The progress and major challenges of immunotherapy for pancreatic cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

CAI Lei ^1,2 , WANG Xianxing ^1,2 ,  WANG Huaizhi ^1,2

1. Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital (Chongqing Academy of Medical Sciences), Chongqing 401147, P. R. China;
2. Chongqing Key Laboratory of Intelligent Medicine Engineering for Hepatopancreatobiliary Diseases, Chongqing 401147, P. R. China;

Corresponding author：

WANG Huaizhi, Email: whuaizhi@qq.com

Keywords：

pancreatic cancer; immunotherapy; immune checkpoint inhibitor

DOI：

10.7507/1007-9424.202307055

Video：

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Pancreatic cancer (PC) is a highly malignant tumor of the digestive system and has a concealed onset with rapid progression. The majority of PC patients are diagnosed in the middle to late stages, and the effectiveness of traditional treatment methods for advanced pancreatic cancer is limited, which results in a poor prognosis. Immunotherapy, as a novel treatment strategy, aims to suppress tumor growth and metastasis by modulating and enhancing the human immune system. It has become a hot point in current cancer prevention and treatment. This article will elaborate on the newest advancements in immunotherapy for PC. Furthermore, we point out the major challenges of PC immunotherapy.

Citation： CAI Lei, WANG Xianxing, WANG Huaizhi. The progress and major challenges of immunotherapy for pancreatic cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2023, 30(9): 1030-1036. doi: 10.7507/1007-9424.202307055 Copy

