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Harnessing the Immune System in Pancreatic Cancer

  • Upper Gastrointestinal Cancers (L Rajdev, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

Managing patients with metastatic pancreatic adenocarcinoma (mPDA) is a challenging proposition for any treating oncologist. Although the potency of first-line therapies has improved with the approvals of FOLFIRINOX and gemcitabine plus nab-paclitaxel, many patients are unable to derive significant benefit from later lines of therapy upon progression. Enrollment on clinical trials remains among the best options for patients with mPDA in all lines of therapy. At our institution, we routinely check for microsatellite instability (MSI-H) and perform next-generation sequencing (NGS) at the time of diagnosis in all good performance status mPDA patients. Although MSI-H status is only found in 1% of patients with mPDA, given pembrolizumab’s tissue-agnostic approval for MSI-H tumors in later-line settings, it is a viable option when deciding on subsequent lines of therapy. Any use of immune therapy in mPDA is investigational outside the MSI-H setting. NGS can identify BRCA or other DNA damage response (DDR) defects in patients which can predict sensitivity to platinum-based therapies and influence choice of both initial and later lines of therapy. It can also identify rare actionable genomic alterations such as HER2 (2%) and TRK fusions (0.1%) and offer patients the option of enrollment on clinical trials with agents targeting these or other identified alterations. We believe enrolling mPDA patients on clinical trials with immune-modulating agents is critical to determine if there are other patient subsets, outside of the MSI-H setting, who would benefit from these approaches. Immunotherapy’s general tolerability and potential to generate durable responses make it particularly appealing for mPDA patients. Although single-modality immunotherapy such as checkpoint inhibitors or vaccines have not demonstrated efficacy in this disease, combinatorial strategies targeting unique aspects of PDA including the tumor microenvironment and desmoplastic stroma have shown preclinical or early-phase success. Validating these treatments with later-phase prospective studies is essential to making immunotherapy a routine component of the treatment armamentarium for mPDA patients.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. SEER Database 2018. https://seer.cancer.gov/statfacts/html/pancreas.html.

  2. Walker E, Ko A. Beyond first-line chemotherapy for advanced pancreatic cancer: an expanding array of therapeutic options? World J Gastroenterol. 2014;20(9):2224–36.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Van Hoff D, Ervin T, Arena F, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691–703.

    Article  CAS  Google Scholar 

  4. Nagrial A, Chin VT, Sjoquist KM, et al. Second-line treatment in inoperable pancreatic adenocarcinoma: a systematic review and synthesis of all clinical trials. Crit Rev Oncol Hematol. 2015;96:483–97.

    Article  PubMed  Google Scholar 

  5. Liu Q, Liao Q, Zheo Y. Chemotherapy and tumor microenvironment of pancreatic cancer. Cancer Cell Int. 2017;17(68):1–17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. •• Johnson B III, Yarchoan M, Lee V, et al. Strategies for increasing pancreatic tumor immunogenicity. Clin Cancer Res. 2017;23(7):1656–69. A detailed review exploring the complex layers of immunosuppression present in the TME of PDA patients and why combinatorial approaches, targeting some of these different elements, is a necessity to making immunotherapy a viable treatment option in this disease.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Zhang Y, Velez-Delgado A, Li M, et al. Myeloid cells are required for PD-1/PD-L1 checkpoint activation and the establishment of an immunosuppressive environment in pancreatic cancer. Gut. 2016;66:124–36.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. •• 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;33:828–33. One of the initial studies demonstrating that single-agent checkpoint inhibitors had very limited activity in mPDA. This demonstrated the need for combinatorial immune-modulating strategies moving forward.

    Article  PubMed  CAS  Google Scholar 

  9. Brahmer J, Tykodi S, Chow L, et al. Safety and activity of anti–PD-L1 antibody in patients with advanced Cancer. N Engl J Med. 2012;366:2455–65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. •• Le D, Durham J, Smith K, et al. Mismatch-repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409–13. A seminal proof-of-principle study which demonstrated that MSI-H tumors have significant response rates to single-agent immunotherapy with pembrolizumab. This led to FDA approval for pembrolizumab in MSI-H tumors of any type after failure of initial-line chemotherapy.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Weiss GJ, Blaydorn L, Beck J, Bornemann-Kolatzki K, Urnovitz H, Schütz E, et al. Phase Ib/II study of gemcitabine, nab-paclitaxel, and pembrolizumab in metastatic pancreatic adenocarcinoma. Investig New Drugs. 2018;36(1):96–102.

