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A Pancreatic Cancer Patient-Derived Xenograft Model for Adoptive Immunotherapy Using Autologous Tumor-Infiltrating Lymphocytes

  • Valentina Leone
    Affiliations
    Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany

    Translational Pancreatic Cancer Research Center, Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany

    Center for Functional Protein Assemblies, Technical University of Munich, Garching, Germany

    Center for Organoid Systems and Tissue Engineering (COS), Technical University of Munich, Garching, Germany
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  • Katja Peschke
    Affiliations
    Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany

    Translational Pancreatic Cancer Research Center, Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany

    Center for Functional Protein Assemblies, Technical University of Munich, Garching, Germany

    Center for Organoid Systems and Tissue Engineering (COS), Technical University of Munich, Garching, Germany
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  • Maximilian Reichert
    Correspondence
    Correspondence: Address correspondence to: Maximilian Reichert, MD, Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich, Trogerstr. 32, 81675, Munich, Germany.
    Affiliations
    Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany

    Translational Pancreatic Cancer Research Center, Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany

    Center for Functional Protein Assemblies, Technical University of Munich, Garching, Germany

    Center for Organoid Systems and Tissue Engineering (COS), Technical University of Munich, Garching, Germany

    German Cancer Consortium (DKTK), Partner site Munich, Munich, Germany
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Open AccessPublished:August 30, 2022DOI:https://doi.org/10.1016/j.gastha.2022.08.008
      Pancreatic cancer, in particular pancreatic ductal adenocarcinoma (PDAC), shows a devastating prognosis with a five-year survival rate less than 11%,
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • et al.
      Cancer statistics, 2022.
      and it is projected to become the second leading cause of cancer-related deaths by 2040.
      • Rahib L.
      • Wehner M.R.
      • Matrisian L.M.
      • et al.
      Estimated projection of US cancer Incidence and death to 2040.
      Available treatment options such as polychemotherapies as well as targeted agents demonstrate limited clinical efficacy in PDAC patients.
      • Conroy T.
      • Desseigne F.
      • Ychou M.
      • et al.
      FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.
      • Von Hoff D.D.
      • Ervin T.
      • Arena F.P.
      • et al.
      Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.
      • Pishvaian M.J.
      • Blais E.M.
      • Brody J.R.
      • et al.
      Overall survival in patients with pancreatic cancer receiving matched therapies following molecular profiling: a retrospective analysis of the Know Your Tumor registry trial.
      In the past years, immunotherapies have demonstrated promising results for the treatment of solid cancers such as melanoma,
      • Ribas A.
      • Wolchok J.D.
      Cancer immunotherapy using checkpoint blockade.
      esophageal cancer,
      • Lampis A.
      • Ratti M.
      • Ghidini M.
      • et al.
      Challenges and perspectives for immunotherapy in oesophageal cancer: a look to the future (Review).
      and colorectal cancer;
      • Ganesh K.
      • Stadler Z.K.
      • Cercek A.
      • et al.
      Immunotherapy in colorectal cancer: rationale, challenges and potential.
      however, only marginal efficacy was observed in pancreatic cancer patients.
      • Henriksen A.
      • Dyhl-Polk A.
      • Chen I.
      • et al.
      Checkpoint inhibitors in pancreatic cancer.
      This is likely due to its highly immunosuppressive tumor microenvironment
      • Feig C.
      • Gopinathan A.
      • Neesse A.
      • et al.
      The pancreas cancer microenvironment.
      and a comparatively low mutational burden.
      • Stone M.L.
      • Beatty G.L.
      Cellular determinants and therapeutic implications of inflammation in pancreatic cancer.
      Still, the presence of tumor-infiltrating lymphocytes (TILs), in particular CD8+ cytotoxic T cells, is associated with better clinical outcomes and increased overall survival in PDAC.
      • Lohneis P.
      • Sinn M.
      • Bischoff S.
      • et al.
      Cytotoxic tumour-infiltrating T lymphocytes influence outcome in resected pancreatic ductal adenocarcinoma.
      On the contrary, Foxp3+ TILs are linked to worse prognosis in PDAC patients.
      • Kiryu S.
      • Ito Z.
      • Suka M.
      • et al.