1.	Siegel RL, Miller KD, Wagle NS, et al. Cancer statistics, 2023. CA Cancer J Clin, 2023, 73(1): 17-48.
2.	Kleeff J, Korc M, Apte M, et al. Pancreatic cancer. Nat Rev Dis Primers, 2016, 2: 16022.
3.	Rawla P, Sunkara T, Gaduputi V. Epidemiology of pancreatic cancer: global trends, etiology and risk factors. World J Oncol, 2019, 10(1): 10-27.
4.	Ryan DP, Hong TS, Bardeesy N. Pancreatic adenocarcinoma. N Engl J Med, 2014, 371(22): 2140-2141.
5.	Halbrook CJ, Lyssiotis CA, Pasca di Magliano M, et al. Pancreatic cancer: Advances and challenges. Cell, 2023, 186(8): 1729-1754.
6.	Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med, 2012, 366(26): 2455-2465.
7.	Bayne LJ, Beatty GL, Jhala N, et al. Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell, 2012, 21(6): 822-835.
8.	Michelakos T, Cai L, Villani V, et al. Tumor microenvironment immune response in pancreatic ductal adenocarcinoma patients treated with neoadjuvant therapy. J Natl Cancer Inst, 2021, 113(2): 182-191.
9.	Le DT, Wang-Gillam A, Picozzi V, et al. Safety and survival with GVAX pancreas prime and Listeria monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J Clin Oncol, 2015, 33(12): 1325-1333.
10.	Li K, Tandurella JA, Gai J, et al. Multi-omic analyses of changes in the tumor microenvironment of pancreatic adenocarcinoma following neoadjuvant treatment with anti-PD-1 therapy. Cancer Cell, 2022, 40(11): 1374-1391.
11.	Ott PA, Hu Z, Keskin DB, et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature, 2017, 547(7662): 217-221.
12.	Beatty GL, Haas AR, Maus MV, et al. Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies. Cancer Immunol Res, 2014, 2(2): 112-120.
13.	Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science, 2018, 359(6382): 1350-1355.
14.	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(8): 828-833.
15.	Le DT, Lutz E, Uram JN, 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): 382-389.
16.	Beatty GL, O’Hara MH, Lacey SF, et al. Activity of mesothelin-specific chimeric antigen receptor T cells against pancreatic carcinoma metastases in a phase 1 trial. Gastroenterology, 2018, 155(1): 29-32.
17.	Du H, Hirabayashi K, Ahn S, et al. Antitumor responses in the absence of toxicity in solid tumors by targeting B7-H3 via chimeric antigen receptor T cells. Cancer Cell, 2019, 35(2): 221-237.
18.	Naidoo J, Page DB, Li BT, et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol, 2016, 27(7): 1362.
19.	Kamath SD, Kalyan A, Kircher S, et al. Ipilimumab and gemcitabine for advanced pancreatic cancer: A phaseⅠ b study. Oncologist, 2020, 25(5): e808-e815.
20.	Le DT, Picozzi VJ, Ko AH, et al. Results from a phaseⅡ b, 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, 2019, 25(18): 5493-5502.
21.	Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med, 2018, 378(5): 439-448.
22.	Gubin MM, Zhang X, Schuster H, et al. Checkpoint blockade cancer immunotherapy targets tumour- specific mutant antigens. Nature, 2014, 515(7528): 577-581.
23.	Birnbaum DJ, Finetti P, Lopresti A, et al. Prognostic value of PDL1 expression in pancreatic cancer. Oncotarget, 2016, 7(44): 71198-71210.
