Clinical Strategies Targeting the Tumor Microenvironment of Pancreatic Ductal Adenocarcinoma
Abstract
Simple Summary
Abstract
1. Introduction
2. TME in PDAC
3. PDAC Is Defined by an Immunosuppressive TME
4. Targeting the PDAC TME with Immune-Modulating Agents
4.1. CD40 Agonists
4.1.1. Role of CD40 in Immunity and Rationale for Its Use in Cancer Patients
4.1.2. Clinical Trials of CD40 Agonists in PDAC Patients
4.2. CXCR4-CXCL12 Axis
4.2.1. Pre-Clinical Rationale
4.2.2. Clinical Studies Targeting the CXCR4-CXCL12 Axis
4.3. Colony-Stimulating Factor Receptor (CSF-1R)
4.3.1. Pre-Clinical Rationale
4.3.2. Clinical Data with CSF-1R Inhibitors
4.4. CD11b
4.5. STING (Stimulator of Interferon Response cGAMP Interactor) Pathway
4.6. CCR2
4.7. CD73/A2A Adenosine Receptor
5. Targeting the Stroma
5.1. FAK Inhibitors
5.2. IL-6
5.3. Vitamin D
5.4. All-Trans Retinoic Acid (ATRA)
5.5. Vascular Endothelial Growth Factor (VEGF)
5.6. Integrins
5.7. Hyaluronan
5.8. Losartan
6. Summary and Perspective
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Mechanism of Action | NCT | Status | Agent | Combination | Phase | PDAC Patient Population | Results Reported? |
---|---|---|---|---|---|---|---|
Targeting immune cells | |||||||
CD40 agonist | NCT00711191 | Comp | Selicrelumab (CP-870,893; RO7009789) | gemcitabine | 1 | advanced | x |
NCT01456585 | Comp | Selicrelumab | Perioperative chemoradiation (gemcitabine) | 1 | resectable | ||
NCT02588443 | Comp | Selicrelumab | ±GN | 1 | resectable | x | |
NCT03193190 | Recr | Selicrelumab | GN + atezolizumab | 1/2 | advanced | ||
NCT03214250 | A-NR | Sotigalimab (APX005M) | GN ± nivolumab | 1b/2 | metastatic | x | |
NCT04536077 | Recr | CDX-1140 | ±CDX-301 (FLT3L) | 1 | resectable | ||
NCT02376699 | A-NR | SEA-CD40 | pembrolizumab ± GN | 1 | advanced | x | |
NCT04888312 | Recr | Mitazalimab | mFFX | 1/2 | metastatic | x | |
Oncovirus: trimerized CD40L and 4-1BBL | NCT02705196 | Recr | LOAd703 (delolimogene mupadenorepvec) | GN, atezolizumab | 1/2 | advanced | x |
NCT03225989 | Recr | LOAd703 | chemo | 1/2 | advanced | x | |
CXCR4 antagonist | NCT02179970 | Comp | Plerixafor (AMD3100) | 1 | advanced | ||
NCT04177810 | Recr | Plerixafor | cemiplimab (anti-PD-1) | 2 | metastatic | ||
NCT02907099 | A-NR | Motixafortide (BL-8040) | pembrolizumab | 2 | metastatic | x | |
NCT02826486 | A-NR | Motixafortide | pembrolizumab ± Nal-iri/5-FU | 2 | metastatic | x | |
NCT4543071 | Recr | Motixafortide | cemiplimab + GN | 2 | |||
CXCL12 antagonist | NCT03168139 | Comp | Olaptesed Pegol (NOX-A12) | pembrolizumab | 1/2 | metastatic | x |
NCT04901741 | NYR | Olaptesed Pegol (NOX-A12) | pembrolizumab, Nal-iri/5-FU or GN | 2 | MSS metastatic | ||
CSF1R inhibitor | NCT03153410 | A-NR | IMC-CS4 (LY3022855) | pembrolizumab, GVAX, cyclophosphamide | 1 | BR | |
NCT02777710 | Comp | Pexidartinib | durvalumab | 1 | advanced | x | |
NCT02713529 | Comp | AMG 820 | pembrolizumab | 1/2 | advanced | x | |
CD11b agonist | NCT04060342 | A-NR | ADH-503 (GB1275) | pembrolizumab or GN | 1/2 | advanced | |
STING agonist | NCT05070247 | Recr | TAK-500 | ±pembrolizumab | 1 | advanced | |
NCT03010176 | Comp | ulevostinag (MK-1454) | ±pembrolizumab | 1 | advanced | x | |
CCR2 antagonist | NCT01413022 | Comp | PF-04136309 | mFFX | 1 | BR | x |
NCT02732938 | Term | PF-04136309 | GN | 1/2 | metastatic | x | |
NCT02345408 | Comp | CCX872-B | FFX | 1 | advanced | x | |
CCR2-CCR5 dual antagonist | NCT03184870 | A-NR | BMS-813160 | ±nivolumab or chemo | 1/2 | advanced | |
CD73/Adenosine Receptor inhibition | NCT02503774 | A-NR | Oleclumab (MEDI9447) | ±durvalumab | 1 | advanced | x |
NCT03611556 | A-NR | Oleclumab | durvalumab and/or chemo | 1/2 | metastatic | ||
NCT03207867 | A-NR | Taminadenant (NIR178) | ±spartalizumab (anti-PD-1) | 2 | advanced | ||
NCT03549000 | A-NR | NZV930 ± taminadenant | ±spartalizumab | 1 | advanced | ||
NCT04104672 | Recr | Quemliclustat (AB680) | GN ± zimberelimab (anti-PD-1) | 1 | metastatic | x |
