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Page 6 of 17 Chi et al. J Cancer Metastasis Treat 2020;6:43 I http://dx.doi.org/10.20517/2394-4722.2020.90

Table 1. Ongoing clinical trials investigating immune check point inhibitors
Study drug Combination Study phase Treatment setting Sponsor Clinicaltrials.gov identifier
Anti-PD-1 antibodies
Nivolumab Nab-paclitaxel ± I Any Celgene NCT02309177
gemcitabine
± Ipilimumab I/II Any Bristol-Myers Squibb NCT01928394
Radiotherapy ± II Second line Herlev Hospital NCT02866383
ipilimumab
Pembrolizumab Radiotherapy I Second line University of Pennsylvania NCT02303990
None I Any Merck Sharp & Dohme NCT02054806
Paricalcitol II Any Translational Genomics NCT03331562
Research Institute
BL-8040 (CXCR4 II Second line MD Anderson NCT02907099
antagonist)
Azacitidine II Second line Columbia University NCT03264404
Anti-PD-L1 antibodies
Atezolizumab None I Any Genentech NCT01375842
None II Any Hoffmann La Roche NCT02458638
Avelumab Binimetinib (MEK II Second line Pfizer NCT03637491
inhibitor) and talazoparib
Durvalumab Pexidartinib (CSF1R I Second line Centre Leon Berard NCT02777710
inhibitor)
Galunisertib (TGFβ I Second line Eli Lilly NCT02734160
antagonist)
None I/II Any MedImmune NCT01693562
Radiotherapy ± I/II Second line National Cancer Institute NCT02311361
tremelimumab
CXCR4: C-X-C chemokine receptor type 4; MEK: itogen-activated protein kinase kinase enzymes; CSF1R: colony stimulating factor 1
receptor; TGFβ: transforming growth factor β

combining chemoXRT with immune therapy may increase tumor immunogenicity and increase pancreatic
[57]
tumor response to immunotherapy . This hypothesis is supported by various studies demonstrating
that PDAC tumors treated with neoadjuvant chemoXRT had increased numbers of CD4+ and CD8+
[58]
T-lymphocytes compared to patients who did not receive neoadjuvant chemoXRT . In another study,
neoadjuvant chemoXRT showed significantly lower numbers of immunosuppressive regulatory T cells
[57]
although there was no difference in the number of CD4+ and CD8+ T cells .

In pre-clinical studies, radiation has shown mixed results. In a mouse model of PDAC, a combination of
radiation with dual blockade of PD-L1 and CTLA-4 resulted in improved survival and tumor responses
[59]
compared to dual blockade without radiation or radiation alone . Another mouse model suggested an
immunosuppressive T cell effect where radiation exposure induced macrophage immunosuppressive
[60]
phenotype with reduction in CD8+ T-cells and increased Tregs . The role of radiation in clinical studies is
still being explored. A phase Ib/II study with neoadjuvant pembrolizumab with chemoXRT is ongoing. The
[61]
combination appears to be safe but efficacy data have not been reported . Other ongoing clinical trials
[Table 1] include a pilot study evaluating SBRT in combination with tremilimumab (anti-CTLA-4) and PD-
L1 monoclonal antibody MEDI4736 (NCT02311361) and an open label phase II study combining radiation
with nivolumab with or without ipilimumab (NCT02866383).

Vaccines
Another strategy to overcome the immune desert of pancreatic cancer that is under investigation is the use
of therapeutic vaccines [Table 2]. Vaccines may potentially turn PDAC into more immunogenic tumors
[62]
by activating specific T cells with the ability to migrate into PDAC tumors . Tumors harbor driver and
passenger mutations that may lead to changes in amino acid sequences, which in turn produces mutant
proteins that are expressed by the tumors. These mutant proteins are processed into short polypeptides and