Combination of IL-33 with PD-1 blockade augment mILC2s-mediated anti-tumor immunity

Construction of an immune predictive model and identification of TRIP6 as a prognostic marker and therapeutic target of CRC by integration of single-cell and bulk RNA-seq data

Keynote webinar | Spotlight on antibody–drug conjugates in cancer