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Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with a five-year survival rate of approximately 5–10%. The immune checkpoint blockade represented by PD-1/PD-L1 inhibitors has been effective in a variety of solid tumors.
- pancreatic ductal adenocarcinoma
- immune checkpoint
- cancer immunotherapy
- PD-L1
1. Introduction
Despite the advancements in conventional systemic therapy, pancreatic ductal adenocarcinoma (PDAC)PDAC is one of the most aggressive cancers, with a 5-year survival rate approaching 5–10% in 2020 [1][2][1,2]. In 2021, it became the third leading cause of cancer-related mortality and is projected to overtake lung cancer as the second leading cause by 2030 [3]. Since most patients (80–85%) have locally advanced or metastatic cancer at first diagnosis, conventional chemotherapy based on drugs such as fluorouracil and gemcitabine remain the main treatment for patients with PDAC. Metastatic PDAC has a median overall survival (OS) of less than a year, and locally-progressing unresectable PDAC is only marginally better [4][5][4,5].
PDAC patients account for over 90% of all cases of pancreatic cancer. The majority of PDAC originate from pancreatic intraepithelial neoplasias, which advance through the acquisition of genetic changes and culminate in the formation of overt PDAC. A minority of PDAC arises from cystic neoplasms [4]. PDAC is characterized histologically by a severely desmoplastic tumor microenvironment (TME), which comprises around 70% of tumor tissue. This fibrotic milieu is produced by cancer-associated fibroblasts (CAFs) [6]. The TME of PDAC consists of immune cells, CAFs, neurons, vessels, and extracellular matrix components such as collagen, fibronectin, and hyaluronic acid [7].
Over the past decade, inhibiting the PD-L1/PD-1 pathway has shown promising results. Although good clinical responses have been achieved in some solid and hematologic tumors, such as melanoma and non-small cell lung cancer (NSCLC), PDAC is mostly resistant to immunotherapies [8]. The profoundly immunosuppressive TME of PDAC should be primarily responsible for this outcome, as regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC), and numerous M2 tumor-associated macrophages (TAM) infiltrate the TME and inhibit the migration and activation of T cells [6][9][6,9]. In addition to the regulatory immunological signature, an effector immune infiltrate, including CD3, CD4, and CD8 T cells, is also present in PDAC [10][11][10,11]. The B7 family is an immunoglobulin superfamily, and secondary signaling for T cell activation is dependent on the B7 family. Immune checkpoints of the B7 family play a key role in regulating the critical bidirectional signals that drive T cell activation and self-tolerance. The B7 family can produce positive signals to initiate and sustain T cell activity as well as negative signals to regulate and inhibit T cell responses. Ultimately, the T cell immune response is determined by the equilibrium between co-stimulatory and co-inhibitory signals [12][13][12,13]. The T cells that infiltrate the TME of PDAC interact with tumor cells (TCs) and immunosuppressive cells, exhibiting an “exhausted” phenotype. When the PD-1/PD-L1 pathway is disrupted, clinical trials show no clinical effect on PDAC, indicating that T cells’ anti-tumor function cannot be restored. This disappointing result demonstrates the urgent need to discover more novel immune checkpoints in the TME of PDAC [14][15][14,15].
The B7 family members have attracted much attention due to their crucial roles in immune evasion and tumorigenesis, and a variety of preclinical and clinical treatments have been established based on them. To date, the B7 family consists of 11 members: B7-1 (CD80), B7-2 (CD86), B7-H1 (PD-L1, CD274), PD-L2 (PDCD1LG2, B7-DC, CD273), B7-H2 (CD275, ICOS-L, B7RP1), B7-H3 (CD276), B7-H4 (B7x, Vtcn1, B7S1), VISTA (B7-H5, GI24, DD1α, SISP1), B7-H6 (NCR3LG1), HHLA2 (B7-H7), and ILDR2 [13]. It has been shown that some B7 family members receive multiple signaling pathways and are widely expressed on a variety of different cell surfaces in the TME of PDAC. Some molecules belonging to the B7 family in the TME of PDAC have been proven to not only regulate the activation or suppression signals of immune cells but also participate in tumor development, invasion, drug resistance, and epithelial-mesenchymal transition (EMT) independent of their immune functions [12][16][17][18][19][12,16,17,18,19].