Mechanism of Action | NCT | Status | Agent | Combination | Phase | PDAC Patient Population | Results Reported? |
---|---|---|---|---|---|---|---|
Direct stroma targeting | |||||||
FAK inhibitor | NCT03727880 | Recr | ±defactinib | pembrolizumab | 2 | resectable | |
NCT04331041 | Recr | ±defactinib | SBRT | 2 | locally advanced | ||
NCT02546531 | Comp | defactinib | pembrolizumab + gemcitabine | 1 | advanced | x | |
NCT02428270 | A-NR | GSK2256098 | trametinib | 2 | advanced | ||
IL-6 antagonist | NCT04191421 | Recr | Siltuximab | spartalizumab (PD-1) | 1/2 | metastatic | |
NCT02767557 | A-NR | ±tocilizumab | GN | 2 | advanced | ||
NCT04258150 | Term | tocilizumab | Nivolumab + ipilimumab + XRT | 2 | advanced | ||
NCT03193190 | Recr | tocilizumab | GN + atezolizumab | 1/2 | metastatic | ||
VitD receptor agonist | NCT02030860 | Comp | ±paricalcitol | GN | 1 | resectable | |
NCT02930902 | A-NR | paricalcitol | pembrolizumab, ±GN | 1 | resectable | ||
NCT02754726 | A-NR | paricalcitol | Pembrolizumab + GN + cisplatin | metastatic | x | ||
NCT03520790 | Recr | paricalcitol | GN | 2 | metastatic | ||
NCT03331562 | Comp | ±paricalcitol | pembrolizumab | 2 | Metastatic, maint | x | |
ATRA | NCT03307148 | Comp | ATRA | GN | 1 | advanced | |
NCT04241276 | A-NR | ATRA | GN | 2 | locally advanced | ||
VEGF inhibition | NCT03797326 | A-NR | lenvatinib | pembrolizumab | 2 | advanced | |
NCT04887805 | Recr | lenvatinib | pembrolizumab | 2 | advanced, maint | ||
NCT05327582 | Recr | lenvatinib | durvalumab, nab-paclitaxel | 1/2 | advanced | ||
NCT05303090 | Recr | lenvatinib | H-101, tislelizumab | 1b | advanced | ||
NCT03193190 | Recr | bevacizumab | GN, atezolizumab | 1/2 | metastatic | ||
Integrin inhibitor | NCT00401570 | Comp | volociximab | gemcitabine | 2 | metastatic | x |
Integrin cytotoxin | NCT05085548 | Recr | ProAgio | 1 | advanced | ||
Hyaluronan dissolution | NCT01453153 | Comp | ±PEGPH20 | gemcitabine | 1/2 | metastatic | x |
NCT01839487 | Comp | ±PEGPH20 | GN | 2 | metastatic | x | |
NCT02715804 | Comp | ±PEGPH20 | GN | 3 | metastatic | x | |
NCT01959139 | A-NR | ±PEGPH20 | FFX | 1/2 | metastatic | x | |
NCT02910882 | Term | PEGPH20 | XRT + gemcitabine | 2 | Locally advanced | ||
NCT02241187 | Comp | PEGPH20 | cetuximab | - | resectable | ||
NCT03193190 | Recr | PEGPH20 | atezolizumab | 1/2 | metastatic | x | |
Angiotensin II receptor blockade | NCT01821729 | A-NR | losartan | FFX + XRT | 2 | Locally advanced | x |
NCT03563248 | Recr | ±losartan | FFX + SBRT + surgery, ± nivolumab | 2 | Resectable, BR or locally advanced | ||
NCT04106856 | Recr | losartan | Hypofractionated radiation | 1 | BR or locally advanced | ||
NCT05077800 | Recr | ±losartan | FFX ± elraglusib (9-ING-41; GSK-3β inhibitor) | 2 | metastatic | ||
NCT05365893 | Recr | losartan | Paricalcitol + hydroxychloroquine | 1 | resectable | ||
NCT04539808 | Recr | losartan | mFFX ± switch to GN followed by capecitabine/XRT | 2 | Resectable, BR or locally advanced |
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Skorupan, N.; Palestino Dominguez, M.; Ricci, S.L.; Alewine, C. Clinical Strategies Targeting the Tumor Microenvironment of Pancreatic Ductal Adenocarcinoma. Cancers 2022, 14, 4209. https://doi.org/10.3390/cancers14174209
Skorupan N, Palestino Dominguez M, Ricci SL, Alewine C. Clinical Strategies Targeting the Tumor Microenvironment of Pancreatic Ductal Adenocarcinoma. Cancers. 2022; 14(17):4209. https://doi.org/10.3390/cancers14174209
Chicago/Turabian StyleSkorupan, Nebojsa, Mayrel Palestino Dominguez, Samuel L. Ricci, and Christine Alewine. 2022. "Clinical Strategies Targeting the Tumor Microenvironment of Pancreatic Ductal Adenocarcinoma" Cancers 14, no. 17: 4209. https://doi.org/10.3390/cancers14174209
APA StyleSkorupan, N., Palestino Dominguez, M., Ricci, S. L., & Alewine, C. (2022). Clinical Strategies Targeting the Tumor Microenvironment of Pancreatic Ductal Adenocarcinoma. Cancers, 14(17), 4209. https://doi.org/10.3390/cancers14174209