New avenues for the treatment of immunotherapy-resistant pancreatic cancer

Table 1 Preclinical studies of combined immunotherapy for resistant pancreatic cancer

Methods	Combination	Results	Ref.
TME modulator + Vaccine + ICI	mAb-AR20.5 + PolyICLC + anti-PD-L1	Rejection of tumor cells expressing MUC1 and increased cytotoxic activity of CD8+ T cells	[201]
TME modulator + ICI	TGF-β inhibitor + anti-PD-L1/anti-CTLA-4	Inhibited tumor growth, improved CD8+ T cell infiltration and increased the population of M1 macrophages in the TME	[202]
TME modulator + ICI	SLC4A4 inhibitor + anti-PD-1/anti-CTLA-4	It reduced the acidity of the TME, increased the infiltration of CD8+ T cells and the number of M1 macrophages	[203]
TME modulator + ICI	MEK and STAT3 inhibitors + anti-PD-1	Attenuated the pro-inflammatory CAF myofibroblastic phenotypes expressing IL6/CXCL1 and increased the recruitment of CD8+ T cells	[204]
IL-17 signaling blocker + ICI	Anti-IL17+ anti-IL17R + anti-PD-1/anti-CTLA-4	Favored the activation of CD8+ T cells, achieved a 50% response rate and increased survival	[205]
NKT activation + recombinant oncolytic virus + ICI	NKT + VSV-IL-15 + anti-PD-1	It increased overall tumor regression, survival time, NK/T CD8 cell infiltration and resulted in complete tumor elimination in 20% of the mice	[206]
Vaccine + ICI + TME modulator + chemotherapy	GVAX + anti-PD-1 + anti-CSF-1R + gemcitabine	It increased the number of infiltrated CD8+T cells, reduced the infiltration of myeloid cells, myeloid-derived suppressor cells and reduced the number of TAMs	[207]

TGF-β: Transforming growth factor-β; TME: Tumor microenvironment; ICI: Immune checkpoint inhibitor; MUC1: Mucin 1; CAF: Cancer-associated fibroblast; CXCL1: C-X-C chemokine ligand 1; NKT: Natural killer T cell; TAMs: Tumor-associated macrophages; PD-1: Programmed cell death-1; IL-6: Interleukin-6; NK: Natural killer.

Table 2 Clinical studies of combined immunotherapy for resistant pancreatic cancer

Combination	Pacients	Phase	Results	Identification	Ref.
Motixafortide (CXCR4 blocker) + pembrolizumab (anti-PD-1)	37	IIa	The disease control rate was 34.5%, survival rate of 7.5 months, a more efficient infiltration of CD8+ T cells and a reduction in MDSCs	NCT02826486	[208]
Acalabrutinib (BTK inhibitor) + pembrolizumab (anti-PD-1)	40	II	The disease control rate was 21.1%, the survival rate was 1.4 months and there was a reduction in MDSCs	NCT02362048	[209]
GVAX + CRS-207	90	II	The disease control rate was 31%, the survival rate was 6.1 months and there was an increase in mesothelin-specific CD8+ T cells	NCT01417000	[210]
GVAX + CRS-207	200	IIb	The survival rate of 175 days (average) and a more efficient infiltration of CD8+ T cells	NCT02004262	[211]

CXCR4: C-X-C chemokine receptor 4; MDSCs: Myeloid-derived suppressor cells; BTK: Bruton's tyrosine kinase; PD-1: Programmed cell death-1.