2. PD-L1
This programmed cell death ligand 1 (PD-L1), which belongs to the B7 family, is a ligand for PD-1 found in a variety of tumors. A high expression level of PD-L1 is found primarily in TCs but can also be found in epithelial cells, macrophages, dendritic cells, lymphocytes, etc., in the TME of PDAC [20][21][20,21]. PD-1 is predominantly expressed in activated lymphocytes. The PD-1 and PD-L1 signaling pathways can suppress the activation of immune cells and induce T cell apoptosis, leading to the exhaustion of activated immune cells and promoting the infiltration of Tregs [22]. Soluble PD-L1, which is a type of PD-L1, is detected in the blood of some patients with PDAC and has predictive significance [23][24][23,24]. Multiple studies have demonstrated the association between a high expression level of PD-L1 in patients with PDAC and a poor prognosis [21][22][24][21,22,24].
Immune checkpoint monoclonal antibody (mAb) inhibitors targeting PD-1/PD-L1 have achieved higher objective response rates (ORR) with very few adverse events in patients with hematological tumors and numerous solid tumors, such as NSCLC, gastric cancer, and melanoma, by disrupting the immunosuppressive microenvironment and reactivating T cells [8][25][26][8,25,26]. However, the benefit of PD-1/PD-L1 inhibitors alone in patients with PDAC is limited due to the complex TME, which exhibits an immunosuppressive immune “desert” phenotype [27]. In a phase I multicenter study in 2012 that included 207 cancer patients to receive an anti-PD-L1 antibody, no objective response was observed in 14 patients with PDAC [28]. To overcome resistance to PD-1/PD-L1 inhibitors and combine different anti-tumor treatment mechanisms, clinical researchers are combining PD-1/PD-L1 inhibitors with chemotherapy, radiotherapy, targeted therapy, or other immunotherapies [28]. Multiple therapeutic strategies that are being evaluated are summarized in Table 1.
Table 1.
Ongoing clinical trials targeting B7 family members in PDAC.
| Agent/Drug | Combination Regimens | Targets | Phase | Number Enrolled | Trial ID | Primary Outcome(s) |
|---|---|---|---|---|---|---|
| Pembrolizumab | Cyclophosphamide + GVAX + SBR | PD-1 | II | 58 | NCT02648282 | DMFS |
| Defactinib | PD-1 | I/II | 59 | NCT02758587 | AEs, DLTs, MTD | |
| Cyclophosphamide + GVAX + IMC-CS4 | PD-1 | Early I | 12 | NCT03153410 | CD8 T cell density, AEs | |
| Epacadostat + CRS-207 + CY + GVAX | PD-1 | II | 40 | NCT03006302 | DMFS | |
| Olaparib | PD-1 | II | 20 | NCT05093231 | ORR | |
| Cabozantinib | PD-1 | II | 21 | NCT05052723 | PFS | |
| Defactinib | PD-1 | II | 36 | NCT03727880 | pCR rate | |
| ENB003 | PD-1 | I/II | 130 | NCT04205227 | ORR, TRAEs | |
| ONC-392 | PD-1 | I/II | 468 | NCT04140526 | DLT, MTD, TRAEs, RP2D | |
| Tadalafil Ipilimumab CRS-207 |
PD-1 | II | 20 | NCT05014776 | ORR | |
| PEGPH20 | PD-1 | II | 35 | NCT03634332 | PFS | |
| Lenvatinib | PD-1 | II | 590 | NCT03797326 | ORR (initial), ORR (expansion), AEs, Discont due to AE | |
| V941 | PD-1 | I | 100 | NCT03948763 | DLTs, AEs | |