    Article  CAS  Google Scholar 

  12. Wainberg Z, Hochster H, George B, et al. Phase I study of nivolumab (nivo) + nab-paclitaxel (nab-P) ± gemcitabine (Gem) in solid tumors: interim results from the pancreatic cancer (PC) cohorts. J Clin Oncol. 2017;35(4):S412.

    Article  Google Scholar 

  13. Beatty G, Chiorean G, Fishman M, et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science. 2012;331(6024):1612–6.

    Article  CAS  Google Scholar 

  14. Beatty G, Torigian D, Chiorean E, et al. A phase I study of an agonist CD40 monoclonal antibody (CP-870,893) in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma. Clin Cancer Res. 2013;19(22):6286–95.

    Article  PubMed  CAS  Google Scholar 

  15. •• Manji G, Bendell J, Oh DY, et al. MORPHEUS: a phase Ib/II multi-trial platform evaluating the efficacy and safety of cancer immunotherapy (CIT)-based combinations in patients (pts) with gastric or pancreatic cancer. J Clin Oncol. 2018;36(4):S530. An example of a platform study which will likely serve as a template for how future immune combinations are trialed in mPDA patients.

    Google Scholar 

  16. Abraham M, Mishalian I, Harel Y, et al. Effect of BL-8040, high-affinity CXCR4 antagonist, on T-cell infiltration, tumor growth, and synergy with immunomodulatory agents. J Clin Oncol. 2017;35(15):S14544.

    Article  Google Scholar 

  17. Hidalgo M, Epelbaum R, Semenisty V, et al. Evaluation of pharmacodynamic (PD) biomarkers in patients with metastatic pancreatic cancer treated with BL-8040, a novel CXCR4 antagonist. J Clin Oncol. 2018;36(5):S88.

    Article  Google Scholar 

  18. O’Reilly E, Oh DY, Dhani N, et al. A randomized phase 2 study of durvalumab monotherapy and in combination with tremelimumab in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): ALPS study. J Clin Oncol. 2018;36(4):S217.

    Google Scholar 

  19. Kaufman HL, Kim-Schulze S, Manson K, et al. Poxvirus-based vaccine therapy for patients with advanced pancreatic cancer. J Transl Med. 2007;5(60):1–10.

    Google Scholar 

  20. Gilliam AD, Broome P, Topuzov EG, Garin AM, Pulay I, Humphreys J, et al. An international multicenter randomized controlled trial of G17DT in patients with pancreatic cancer. IJ Pancreas. 2012;41(3):374–9.

    Article  CAS  Google Scholar 

  21. Le DT, Wang-Gillam A, Picozzi VJ, et al. Interim safety and efficacy analysis of a phase II, randomized study of GVAX pancreas and CRS-207 immunotherapy in patients with metastatic pancreatic cancer. J Clin Oncol. 2013;31(suppl):abstr 4040.

    Google Scholar 

  22. • Le D, Crocenzi T, Urum J, et al. Randomized phase II study of the safety, efficacy and immune response of GVAX pancreas (with cyclophosphamide) and CRS-207 with or without nivolumab in patients with previously treated metastatic pancreatic adenocarcinoma (STELLAR). J Immunother Cancer. 2015;3(S2):P155. An important study assessing the potential mechanistic synergy between vaccines and checkpoint blockade. It highlights the pre-clinical principle that vaccination increases intra-tumoral lymphocyte influx while PD-1 inhibition maintains the activation of these cells.

    Article  PubMed Central  Google Scholar 

  23. Le D, Ko A, Wainberg Z, et al. Results from a phase 2b, randomized, multicenter study of GVAX pancreas and CRS-207 compared to chemotherapy in adults with previously-treated metastatic pancreatic adenocarcinoma (ECLIPSE Study). J Clin Oncol. 2017;35(4):S345.

    Article  Google Scholar 

  24. Le D, Lutz E, Uram J, et al. Evaluation of Ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. J Immunother. 2013;36(7):382–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Chumsri S, Necela BM, Ordentlich P, et al. Immunomodulatory effects of entinostat on PD-L1 and MHC class I and II in different subtypes of breast cancer. Cancer Res. 2016;76(4):SABCS15-P2–04-02.

    Google Scholar 

  26. Postow M, Callahan M, Barker C, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366:925–31.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Shi F, Wang X, Teng F, Kong L, Yu J. Abscopal effect of metastatic pancreatic cancer after local radiotherapy and granulocyte-macrophage colony-stimulating factor therapy. Cancer Biol Ther. 2017;18(3):137–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Davis-Yadley A, Malafa M. Vitamins in pancreatic cancer: a review of underlying mechanisms and future applications. Adv Nutr. 2015;6(6):774–802.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Chung V, Borazanci E, Jameson G. A SU2C catalyst randomized phase II trial of pembrolizumab with or without paricalcitol in patients with stage IV pancreatic cancer who have been placed in best possible response. J Clin Oncol. 2018;36(15):S4154.