      Prognostic value of immune factors in the tumor microenvironment of patients with pancreatic ductal adenocarcinoma.
      Various studies are now focusing on using adoptive cell therapies (ACTs), in which autologous TILs are isolated from patients and expanded/engineered in vitro to be reinfused in large numbers to potently attack tumor cells. Current clinical trials, however, show mixed efficacy of ACT therapies in PDAC cases, underscoring the urgent need to model and mechanistically decipher the interaction between pancreatic tumor cells and TILs.
      • Timmer F.E.F.
      • Geboers B.
      • Nieuwenhuizen S.
      • et al.
      Pancreatic cancer and immunotherapy: a clinical Overview.
      In this issue, a study by Nilsson et al employed IL2-humanized-NOG (non-obese severe combined immune deficient interleukin-2 chain receptor γ knockout mice) patient-derived xenografts (PDXv2s) to model autologous TIL-based therapy for PDAC.
      • Nilsson L.M.
      • Vilhav C.
      • Karlsson J.W.
      • et al.
      Genetics and therapeutic responses to TIL therapy of pancreatic cancer PDX models.
      From 29 patient biopsies, percutaneous transplantation into immunocompromised NOG mice resulted in 11 PDX tumors. In line with previous results,
      • Hidalgo M.
      • Amant F.
      • Biankin A.V.
      • et al.
      Patient-derived xenograft models: an emerging platform for translational cancer research.
      PDX tumors displayed histological similarities to the parental tumors. In addition, PDX tumors maintained their transcriptional subtype, in terms of classical and basal-like signatures,
      • Moffitt R.A.
      • Marayati R.
      • Flate E.L.
      • et al.
      Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma.
      as well as mutational alterations. Applying deconvolution to bulk RNA sequencing results revealed that PDX tumors lost patient-derived immune and stroma cells, which correlated with the absence of expression of HLA-A/-B/-C by immunohistochemistry. In parallel to tumor growth in PDX models, autologous TILs were expanded in vitro. This expansion process was successful in 6 biopsy samples in which PDX tumors (n = 11) were also available. As previously demonstrated by the group for melanoma, long-time survival and antitumor activity of injected autologous TILs require a constant source of IL2 in vivo.
      • Jespersen H.
      • Lindberg M.F.
      • Donia M.
      • et al.
      Clinical responses to adoptive T-cell transfer can be modeled in an autologous immune-humanized mouse model.
      Therefore, analogous to their melanoma model,
      • Jespersen H.
      • Lindberg M.F.
      • Donia M.
      • et al.
      Clinical responses to adoptive T-cell transfer can be modeled in an autologous immune-humanized mouse model.
      in vitro expanded autologous TILs were transplanted into PDAC-bearing PDXv2 mice. Importantly, in 3 out of 6 PDXv2 mice, tumor regression was observed after ACT. PDXv2 mice not receiving TILs showed no tumor regression.
      Limitations of this study include that the authors did not further characterize the expanded patient-derived TILs regarding T-cell type (CD4+ or CD8+ cells). As the authors of the study discussed, Poschke et al showed a clonal selection process occurring during TIL expansion, which leads to a loss of predominant TILs and an outgrowth of newly emerging TILs resulting in a reduced tumor-killing capacity.
      • Poschke I.C.
      • Hassel J.C.
      • Rodriguez-Ehrenfried A.
      • et al.
      The outcome of Ex vivo TIL expansion is highly influenced by Spatial Heterogeneity of the tumor T-cell Repertoire and Differences in Intrinsic in vitro growth capacity between T-cell Clones.
      This might explain why in 3 out of 6 treated PDXv2 mice, TIL infusion was not effective in tumor reduction.
      Overall, this model is an exciting and promising tool to explore adoptive immunotherapies for PDAC, allowing to improve therapeutic efficacy of TILs possibly by genetic engineering. Another avenue might be to perform and investigate combinatorial treatments such as a combination of chemoradiation and immune checkpoint inhibition which is also currently being tested in early clinical trials of pancreatic cancer.
      • Rahma O.E.
      • Katz M.H.G.
      • Wolpin B.M.
      • et al.
      Randomized multicenter phase Ib/II study of neoadjuvant chemoradiation therapy (CRT) alone or in combination with pembrolizumab in patients with resectable or borderline resectable pancreatic cancer.
      In the future, larger preclinical cohorts are needed in order to validate the efficacy of TIL-based treatment and investigate underlying molecular mechanisms as well as possible selection criteria which ultimately are needed for successful translation into the clinic and improvement of PDAC patient care.