24.	Isazadeh A, Hajazimian S, Garshasbi H, et al. Resistance mechanisms to immune checkpoints blockade by monoclonal antibody drugs in cancer immunotherapy: Focus on myeloma. J Cell Physiol, 2021, 236(2): 791-805.
25.	Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell, 2015, 27(4): 450-461.
26.	Doroshow DB, Bhalla S, Beasley MB, et al. PD-L1 as a biomarker of response to immune-checkpoint inhibitors. Nat Rev Clin Oncol, 2021, 18(6): 345-362.
27.	Koikawa K, Kibe S, Suizu F, et al. Targeting Pin1 renders pancreatic cancer eradicable by synergizing with immunochemotherapy. Cell, 2021, 184(18): 4753-4771.
28.	Mace TA, Ameen Z, Collins A, et al. Pancreatic cancer-associated stellate cells promote differentiation of myeloid-derived suppressor cells in a STAT3-dependent manner. Cancer Res, 2013, 73(10): 3007-3018.
29.	McGranahan N, Swanton C. Clonal heterogeneity and tumor evolution: past, present, and the future. Cell, 2017, 168(4): 613-628.
30.	Somani VK, Zhang D, Dodhiawala PB, et al. IRAK4 signaling drives resistance to checkpoint immunotherapy in pancreatic ductal adenocarcinoma. Gastroenterology, 2022, 162(7): 2047-2062.
31.	Lybaert L, Lefever S, Fant B, et al. Challenges in neoantigen-directed therapeutics. Cancer Cell, 2023, 41(1): 15-40.
32.	Tang S, Shi L, Luker BT, et al. Modulation of the tumor microenvironment by armed vesicular stomatitis virus in a syngeneic pancreatic cancer model. Virol J, 2022, 19(1): 32.
33.	Kemp SB, Cheng N, Markosyan N, et al. Efficacy of a small-molecule inhibitor of krasG12D in immunocompetent models of pancreatic cancer. Cancer Discov, 2023, 13(2): 298-311.
34.	Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature, 2014, 515(7528): 568-571.
35.	Chakrabarti S, Bucheit L, Starr JS, et al. Detection of microsatellite instability-high (MSI-H) by liquid biopsy predicts robust and durable response to immunotherapy in patients with pancreatic cancer. J Immunother Cancer, 2022, 10(6): e004485.
36.	Galluzzi L, Buqué A, Kepp O, et al. Immunological effects of conventional chemotherapy and targeted anticancer agents. Cancer Cell, 2015, 28(6): 690-714.
37.	Mariathasan S, Turley SJ, Nickles D, et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature, 2018, 554(7693): 544-548.
38.	Johnston RJ, Comps-Agrar L, Hackney J, et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8⁺ T cell effector function. Cancer Cell, 2014, 26(6): 923-937.
39.	Michelakos T, Kontos F, Barakat O, et al. B7-H3 targeted antibody-based immunotherapy of malignant diseases. Expert Opin Biol Ther, 2021, 21(5): 587-602.
40.	Balachandran VP, Łuksza M, Zhao JN, et al. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature, 2017, 551(7681): 512-516.
41.	Zemek RM, De Jong E, Chin WL, et al. Sensitization to immune checkpoint blockade through activation of a STAT1/NK axis in the tumor microenvironment. Sci Transl Med, 2019, 11(501): eaav7816.
42.	Stadtmauer EA, Fraietta JA, Davis MM, et al. CRISPR-engineered T cells in patients with refractory cancer. Science, 2020, 367(6481): eaba7365.

