The Role of Tumor Microenvironment in Pancreatic Cancer Immunotherapy: Current Status and Future Perspectives
Abstract
:1. Introduction
2. Current Therapies for Pancreatic Cancer
2.1. Surgery
2.2. Chemotherapy
2.3. Radiotherapy
2.4. Targeted Therapies
3. Pancreatic Tumor Microenvironment and Opportunities for Therapeutic Interventions
3.1. Non-Cellular Components and Desmoplasia in the Pancreatic TME
3.2. Non-Immune Cellular Components in the TME
3.2.1. Pancreatic Stellate Cells (PSCs)
3.2.2. Myofibroblastic and Inflammatory CAFs
3.2.3. Endothelial Cells
3.3. Immune Cell Populations in the PDAC TME
3.3.1. Tumor-Associated Macrophages (TAMs)
3.3.2. Myeloid-Derived Suppressor Cells
3.3.3. Natural Killer Cells
3.3.4. Neutrophils
3.3.5. Dendritic Cells
3.3.6. T Lymphocytes
3.3.7. B Lymphocytes
4. Current and Future Immunotherapy Strategies for Pancreatic Cancer
Drug(s) | Mechanism | Population | Clinical Trial/Year of Completion | Phase of Trial | Trial Design/Number of Patients | Primary Endpoint |
---|---|---|---|---|---|---|
CP-870,893 in combination with gemcitabine | CD40 agonist antibody with chemotherapy | Chemotherapy-naïve, surgically incurable PC | NCT00711191 01/2011 | I | Single group assignment/22 | Dose-limiting toxicities (DLTs), adverse events [165] |
Ipilimumab (BMS-734016) and PC vaccine | CTLA-4 inhibitor with allogeneic pancreatic tumor cells transfected with a GM-CSF gene | Locally advanced, unresectable, or metastatic pancreatic adenocarcinoma | NCT00836407 07/2012 | I | Two-arm trial: Ibilimumab alone and Ibilimumab plus PC vaccine/30 | Unacceptable toxicity [180] |
MEDI4736 in combination with nab-paclitaxel and gemcitabine or with AZD5069 | Anti-PD-L1 monoclonal antibody with chemotherapy or CXCR2 antagonist | Metastatic PDAC | NCT02583477 07/2018 | I/II | Parallel assignment/23 | Adverse events, DLTs, ORR |
TG01/GM-CSF with gemcitabine | TG01 and granulocyte macrophage colony-stimulating factor with chemotherapy | Resected adenocarcinoma of the pancreas | NCT02261714 05/2019 | I/II | Single group assignment/32 | Immune responses, adverse events [181] |
Ipilimumab, vaccine, FOLFIRINOX | CTLA-4 inhibitor with allogeneic GM-CSF-transfected pancreatic tumor vaccine against chemotherapy | Metastatic PC | NCT01896869 05/2019 | II | Two-arm trial: Ibilimumab plus vaccine or FOLFIRINOX alone/83 | Overall survival (OS) |
FOLFIRINOX, Losartan, Proton Beam Radiation | Combination of 5-fluorouracil, leucovorin and oxaliplatin with proton beam therapy | Locally advanced disease | NCT01821729 09/2021 | II | Single group assignment/50 | Number of participants with R0 resection |
Cyclophosphamide, GVAX PC vaccine, Pembrolizumab, radiation | Chemotherapy, GM-CSF-secreting allogeneic PC vaccine with PD-1 blockade antibody and stereotactic body radiation therapy | Locally advanced adenocarcinoma of the pancreas | NCT02648282 01/2022 | II | Single group assignment/58 | Distant metastasis-free survival |
Oleclumab (MEDI9447), Durvalumab, Gemcitabine, Nab-paclitaxel, Oxaliplatin, Folinic acid, 5-FU | Anti-CD73 monoclonal antibody, anti-PD-L1 monoclonal antibody in combination with chemotherapy | Metastatic PDAC | NCT03611556 07/2022 | I/II | Parallel assignment/213 | TEAEs, TESAEs, DLTs, abnormal vital signs, electrocardiogram and clinical laboratory parameters, ORR |
Plerixafor and Cemiplimab | CXCR4 inhibitor (small molecule) and PD-1 blocking antibody | Metastatic PC | NCT04177810 05/2023 | II | Single group assignment/25 | ORR |