    Article  Google Scholar 

  30. Borazanci E, Jameson G, Borad M, et al. A phase II pilot trial of nivolumab (N) + albumin bound paclitaxel (AP) + paricalcitol (P) + cisplatin (C) + gemcitabine (G) (NAPPCG) in patients with previously untreated metastatic pancreatic ductal adenocarcinoma (PDAC). J Clin Oncol. 2018;36(4):S358.

    Google Scholar 

  31. Zhu Y, Knolhoff B, Meyer M. E t al. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res. 2014;74(18):5057–69.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Wainberg ZA, Piha-Paul SA, Luke JJ et al. First-in-human phase 1 dose escalation and expansion of a novel combination, anti–CSF-1 receptor (cabiralizumab) plus anti–PD-1 (nivolumab), in patients with advanced solid tumors. Presented at: 32nd SITC Annual Meeting; November 8-12, 2017; National Harbor, MD Abstract O4.

  33. Calvo A, Joensuu H, Sebastian M, et al. Phase Ib/II study of lacnotuzumab (MCS110) combined with spartalizumab (PDR001) in patients (pts) with advanced tumors. J Clin Oncol. 2018;36(15):S3014.

    Article  Google Scholar 

  34. • Cui R, Yue W, Lattime E, et al. Targeting tumor-associated macrophages to combat pancreatic cancer. Oncotarget. 2016;7(31):50735–54. A comprehensive review detailing the double-edged role of macrophages in both promoting tumorigenesis and limiting the process. The article delves into the role of cytokines such as CCL2 and CCL5 in generating tumor promoting macrophages (Th2).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Zhu Y, Herndon J, Sojka D, et al. Tissue-resident macrophages in pancreatic ductal adenocarcinoma originate from embryonic hematopoiesis and promote tumor progression. Immunity. 2017;47(2):323–38.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Jiang H, Hedge S, Knolhoff B, et al. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat Med. 2016;22:851–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Wang-Gillam A, Lockhart C, Tan B, et al. Phase I study of defactinib combined with pembrolizumab and gemcitabine in patients with advanced cancer. J Clin Oncol. 2018;36(4):S380.

    Google Scholar 

  38. Rastelli L, Gupta S, Jagga Z, et al. Efficacy and immune modulation by BXCL701 a dipeptidyl peptidase inhibitor, NKTR-214 a CD122-biased immune agonist with PD1 blockade in murine pancreatic tumors. J Clin Oncol. 2018;36(15):S3085.

    Article  Google Scholar 

  39. Friberg M, Nielsen B, Mortensen MB, et al. Key players in pancreatic cancer-stroma interaction: Cancer-associated fibroblasts, endothelial and inflammatory cells. World J Gastroenterol. 2016;22(9):2678–700.

    Article  CAS  Google Scholar 

  40. Ping L, Ding N, Shi Y, Feng L, Li J, Liu Y, et al. The Bruton’s tyrosine kinase inhibitor ibrutinib exerts immunomodulatory effects through regulation of tumor-infiltrating macrophages. Oncotarget. 2017;8(24):39218–29.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Tempero M, Coussens L, Fong L, et al. A randomized, double-blind, placebo-controlled study of ibrutinib, a Bruton tyrosine kinase inhibitor, with nab-paclitaxel and gemcitabine in the first-line treatment of patients with metastatic pancreatic adenocarcinoma (RESOLVE). J Clin Oncol. 2016;34(15):S2601.

    Article  Google Scholar 

  42. Hong D, Rasco D, Veeder M, et al. A multicenter study of the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib plus durvalumab in patients with relapsed/refractory (R/R) solid tumors. J Clin Oncol. 2018;36(15):S2578.

    Article  Google Scholar 

  43. Xia X, Wu W, Huang C, Cen G, Jiang T, Cao J, et al. SMAD4 and its role in pancreatic cancer. Tumour Biol. 2015;36(1):111–9.

    Article  PubMed  CAS  Google Scholar 

  44. Ahmed S, Bradshaw AD, Gera S, Dewan M, Xu R. The TGF-β/Smad4 signaling pathway in pancreatic carcinogenesis and its clinical significance. J Clin Med. 2017;6(1):5.

    Article  PubMed Central  CAS  Google Scholar 

  45. Melisi D, Garcia-Carbonero R, Macarulla T, et al. A phase II, double-blind study of galunisertib+gemcitabine (GG) vs gemcitabine+placebo (GP) in patients (pts) with unresectable pancreatic cancer (PC). J Clin Oncol. 2016;34(15):S4019.