| CPI-006 + ciforadenant | PD-1 | I | 378 | NCT03454451 | Incidence of DLTs, TRAEs; MDL | |
| INT230-6 + anti-CTLA-4 antibody | PD-1 | I/II | 110 | NCT03058289 | TRAEs | |
| BCA101 | PD-1 | I | 292 | NCT04429542 | DLTs, safety, tolerability | |
| Spartalizumab | Siltuximab | PD-1 | I/II | 42 | NCT04191421 | MTD |
| Canakinumab injection + nab-paclitaxel + gemcitabine | PD-1 | I | 10 | NCT04581343 | RP2/3D | |
| Dostarlimab | Niraparib | PD-1 | II | 20 | NCT04493060 | DCR |
| Sintilimab | Gemcitabine + Albumin-paclitaxel | PD-1 | II | 20 | NCT05346146 | % R0 resection |
| Surufatinib + AG | PD-1 | II | 32 | NCT05481476 | ORR | |
| Toripalimab | Anlotinib + Nab-paclitaxel | PD-1 | II | 53 | NCT04718701 | PFS |
| YH003 + Nab-paclitaxel + Gemcitabine | PD-1 | II | 129 | NCT05031494 | ORR | |
| Camrelizumab | Nab paclitaxel + Gemcitabine Injection | PD-1 | II | 117 | NCT04498689 | ORR, PFS |
| Chemotherapy + Ablation | PD-1 | Not Applicable | 34 | NCT04420130 | 6-month PFS rate | |
| Surufatinib + nab-paclitaxel + S-1 gemcitabine |
PD-1 | II | 68 | NCT05218889 | DLTs, ORR, RP2D | |
| Paclitaxel (Albumin Bound) + Gemcitabine + Placebo | PD-1 | III | 401 | NCT04674956 | PFS | |
| Apatinib | PD-1 | II | 48 | NCT04415385 | ORR | |
| Capecitabine | PD-1 | I | 20 | NCT04932187 | AEs | |
| Nivolumab | Tadalafil + oral vancomycin | PD-1 | II | 22 | NCT03785210 | BOR |
| Recombinant Human IL12/15-PDL1B Oncolytic HSV-1 Injection (Vero Cell) | PD-1 | I/II | 51 | NCT05162118 | DCR (phase 2), MTD, AEs, DLT (phase 1), RP2D (phase 1) | |
| Cyclophosphamide + Ipilimumab + GVAX Pancreas Vaccine + CRS-207 | PD-1 | II | 63 | NCT03190265 | ORR | |
| Ipilimumab + Stereotactic body radiation therapy + Low dose irradiation | PD-1 | I | 10 | NCT05088889 | ORR | |
| Nivolumab | Anetumab Ravtansine + Gemcitabine Hydrochloride + Ipilimumab | PD-1 | I/II | 74 | NCT03816358 | MTD |
| Irreversible Electroporation (IRE) + Toll-Like Receptor 9 | PD-1 | I | 18 | NCT04612530 | Safety | |
| Irreversible electroporation (IRE) | PD-1 | II | 12 | NCT05435053 | Safety, tolerability | |
| SX-682 | PD-1 | I | 20 | NCT04477343 | MTD | |
| Cyclophosphamide + GVAX Pancreas Vaccine + Stereotactic Body Radiation (SBRT) | PD-1 | II | 30 | NCT03161379 | CD8 count in the TME | |
| Cabiralizumab | PD-1 | I | 313 | NCT02526017 | ORR, RD, Safety | |
| AK105 | Anlotinib | PD-1 | I/II | 29 | NCT04803851 | DCR |
| Camrelizumab | Paclitaxel (Albumin Bound) + Gemcitabine | PD-1 | III | 401 | NCT04674956 | PFS |
| Anti-PD-1 mAb | PD-1 | III | 830 | NCT03983057 | PFS | |
| Anti-PD-1 antibody | Chemotherapy | PD-1 | III | 110 | NCT03977272 | OS |
| Radiation | PD-1 | II | 21 | NCT03374293 | Local control | |
| SBRT | PD-1 | I | 36 | NCT03716596 | OS | |
| Radiotherapy + Gemcitabine + cisplatin + Apatinib | PD-1 | 150 | NCT04365049 | PFS | ||
| Durvalumab | Gemcitabine | PD-L1 | II | 71 | NCT03572400 | DFS |
| Tremelimumab + Gemcitabine + Minimally Invasive Surgical Microwave Ablation | PD-L1 | II | 20 | NCT04156087 | PFS | |