1. Siegel RL, Miller KD, Wagle NS, et al. Cancer statistics, 2023. CA Cancer J Clin, 2023, 73(1): 17-48.
2. Kleeff J, Korc M, Apte M, et al. Pancreatic cancer. Nat Rev Dis Primers, 2016, 2: 16022.
3. Rawla P, Sunkara T, Gaduputi V. Epidemiology of pancreatic cancer: global trends, etiology and risk factors. World J Oncol, 2019, 10(1): 10-27.
4. Ryan DP, Hong TS, Bardeesy N. Pancreatic adenocarcinoma. N Engl J Med, 2014, 371(22): 2140-2141.
5. Halbrook CJ, Lyssiotis CA, Pasca di Magliano M, et al. Pancreatic cancer: Advances and challenges. Cell, 2023, 186(8): 1729-1754.
6. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med, 2012, 366(26): 2455-2465.
7. Bayne LJ, Beatty GL, Jhala N, et al. Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell, 2012, 21(6): 822-835.
8. Michelakos T, Cai L, Villani V, et al. Tumor microenvironment immune response in pancreatic ductal adenocarcinoma patients treated with neoadjuvant therapy. J Natl Cancer Inst, 2021, 113(2): 182-191.
9. Le DT, Wang-Gillam A, Picozzi V, et al. Safety and survival with GVAX pancreas prime and Listeria monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J Clin Oncol, 2015, 33(12): 1325-1333.
10. Li K, Tandurella JA, Gai J, et al. Multi-omic analyses of changes in the tumor microenvironment of pancreatic adenocarcinoma following neoadjuvant treatment with anti-PD-1 therapy. Cancer Cell, 2022, 40(11): 1374-1391.
11. Ott PA, Hu Z, Keskin DB, et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature, 2017, 547(7662): 217-221.
12. Beatty GL, Haas AR, Maus MV, et al. Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies. Cancer Immunol Res, 2014, 2(2): 112-120.
13. Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science, 2018, 359(6382): 1350-1355.
14. 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(8): 828-833.
15. Le DT, Lutz E, Uram JN, 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): 382-389.
16. Beatty GL, O’Hara MH, Lacey SF, et al. Activity of mesothelin-specific chimeric antigen receptor T cells against pancreatic carcinoma metastases in a phase 1 trial. Gastroenterology, 2018, 155(1): 29-32.
17. Du H, Hirabayashi K, Ahn S, et al. Antitumor responses in the absence of toxicity in solid tumors by targeting B7-H3 via chimeric antigen receptor T cells. Cancer Cell, 2019, 35(2): 221-237.
18. Naidoo J, Page DB, Li BT, et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol, 2016, 27(7): 1362.
19. Kamath SD, Kalyan A, Kircher S, et al. Ipilimumab and gemcitabine for advanced pancreatic cancer: A phaseⅠ b study. Oncologist, 2020, 25(5): e808-e815.
20. Le DT, Picozzi VJ, Ko AH, et al. Results from a phaseⅡ b, 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, 2019, 25(18): 5493-5502.
21. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med, 2018, 378(5): 439-448.
22. Gubin MM, Zhang X, Schuster H, et al. Checkpoint blockade cancer immunotherapy targets tumour- specific mutant antigens. Nature, 2014, 515(7528): 577-581.
23. Birnbaum DJ, Finetti P, Lopresti A, et al. Prognostic value of PDL1 expression in pancreatic cancer. Oncotarget, 2016, 7(44): 71198-71210.
24. Isazadeh A, Hajazimian S, Garshasbi H, et al. Resistance mechanisms to immune checkpoints blockade by monoclonal antibody drugs in cancer immunotherapy: Focus on myeloma. J Cell Physiol, 2021, 236(2): 791-805.
25. Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell, 2015, 27(4): 450-461.
26. Doroshow DB, Bhalla S, Beasley MB, et al. PD-L1 as a biomarker of response to immune-checkpoint inhibitors. Nat Rev Clin Oncol, 2021, 18(6): 345-362.
27. Koikawa K, Kibe S, Suizu F, et al. Targeting Pin1 renders pancreatic cancer eradicable by synergizing with immunochemotherapy. Cell, 2021, 184(18): 4753-4771.
28. Mace TA, Ameen Z, Collins A, et al. Pancreatic cancer-associated stellate cells promote differentiation of myeloid-derived suppressor cells in a STAT3-dependent manner. Cancer Res, 2013, 73(10): 3007-3018.
29. McGranahan N, Swanton C. Clonal heterogeneity and tumor evolution: past, present, and the future. Cell, 2017, 168(4): 613-628.
30. Somani VK, Zhang D, Dodhiawala PB, et al. IRAK4 signaling drives resistance to checkpoint immunotherapy in pancreatic ductal adenocarcinoma. Gastroenterology, 2022, 162(7): 2047-2062.
31. Lybaert L, Lefever S, Fant B, et al. Challenges in neoantigen-directed therapeutics. Cancer Cell, 2023, 41(1): 15-40.
32. Tang S, Shi L, Luker BT, et al. Modulation of the tumor microenvironment by armed vesicular stomatitis virus in a syngeneic pancreatic cancer model. Virol J, 2022, 19(1): 32.
33. Kemp SB, Cheng N, Markosyan N, et al. Efficacy of a small-molecule inhibitor of krasG12D in immunocompetent models of pancreatic cancer. Cancer Discov, 2023, 13(2): 298-311.
34. Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature, 2014, 515(7528): 568-571.
35. Chakrabarti S, Bucheit L, Starr JS, et al. Detection of microsatellite instability-high (MSI-H) by liquid biopsy predicts robust and durable response to immunotherapy in patients with pancreatic cancer. J Immunother Cancer, 2022, 10(6): e004485.
36. Galluzzi L, Buqué A, Kepp O, et al. Immunological effects of conventional chemotherapy and targeted anticancer agents. Cancer Cell, 2015, 28(6): 690-714.
37. Mariathasan S, Turley SJ, Nickles D, et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature, 2018, 554(7693): 544-548.
38. Johnston RJ, Comps-Agrar L, Hackney J, et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8⁺ T cell effector function. Cancer Cell, 2014, 26(6): 923-937.
39. Michelakos T, Kontos F, Barakat O, et al. B7-H3 targeted antibody-based immunotherapy of malignant diseases. Expert Opin Biol Ther, 2021, 21(5): 587-602.
40. Balachandran VP, Łuksza M, Zhao JN, et al. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature, 2017, 551(7681): 512-516.
41. Zemek RM, De Jong E, Chin WL, et al. Sensitization to immune checkpoint blockade through activation of a STAT1/NK axis in the tumor microenvironment. Sci Transl Med, 2019, 11(501): eaav7816.
42. Stadtmauer EA, Fraietta JA, Davis MM, et al. CRISPR-engineered T cells in patients with refractory cancer. Science, 2020, 367(6481): eaba7365.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

The progress and major challenges of immunotherapy for pancreatic cancer

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