    Article  Google Scholar 

  46. Papadopolous K, Naing A, Infante J, et al. Anti-tumor activity of PEGylated human IL-10 (AM0010) in patients with pancreatic or colorectal cancer. J Clin Oncol. 2016;34(15):S3082.

    Article  Google Scholar 

  47. Hecht JR, Naing A, Falchook G, et al. Phase 1b study with PEGylated human IL-10 (AM0010) with 5-FU and oxaliplatin (FOLFOX) in metastatic pancreatic adenocarcinoma (PDAC). J Clin Oncol. 2017;35(4):S399.

    Article  Google Scholar 

  48. Jin D, Fan J, Wang L, Thompson LF, Liu A, Daniel BJ, et al. CD73 on tumor cells impairs antitumor T-cell responses: a novel mechanism of tumor-induced immune suppression. Cancer Res. 2010;70(6):2245–55.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Overman M, LoRusso P, Strickler J, et al. Safety, efficacy and pharmacodynamics (PD) of MEDI9447 (oleclumab) alone or in combination with durvalumab in advanced colorectal cancer (CRC) or pancreatic cancer (panc). J Clin Oncol. 2018;suppl:abstr 4123.

    Article  Google Scholar 

  50. Pendergrast G, Malachowski W, DuHadaway J, et al. Discovery of IDO1 inhibitors: from bench to bedside. Cancer Res. 2017;77(24):6795–811.

    Article  CAS  Google Scholar 

  51. Zhang T, Tan XL, Xu Y, Wang ZZ, Xiao CH, Liu R. Expression and prognostic value of indoleamine 2,3-dioxygenase in pancreatic cancer. Chin Med J. 2017;130(6):710–6.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Bahary N, Garrido-Laguna I, Wang-Gillam A, et al. Results of the phase Ib portion of a phase I/II trial of the indoleamine 2,3-dioxygenase pathway (IDO) inhibitor indoximod plus gemcitabine/nab-paclitaxel for the treatment of metastatic pancreatic cancer. J Clin Oncol. 2016;34(4):S452.

    Article  Google Scholar 

  53. Lum L, Choi M, Thakur A, et al. Five advanced pancreatic cancer patients in a phase I study of anti-CD3 x anti-EGFR bispecific antibody armed activated T cells (BATS). J Immunother Cancer. 2015;3(Suppl 2):P55.

    Article  PubMed Central  Google Scholar 

  54. Salnikov AV, Groth A, Apel A, Kallifatidis G, Beckermann BM, Khamidjanov A, et al. Targeting of cancer stem cell marker EpCAM by bispecific antibody EpCAMxCD3 inhibits pancreatic carcinoma. J Cell Mol Med. 2009;13(9B):4023–33.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Cioffi M, Dorado J, Baeurle PA, et al. EpCAM/CD3-bispecific T-cell engaging antibody MT110 eliminates primary human pancreatic cancer stem cells. Clin Cancer Res. 2012;8(2):465–74.

    Article  CAS  Google Scholar 

  56. Heiss MM, Murawa P, Koralewski P, et al. The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: results of a prospective randomized phase II/III trial. Int J Cancer. 2010;27(9):2209–21.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Hematology and Oncology, Department of Internal Medicine, Vanderbilt University Medical Center, 2220 Pierce Avenue, 777 Preston Research Building, Nashville, TN, 37232, USA

    Satya Das MD, Jordan Berlin MD & Dana Cardin MD, MSCI

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  1. Satya Das MD
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  2. Jordan Berlin MD
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  3. Dana Cardin MD, MSCI
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Correspondence to Satya Das MD.

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Conflict of Interest

Satya Das has received compensation from Targeted Oncology for service as a consultant (Clinical Congress Consultants).

Dana B. Cardin has received research funding from Celgene, EMD Serono, Hoffman-La Roche, Incyte, Oncolytics Biotech, Synta Pharmaceuticals, Bristol-Myers Squibb, Advaxis, and Lilly, and has received compensation from Cornerstone Pharmaceuticals, Rafael Pharmaceuticals, and AbbVie for service as a consultant.

Jordan Berlin has received research funding from Novartis, AbbVie, Immunomedics, Taiho, Genentech/Roche, Bayer, Incyte, Pharmacyclics, Five Prime, EMD Serono, and Loxo.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on Upper Gastrointestinal Cancers

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Das, S., Berlin, J. & Cardin, D. Harnessing the Immune System in Pancreatic Cancer. Curr. Treat. Options in Oncol. 19, 48 (2018). https://doi.org/10.1007/s11864-018-0566-5

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