| Olaparib + Radiation Therapy | PD-L1 | I | 18 | NCT05411094 | DLTs | |
| Radiotherapy + Tremelimumab | PD-L1 | I | 30 | NCT02639026 | Number of AEs | |
| Gemcitabine + Nab-paclitaxel + Oleclumab | PD-L1 | II | 30 | NCT04940286 | Incidence of AEs, RR | |
| Romidepsin + Azacitidine + nab-Paclitaxel + Gemcitabine + Lenalidomide capsule | PD-L1 | I/II | 75 | NCT04257448 | RDE, safety and tolerability | |
| Capecitabine + Bevacizumab + CV301 | PD-L1 | I/II | 8 | NCT03376659 | PFS(4 and 8.5 month) RP2D | |
| Oleclumab+gemcitabine + nab-paclitaxel + oxaliplatin + leucovorin + 5-FU | PD-L1 | I/II | 212 | NCT03611556 | Incidence of AEs, clinically significant ECG abnormalities and laboratory values, ORR | |
| Tazemetostat | PD-L1 | II | 173 | NCT04705818 | Assessment of antitumor activity | |
| Galunisertib | PD-L1 | I | 37 | NCT02734160 | DLTs | |
| Avelumab | Aldoxorubicin HCl + ALT-803 + ETBX-011 + GI-4000 etc. | PD-L1 | I/II | 173 | NCT03387098 | Incidence of AEs and SAEs, ORR |
| ALT-803 + ETBX-011 + GI-4000 + haNK etc. | PD-L1 | I/II | 80 | NCT03329248 | Incidence of AEs and SAEs, ORR | |
| Aldoxorubicin HCl + ALT-803 + ETBX-011 + ETBX-021 etc. | PD-L1 | I/II | 173 | NCT03586869 | Incidence of AEs and SAEs, ORR | |
| Cyclophosphamide + Oxaliplatin + Capecitabine + 5-Fluorouracil etc. | PD-L1 | I/II | 3 | NCT03136406 | Incidence of AEs and SAEs, ORR | |
| Atezolizumab | Cabozantinib | PD-L1 | II | 29 | NCT04820179 | ORR or stable disease |
| KY1044 | PD-L1 | I/II | 412 | NCT03829501 | Safety, tolerability, DLTs, ORR, survival rate | |
| FT500 + Nivolumab + Pembrolizuma + Cyclophosphamide etc. | PD-L1 | I | 37 | NCT03841110 | DLTs | |
| RO7198457 + mFOLFIRINOX | PD-L1 | I | 29 | NCT04161755 | Toxicity | |
| MEDI4736 | Tremelimumab | PD-L1 | II | 64 | NCT02527434 | OR |
| SHR-1701 (PD-L1/TGF-β bsAb) | PD-L1 | I/II | 56 | NCT04624217 | ORR, RP2D | |
| Pembrolizumab | Cabozantinib (RKTs Inhibitor) | PD-L2 | II | 21 | NCT05052723 | PFS |
| PEGPH20 | PD-L2 | II | 35 | NCT03634332 | PFS | |
| CD276 CAR-T cells | B7-H3 | I/II | 10 | NCT05143151 | ORR | |
| MGD009 (B7-H3/CD3 bsAb) | B7-H3 | I | 67 | NCT02628535 | AEs | |
| SGN-B7H4V (B7-H4 ADC) | B7-H4 | I | 375 | NCT05194072 | AEs, DLTs, laboratory abnormalities | |
| HS-20089 (B7-H4 ADC) | B7-H4 | I | 177 | NCT05263479 | MTD | |
| JNJ-61610588 (B7-H5 mab) | VISTA | I | 12 | NCT02671955 | Markers of monocyte activation, T-cell activation, immune infiltration; total blood cell counts; protein expression of VISTA; DLTs; AEs; SAEs |
DMFS, distant metastasis-free survival; AEs, adverse events; SAEs, serious AEs; DLTs, dose limiting toxicities; MTD, maximum tolerated dose; ORR, objective response rate; PFS, progression-free survival; pCR rate, pathologic complete response (pCR) rate; TRAE, rate of treatment related adverse events; RP2D, recommended phase 2 dose; MTD, maximal tolerated dose; BOR, best overall response; RD, recommended dose; DCR, disease control rate; OS, overall survival; RR, major pathological response rate; RDE, recommended dose for expansion; TEAEs, treatment-emergent AEs.