Cyclophosphamide, Nivolumab, Ipilimumab, GVAX Pancreas Vaccine, CRS-207 | Chemotherapy plus immunotherapy (anti-PD-1 and anti-CTLA-4) plus PC vaccine | Previously treated metastatic pancreatic adenocarcinoma | NCT03190265 08/2023 | II | Parallel assignment with or without PC vaccine/61 | Objective response rate (ORR) |
Drug(s) | Mechanism | Type of Disease | ID | Phase | Trial Design/Number of Patients | Primary Endpoint |
---|---|---|---|---|---|---|
Ipilimumab in combination with pembrolizumab and durvalumab | Combination of three antibodies against PD1, PDL1, and CTLA4 | Advanced solid tumors | NCT05187338 | I/II | Single group assignment/100 (estimated) | Drug safety, progression-free survival (PFS), disease control rate, duration of remission |
XH001 combination with Ipilimumab and gemcitabine /capecitabine | mRNA neoantigen cancer vaccine in combination with immunotherapy that targets CTLA-4 protein on T cells plus chemotherapy | Resected PC | NCT06353646 | N/A | Single-center, open-label, single-arm/12 (estimated) | Efficacy and safety trial |
Tadalafil, Pembrolizumab, Ipilimumab, CRS-207 | PD-1/CTLA-4-blocking antibodies in combination with immunotherapy | Previously treated metastatic PDAC | NCT05014776 | II | Single group assignment/17 (actual) | Objective response rate (irORR) using immune response evaluation criteria for solid tumors (iRECIST) |
KRAS peptide vaccine Nivolumab Ipilimumab | KRAS peptide vaccine with poly-ICLC adjuvant in combination with immunotherapy | Resected mismatch repair protein (MMR-p), Colorectal and PC | NCT04117087 | I | Parallel assignment/30 (estimated) | Number of participants experiencing study drug-related toxicities Fold change in interferon-producing mutant-KRAS-specific cytotoxic (CD8) and helper (CD4) T cells at 16 weeks |
Nivolumab Ipilimumab Stereotactic body radiation therapy Low-dose irradiation | Cytotoxic chemotherapy followed by hypofractionated radiotherapy to sensitize pancreatic cancer to immunotherapy consisting of combined PD-1 and CTLA4 blockade | First-line treatment stage IV pancreatic cancer | NCT05088889 | I | Study arm/10 (estimated) | Objective tumor response rate 1 (ORR1) in study patients, assessed by RECIST v1.1 Objective tumor response rate 2 (ORR2) after first progression, assessed by RECIST v1.1 |
Combination of anetumab ravtansine with Either nivolumab, nivolumab and ipilimumab, or gemcitabine and nivolumab | Monoclonal antibody linked to a chemotherapy drug called DM4 attaches to mesothelin-positive cancer cells and delivers DM4 to kill them. Immunotherapy chemotherapy | Advanced PC | NCT03816358 | I | Parallel assignment/ 74 (estimated) | Maximum tolerated dose (MTD) |
Checkpoint inhibitor (CPI) such as Pembrolizumab plus chemotherapy | Trans-artery/intra-tumor infusion of PD1/PDL1 antibody and/or CTLA4 antibody ipilimumab plus chemotherapeutic drug and comparison of their differences. | Advanced solid tumors | NCT03755739 | II/III | Parallel assignment/200 (estimated) | Overall survival Complete response (CR) rate before or at month 6 |
Nivolumab and Ipilimumab | Immunotherapy with monoclonal antibodies | Rare pancreatic tumors including acinar cell carcinoma, mucinous cystadenocarcinoma, or serous cystadenocarcinoma | NCT02834013 | II | Parallel assignment/818 (estimated) | ORR |
9-ING-41 Losartan Ferumoxytol FOLFIRINOX | Blocking of GSK-3β activity using 9-ING-41 and blocking of TGF-β function using Losartan to inhibit cancer cell resistance to FOLFIRINOX chemotherapy | Metastatic PDAC without prior therapy | NCT05077800 | II | Single group assignment/70 (estimated) | PFS |
