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Koukourakis et al. J Cancer Metastasis Treat 2022;8:38 https://dx.doi.org/10.20517/2394-4722.2022.43 Page 17 of 23

NEOADJUVANT IMMUNOTHERAPY FOR PDAC
In the last decade, immunotherapy with immune checkpoint inhibitors has revolutionized the clinical
practice of oncology in the majority of human carcinomas. A striking exception is PDAC. In a review by
Henriksen et al. of 24 identified studies on the treatment of metastatic PDAC with ipilimumab and anti-PD-
1/PD-L1 MoAbs with or without chemotherapy, the response rates were disappointing, and the median
[119]
survival did not exceed six months . The poor response to immunotherapy is related to the
immunosuppressive tumor microenvironment, low percentage of PDACs with mismatch repair deficiency,
high expression of arginase and IDO that promote immunological tolerance, and infiltration of the tumor
stroma by regulatory T cells and myeloid cells .
[120]
Struggling to uncover the immuno-resistance of advanced PDAC, it is unlikely to expect the launch of
neoadjuvant immunotherapy trials. A small randomized trial on preoperative administration of IL-2 did not
[121]
show any benefit . However, encouraging results were reported in a subsequent study on 30 patients,
suggesting an improvement in PFS and OS . A recent analysis identified 526 patients in the National
[122]
[123]
Cancer Database who received neoadjuvant (408) or adjuvant immunotherapy (118) ; patients treated
with neoadjuvant immunotherapy had longer survival. A phase I trial on the preoperative administration of
the CD40 agonist MoAb selicrelumab demonstrated significant changes in the tumor microenvironment
with less fibrosis, fewer M2-type macrophages, and increased presence of mature dendritic cells compared
to cases that had received chemo-RT . Furthermore, the combination of an anti-CD40 MoAb with nab-
[124]
paclitaxel is under investigation in a phase I trial (NCT02588443). In 2022, the results of maintenance
vaccination with the OSE2101 vaccine after induction chemotherapy with FOLFIRINOX for patients with
advanced pancreatic cancer were reported; OSE2101 conferred a 12-month OS rate of 40% (vs. 44% in
patients who continued treatment with FOLFIRINOX) and was not associated with grade 3 or higher
[125]
toxicities . Ongoing trials on neoadjuvant immunotherapy are shown in Table 5.

FURTHER TREATMENT APPROACHES
It is important to underline that, alongside the ongoing trials assessing the efficacy of combined treatment
modalities for PDAC, new strategies are also being tested in the neoadjuvant setting. Most notably, adoptive
therapy incorporates alternation between treatments according to patient tolerance and tumor response.
The NeoOPTIMIZE (NCT04539808) and NCT03322995 phase II trials are focusing on the early adoption of
different chemotherapy regimens or chemoradiation when the initial drug combination is associated with
increased toxicity or poor clinical response. Moreover, tumor subtype-based therapy is another approach
under evaluation. In the NCT04683315 phase II trial, RNA expression profiling is being used to categorize
PDAC as either basal or classical. Patients with the molecular basal and classical tumor subtypes will receive
GnP and FFX, respectively, and treatment response will be assessed. GATA6 expression is another
biomarker which could potentially impact treatment choice (NCT04472910). Finally, circulating tumor
DNA (ctDNA) is also under investigation as an early marker of tumor response or resistance to
neoadjuvant chemotherapy (NCT04616131).

CONCLUSIONS
The results from retrospective studies and phase II/III randomized trials on the neoadjuvant treatment of
PDAC are quite encouraging. Ongoing phase III trials investigating chemotherapy, chemo-RT,
immunotherapy, targeting agents and their combinations will shed more light on the advantages of this
rising clinical practice and potentially herald a new era in the treatment algorithm of non-metastatic PDAC.