. 2017 Sep 4;28(12):2950–2961. doi: 10.1093/annonc/mdx503

Table 3.

Selected trials assessing novel immunomodulatory agents in PDAC

Identification	Trial and strategy	Mechanism of action	Study design	Results
Royal et al. [40]	Phase II study of single agent ipilimumab (CTLA4 inhibitor) in locally advanced and metastatic PDAC patients	Check point inhibitor to overcome T-cell exhaustion	Single arm: patients received Ipilimumab intravenously (3.0 mg/kg every 3 weeks; 4 doses/course) for a maximum of 2 courses	Three patients had grade >3 adverse effects. N = 1 of 27 had a delayed objective response, but had confirmed POD initially
Aglietta et al. [41]	Phase I study of single agent tremelimumab in combination with gemcitabine in chemotherapy naive PDAC patients	Check point inhibitor (CTLA4 inhibitor) to overcome T-cell exhaustion	Single arm: 34 patients received tremelimumab on the first day of the 84-day cycle and standard gemcitabine dosing (1000 mg/m² on days 1, 8, and 15 of each 28-day cycles)	Well tolerated. Grade 3/4 asthenia and nausea. No DLT. Two patients out of 34 had a partial response all of whom received complete course of tremelimumab
Brahmer et al. [42]	Phase I study of BMS-936559 (an anti-PD-L1 antibody) as a single agent in advanced stage PDAC patients	Check point inhibitor (CTLA4 inhibitor) to overcome T-cell exhaustion	Single arm: multiple solid tumor patients included. Fourteen PDAC patients received BMS-936559 with a dose of 0.3–10 mg/kg on days 1, 15, and 29	Well tolerated. No objective response was demonstrated in PDAC patients
Beatty at al. [43]	Phase I study of anti-CD40 antibody in combination with gemcitabine in advanced stage PDAC patients	CTL activation with CD40 provocation	Single arm: CP-870,893 (anti-40 antibody) at 0.1 or 0.2 mg/kg were infused on day 3 of each 28-day cycle along with standard gemcitabine treatment	One dose limiting event (CVC). Grade 1/2 cytokine release syndrome. Mixed response in metastatic lesions with decrease FDG uptake
Nywening et al. [48]	Phase Ib trial of CCR2 inhibitors in combination with FOLFIRINOX in borderline resectable and locally advanced PDAC patients	Inhibition of tumor associated macrophages to remove the negative/inhibitory feedback on cytotoxic T cells	Arm A: FOLFIRINOX (N = 9 pts). Arm B: oral PF-04136309 (small molecule CCR2 inhibitor), administered at a starting dose of 500 mg twice daily in a standard 3 + 3 dose de-escalation design with concurrent FOLFIRINOX (N = 39 pts)	One patient had dose limiting event. Otherwise well tolerated. Objective response in FOLFIRINOX alone and experimental arm were 49% versus 0%, respectively. Disease control was achieved in 97% of experiment group and 80% with FOLFIRINOX alone
Kondo et al. [54]	Generation of adoptive immunotherapy against Mucin-1 by using DCs in unresectable and recurrent PDAC patients	CTLs reactive to mucin-1 were generated by DCs presenting mucin-1 to create antitumor immunity	Single arm: N = 20 patients received expanded clone CTLs which were generated ex vivo environment	Well tolerated. N = 5 had stable disease. One patient had complete response. Median OS was 9.8 months
Hecht et al. [73]	Phase 1/2 trial of intratumoral endoscopic ultrasound injection of ONYX-015 in unresectable PDAC	Proliferation of genetically modified adenoviruses viruses in p53-mutant pancreatic cancer cells to induce oncolysis	Single arm; N = 21 received 2 x 10¹⁰ (n = 3) or 2 x 10¹¹ (n = 18) viral copies/treatment which were injected directly into pancreatic tumor. Patients also received standard dose of gemcitabine	Feasible approach. Generally, well tolerated. N = 10 either had partial response or stable disease and N = 11 patients had progressive disease

PDAC, pancreatic adenocarcinoma; CTL, cytotoxic T cells; DCs, dendritic cells; OS, overall survival; DLT, dose-limiting toxicity.