Losartan and nivolumab in Combination with FOLFIRINOX and SBRT | Combination chemotherapy. Losartan is used to lower blood pressure. Nivolumab is an antibody that may cause apoptosis. Radiation by stereotactic body radiation therapy | Localized PDAC; borderline/potentially resectable or locally advanced. | NCT03563248 | II | Parallel assignment/168 (actual) | Proportion of participants with R0 resection |
Motixafortide Cemiplimab Gemcitabine Nab-paclitaxel | Combination chemotherapy (gemcitabine and nab-paclitaxel), chemokine (C-X-C) motif receptor 4 inhibitor (BL-8040), and immune checkpoint blockade (Cemiplimab) | Metastatic treatment-naïve PDAC | NCT04543071 | II | Single group assignment/10 (estimated) | Overall response rate (complete response (CR) + partial response (PR)) |
Durvalumab Rintatolimod | Combination therapy of ICI therapy with a toll-like receptor 3 (TLR-3) agonist | Metastatic PC | NCT05927142 | I/II | Sequential assignment/43 (estimated) | Phase Ib: Determine safety of combination therapy with durvalumab and rintatolimod Phase II: Determine the clinical benefit rate of combination therapy with durvalumab and rintatolimod. |
PT199 Tislelizumab | PT199 counters the adenosine-mediated immunosuppressive TME, rendering anti-tumor immune cells more responsive to checkpoint immunotherapies, such as PD-1/PD-L1 inhibitors | Advanced solid tumors | NCT05431270 | I | Sequential assignment/40 (estimated) | MTD, DLT, Safety of PT199 |
IMM-101, Pembrolizumab, Gemcitabine | Combination of a heat-inactivated mycobacterium, immune modulator with chemotherapy | Metastatic PC | NCT06498518 | II | Single group assignment/50 (estimated) | ORR |
Ipilimumab Nivolumab Radiation Therapy | Ipilimumab inhibits cancer cell growth. Nivolumab induces apoptosis. Radiation therapy may increase the likelihood of response to interventions. | Metastatic, microsatellite-stable PC | NCT04361162 | II | Single group assignment/30 (estimated) | ORR |
Pembrolizumab With Olaparib | PD-1 inhibitor in combination with PARP inhibitor | Metastatic PDAC with mismatch repair deficiency or tumor mutation burden > 4 mutations/Mb | NCT05093231 | II | Single group assignment/20 (estimated) | ORR |
Nivolumab Ipilimumab SBRT TGFβ-B-15 peptide | Combination of checkpoint-blocking antibodies with immunomodulation of the TME; TGFβ-15 immune response is correlated to clinical benefit | Refractory PC | NCT05721846 | I | Single group assignment/20 (estimated) | Adverse effects |
Pembrolizumab Folfirinox SABR | Combination of chemotherapy, PD-1 inhibition, and radiotherapy | Borderline resectable PC | NCT06384560 | I/II | Single group assignment/66 (estimated) | Percentage of patients with progression free survival at 18 months (RECIST 1.1) |
Lenvatinib Pembrolizumab | Inhibition of cell growth, PD-1 inhibition | Advanced unresectable PC | NCT04887805 | II | Single group assignment/28 (estimated) | PFS |
Pembrolizumab With Olaparib/Olaparib alone | PD-1 inhibitor in combination with PARP inhibitor | Advanced PC with germline BRCA1 or BRCA2 mutations | NCT04548752 | II | Parallel assignment /88 (estimated) | PFS |
Pembrolizumab Defactinib | Reprogramming the TME by targeting FAK following chemotherapy to potentiate anti-PD-1 antibody | Resectable PDAC | NCT03727880 | II | Parallel assignment /36 (estimated) | Pathologic complete response (pCR) rate |
SBRT Nivolumab CCR2/CCR5 dual antagonist GVAX | Combination therapy to enhance the infiltration of CD8+CD137+ cells in PDAC | Locally advanced PDAC | NCT03767582 | I/II | Sequential assignment /30 (estimated) | Number of Participants experiencing study drug-related toxicities Percentage of participants treated with immunotherapy who achieve an immune response |