      References

        • Siegel R.L.
        • Miller K.D.
        • Fuchs H.E.
        • et al.
        Cancer statistics, 2022.
        CA Cancer J Clin. 2022; 72: 7-33
        • Rahib L.
        • Wehner M.R.
        • Matrisian L.M.
        • et al.
        Estimated projection of US cancer Incidence and death to 2040.
        JAMA Netw Open. 2021; 4: e214708
        • Conroy T.
        • Desseigne F.
        • Ychou M.
        • et al.
        FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.
        N Engl J Med. 2011; 364: 1817-1825
        • Von Hoff D.D.
        • Ervin T.
        • Arena F.P.
        • et al.
        Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.
        N Engl J Med. 2013; 369: 1691-1703
        • Pishvaian M.J.
        • Blais E.M.
        • Brody J.R.
        • et al.
        Overall survival in patients with pancreatic cancer receiving matched therapies following molecular profiling: a retrospective analysis of the Know Your Tumor registry trial.
        Lancet Oncol. 2020; 21: 508-518
        • Ribas A.
        • Wolchok J.D.
        Cancer immunotherapy using checkpoint blockade.
        Science. 2018; 359: 1350-1355
        • Lampis A.
        • Ratti M.
        • Ghidini M.
        • et al.
        Challenges and perspectives for immunotherapy in oesophageal cancer: a look to the future (Review).
        Int J Mol Med. 2021; 47: 97
        • Ganesh K.
        • Stadler Z.K.
        • Cercek A.
        • et al.
        Immunotherapy in colorectal cancer: rationale, challenges and potential.
        Nat Rev Gastroenterol Hepatol. 2019; 16: 361-375
        • Henriksen A.
        • Dyhl-Polk A.
        • Chen I.
        • et al.
        Checkpoint inhibitors in pancreatic cancer.
        Cancer Treat Rev. 2019; 78: 17-30
        • Feig C.
        • Gopinathan A.
        • Neesse A.
        • et al.
        The pancreas cancer microenvironment.
        Clin Cancer Res. 2012; 18: 4266-4276
        • Stone M.L.
        • Beatty G.L.
        Cellular determinants and therapeutic implications of inflammation in pancreatic cancer.
        Pharmacol Ther. 2019; 201: 202-213
        • Lohneis P.
        • Sinn M.
        • Bischoff S.
        • et al.
        Cytotoxic tumour-infiltrating T lymphocytes influence outcome in resected pancreatic ductal adenocarcinoma.
        Eur J Cancer. 2017; 83: 290-301
        • Kiryu S.
        • Ito Z.
        • Suka M.
        • et al.
        Prognostic value of immune factors in the tumor microenvironment of patients with pancreatic ductal adenocarcinoma.
        BMC Cancer. 2021; 21: 1197
        • Timmer F.E.F.
        • Geboers B.
        • Nieuwenhuizen S.
        • et al.
        Pancreatic cancer and immunotherapy: a clinical Overview.
        Cancers (Basel). 2021; 13: 4138
        • Nilsson L.M.
        • Vilhav C.
        • Karlsson J.W.
        • et al.
        Genetics and therapeutic responses to TIL therapy of pancreatic cancer PDX models.
        Gasto Hep Adv. 2022; 1: 1037-1048
        • Hidalgo M.
        • Amant F.
        • Biankin A.V.
        • et al.
        Patient-derived xenograft models: an emerging platform for translational cancer research.
        Cancer Discov. 2014; 4: 998-1013
        • Moffitt R.A.
        • Marayati R.
        • Flate E.L.
        • et al.
        Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma.
        Nat Genet. 2015; 47: 1168-1178
        • Jespersen H.
        • Lindberg M.F.
        • Donia M.
        • et al.
        Clinical responses to adoptive T-cell transfer can be modeled in an autologous immune-humanized mouse model.
        Nat Commun. 2017; 8: 707
        • Poschke I.C.
        • Hassel J.C.
        • Rodriguez-Ehrenfried A.
        • et al.
        The outcome of Ex vivo TIL expansion is highly influenced by Spatial Heterogeneity of the tumor T-cell Repertoire and Differences in Intrinsic in vitro growth capacity between T-cell Clones.
        Clin Cancer Res. 2020; 26: 4289-4301
        • Rahma O.E.
        • Katz M.H.G.
        • Wolpin B.M.
        • et al.
        Randomized multicenter phase Ib/II study of neoadjuvant chemoradiation therapy (CRT) alone or in combination with pembrolizumab in patients with resectable or borderline resectable pancreatic cancer.
        J Clin Oncol. 2021; 39: 4128

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