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Review
. 2021 Apr 28:504:1-14.
doi: 10.1016/j.canlet.2021.01.031. Epub 2021 Feb 4.

Trials and tribulations of pancreatic cancer immunotherapy

Daniel R Principe  1 , Murray Korc  2 , Suneel D Kamath  3 , Hidayatullah G Munshi  4 , Ajay Rana  5
Affiliations
Review

Trials and tribulations of pancreatic cancer immunotherapy

Daniel R Principe et al. Cancer Lett. .

Abstract

Immunotherapy has revolutionized cancer treatment in the last decade, and strategies to re-activate cytotoxic immunity are now standard of care in several malignancies. Despite rapid advances in immunotherapy for most solid cancers, progress in immunotherapy against pancreatic ductal adenocarcinoma (PDAC) has been exceptionally difficult. This is true for several approaches, most notably immune checkpoint inhibitors (ICIs) and GM-CSF cell-based vaccines (GVAX). Though many immunotherapies have been explored in clinical trials, few have shown significant therapeutic efficacy. Further, many have shown high rates of serious adverse effects and dose-limiting toxicities, and to date, immunotherapy regimens have not been successfully implemented in PDAC. Here, we provide a comprehensive summary of the key clinical trials exploring immunotherapy in PDAC, followed by a brief discussion of emerging molecular mechanisms that may explain the relative failure of immunotherapy in pancreas cancer thus far.

Keywords: Immune checkpoint inhibition; Immunotherapy; Pancreatic cancer; Tumor immunology; Tumor microenvironment.

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Conflict of interest statement

Conflict of Interest Disclosure: The authors have no conflicts to disclose.

Figures

Figure 1.
Figure 1.. Barriers to the efficacy of immunotherapy within the pancreatic tumor microenvironment
The pancreatic tumor microenvironment (TME) harbors several immunosuppressive cell types and cytokines that impede the therapeutic efficacy of various immunotherapy regimens. In addition to cytokines such as TGFβ and various CXCR4 ligands that are produced by a different cell types, the stroma comprises a diverse population of cancer-associated fibroblasts (CAFs) and pancreatic stellate cells (PSCs), which in addition to producing a variety of extracellular matrix (ECM) proteins, have emerging roles in regulating immune tolerance. The TME also contains several highly immunosuppressive leukocyte subsets, including regulatory T-cells (T-regs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and several species of bacteria, all of which cooperate to suppress the anti-cancer immune program.
See this image and copyright information in PMC

References

    1. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ, Improved survival with ipilimumab in patients with metastatic melanoma, N Engl J Med, 363 (2010) 711–723. - PMC - PubMed
    1. Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr., Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD, Ipilimumab plus dacarbazine for previously untreated metastatic melanoma, N Engl J Med, 364 (2011) 2517–2526. - PubMed
    1. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhaufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crino L, Blumenschein GR Jr., Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR, Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer, N Engl J Med, 373 (2015) 1627–1639. - PMC - PubMed
    1. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, Carcereny E, Ahn MJ, Felip E, Lee JS, Hellmann MD, Hamid O, Goldman JW, Soria JC, Dolled-Filhart M, Rutledge RZ, Zhang J, Lunceford JK, Rangwala R, Lubiniecki GM, Roach C, Emancipator K, Gandhi L, K.-. Investigators, Pembrolizumab for the treatment of non-small-cell lung cancer, N Engl J Med, 372 (2015) 2018–2028. - PubMed
    1. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD, Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma, N Engl J Med, 373 (2015) 23–34. - PMC - PubMed

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