Although the combination of PD-1/PD-L1 inhibitors with chemotherapy, radiotherapy, or targeted therapy did not produce the expected results in terms of progression-free survival (PFS) and OS, an overall improvement was observed in some clinical trials [29][30][29,30]. In a phase Ib clinical trial, 12 patients with metastatic pancreatic cancer were treated with the CD40 agonist APX005M (Sotigalimab, 0.1 mg/kg or 0.3 mg/kg on day 3 or 10), gemcitabine (1000 mg/m2 on days 1, 8, and 15 every 4 weeks), and nab-paclitaxel (125 mg/m2 on days 1, 8, and 15 every 4 weeks) in combination with the anti-PD-1 mAb nivolumab (240 mg on day 1, 15 cases every 4 weeks). Among them, eight individuals achieved a partial response (PR) and three exhibited stable disease. The cycles of chemotherapy and dose reduction (except for nivolumab) were permitted to control toxicity. The medicine exhibited an excellent safety profile, with a median PFS of 10.8 months (0.1 mg/kg APX005M) and 12.4 months (0.3 mg/kg APX005M), but further clinical trials are necessary to verify its clinical efficacy [31]. A PD-1 inhibitor plus a CD40 agonist produced a better clinical response. Moreover, unlike partial blocking of tumor progression or invasive signals, CD40 agonists are “ignition” signals that promote the initiation of immune responses in PDAC, contributing to anti-tumor immunity dependent on CD8 T cells and activated antigen-presenting cells (APCs) [32]. Combining PD-1/PD-L1 blockade and anti-CTLA-4 therapy is based on the theory that they function at different phases of the immune response. The overall response rates for single- and double-dose immune checkpoint blockade in combination with anti-PD-1 and anti-CTLA-4 drugs were 0% and 3%, respectively [28][33][28,33]. The comparison between gemcitabine and nab-paclitaxel plus the anti-PD-L1 mAb dulvalumab versus the CTLA-4 inhibitor tremelimumab has been made in a randomized, multicenter, phase II trial (NCT02879318) to assess the safety and efficacy of combination chemotherapy/immune checkpoint inhibitors (ICI) for PDAC. In an unselected group of patients with PDAC, adding dulvalumab and tremelimumab to gemcitabine and nab-paclitaxel as the first-line therapy failed to improve survival [34]. Other studies have shown that most effects of monotherapy are additive in the context of combination therapy to facilitate the expansion of phenotypically deficient CD8 T cells converted to activated effector CD8 T cells [35], demonstrating the good prospect of PD-L1 in combination with other new checkpoints for cancer treatment. However, PD-L1 with CTLA4 may not be the optimal choice for PDAC, and additional immune checkpoints need to be sought [28][33][34][28,33,34]. Furthermore, the combination of multiple immunotherapies, such as TGF-β inhibitors, oncolytic viruses, tumor vaccines, and adoptive cell therapy, has shown a good safety and tolerability profile, but clinical outcomes must be evaluated further [29][30][36][29,30,36].
Several studies have revealed that PD-L1 expression in tumor membranes of patients with PDAC is not associated with treatment response or PFS, and microsatellite instability-high/defective mismatch repair status is considered a more reliable biomarker than PD-L1 for predicting the efficacy of immunotherapy in PDAC [37][38][37,38]. Unfortunately, even so, only a small percentage (1–2%) of PDACs are microsatellite instability-high [39]. More diagnostic markers are needed to predict immunotherapy prognosis, in addition to the development of additional systemic treatment strategies with the PD-L1 inhibitors. Importantly, future immunotherapy for PDAC will benefit more from the discovery of novel immunosuppressive targets and mechanisms in these patients.