Nivolumab Ipilimumab SBRT Low dose irradiation | Cytotoxic chemotherapy followed by hypofractionated radiotherapy to sensitize PC to combined PD-1 and CTLA4 blockade | Stage IV PDAC | NCT05088889 | I | Single group assignment/10 (estimated) | Objective tumor response rate 1 (ORR1) in study patients, assessed by RECIST v1.1 Objective tumor response rate 2 (ORR2) after first progression, assessed by RECIST v1.1 |
Nivolumab Ipilimumab Hydroxychloroquine (HCQ) | Immunotherapy in combination with standard-of-care chemotherapy | Previously untreated PDAC | NCT04787991 | I | Parallel assignment/45 (estimated) | Incidence and severity of adverse events |
Tumor-Infiltrating Lymphocytes Pembrolizumab | Autologous tumor-infiltrating lymphocytes following a lymphodepleting regimen plus PD-1 inhibition | Metastatic PC | NCT01174121 | II | Parallel assignment/332 (estimated) | Response rate |
Epacadostat Pembrolizumab CRS-207 | IDO-1 inhibition, PD-1 inhibition, stimulation of immune response to mesothelin | Metastatic PC | NCT03006302 | II | Parallel assignment/ 41 (estimated) | MTD 6-month survival |
Atezolizumab Tivozanib | Inhibition of VEGF, inhibition of PD-1 | Immunogenically cold PDAC | NCT05000294 | I/II | Sequential assignment/29 (estimated) | ORR |
Gemcitabine, Nab-paclitaxel, Capecitabine, Cisplatin, Irinotecan Olaparib and Pembrolizumab | Low-dose chemotherapy followed by maintenance with PD-1 and PARP inhibition | Metastatic untreated PDAC | NCT04753879 | II | Single group assignment/38 (estimated) | PFS |
mFOLFIRINOX Verteporfin Pembrolizumab | Photoradiation with verteporfin, PD-1 inhibition plus standard-of-care chemotherapy | Locally Advanced or Metastatic PC | NCT06381154 | II | Single group assignment /25 (estimated) | ORR |
Nivolumab Ipilimumab Radiation Therapy | Blocking PD-1/PD-L1 and CTLA-4 pathways | PC | NCT03104439 | II | Single group assignment /80 (estimated) | Disease control rate |
Gemcitabine Nab-paclitaxel Nivolumab | ICIs with chemotherapy | Borderline resectable, locally advanced or mPC | NCT03970252 | I/II | Single group assignment /40 (estimated) | Incidence of treatment-related AEs, SAEs, AEs leading to discontinuation, death, and laboratory abnormalities |
Futibatinib Pembrolizumab Cisplatin | ICIs with chemotherapy | PDAC | NCT05945823 | II | Parallel group assignment /40 (estimated) | ORR |
LGK974 PDR001 | PORCN inhibitor PD-1 inhibitor | PC that has progressed despite standard therapy or for which no effective standard therapy exists | NCT01351103 | I | Single group assignment/185 (actual) | Maximum tolerated dose or recommended dose for expansion of LGK974 as a single agent or in combination with PDR001 in treated patients |
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Poyia, F.; Neophytou, C.M.; Christodoulou, M.-I.; Papageorgis, P. The Role of Tumor Microenvironment in Pancreatic Cancer Immunotherapy: Current Status and Future Perspectives. Int. J. Mol. Sci. 2024, 25, 9555. https://doi.org/10.3390/ijms25179555
Poyia F, Neophytou CM, Christodoulou M-I, Papageorgis P. The Role of Tumor Microenvironment in Pancreatic Cancer Immunotherapy: Current Status and Future Perspectives. International Journal of Molecular Sciences. 2024; 25(17):9555. https://doi.org/10.3390/ijms25179555
Chicago/Turabian StylePoyia, Fotini, Christiana M. Neophytou, Maria-Ioanna Christodoulou, and Panagiotis Papageorgis. 2024. "The Role of Tumor Microenvironment in Pancreatic Cancer Immunotherapy: Current Status and Future Perspectives" International Journal of Molecular Sciences 25, no. 17: 9555. https://doi.org/10.3390/ijms25179555