Immunotherapy in gastrointestinal stromal tumors: Current landscape and future horizons

Table 1 summarizes the results of clinical trials evaluating various immunotherapeutic approaches in gastrointestinal stromal tumors

Ref.	Treatment	Phase	Number of patients	ORR (%)	Median PFS	Median OS	Discussion
Chen et al[5], 2012	Peg-IFNa2b + Imatinib	II	8	100%	NR (> 3 years)	NR	New PR achieved after reintroduction of Peg-IFNa2b in a patient who progressed on imatinib maintenance therapy
D’Angelo et al[6], 2017	Dasatinib + Ipilimumab	Ib	20	53.8% (by Choi criteria)	2.8 months	13.5 months	7/13 evaluable GISTs had PR by Choi criteria
Toulmonde et al[7], 2018	Pembrolizumab + Cyclophosphamide	II	9	0%	6 months PFS: 11%	-	63% of GISTs showed high IDO expression
Singh et al[8], 2019	Nivolumab +/- Ipilimumab	II	N: 15, N + I: 12	N: 0%, N + I: 8.3%	N: 8.57 weeks, N + I: 9.1 weeks	N:9.1 months, N + I: 12.1 months	Responses and disease control observed, drugs well tolerated
Chen et al[9], 2020	Nivolumab +/- Ipilimumab	II	N: 9, N + I: 9	N: 0%, N + I: 0%	N: 1.5 months, N + I: 2.9 months	-	No confirmed responses in GIST
NCT05152472[10]	Imatinib + Atezolizumab vs Imatinib alone	II	110 (planned)	Ongoing	Ongoing	Ongoing	Trial ongoing to assess PFS improvement with combination therapy
NCT03609424[10]	PDR001 + Imatinib	I/II	39	Not reported	Not reported	Not reported	Not reported

Peg-IFNa2b: Pegylated interferon alpha-2b; PFS: Progression-free survival; OS: Overall survival; ORR: Objective response rate; PR: Partial response; NR: Not reached; IDO: Indoleamine 2,3-dioxygenase; N: Nivolumab; I: Ipilimumab.

Table 2 summarizes the basic categories of potential gastrointestinal stromal tumors biomarkers

Type	Biomarker	Clinical relevance	Ref.
Genetic	KIT and PDGFRA mutations	Guide TKI therapy; KIT exon 11 mutations respond well, PDGFRA-D842V mutations show resistance	[58]
Genetic	SDH-deficient/competent GIST	Show resistance to TKIs; alternative treatments required	[58]
Inflammatory biomarker	Neutrophil-to-lymphocyte ratio	High ratio indicates poor prognosis due to increased neutrophil-driven inflammation and reduced lymphocyte-mediated immunity	[53]
Inflammatory biomarker	Systemic immune-inflammation index	Elevated index correlates with tumor progression by promoting pro-tumor inflammation	[48,49]
Immune cell marker	CD8+ T lymphocyte infiltration	Increased CD8+ T cells enhance cytotoxic responses against tumor cells, improving survival	[27,50,52]
Immune cell marker	M2 macrophage infiltration	High M2 macrophages suppress immune responses and promote tumor growth and angiogenesis	[53]
Immune cell marker	B Cell and TLS presence	Dense B cells and TLS formation boost antitumor immunity and predict better immunotherapy response	[59]
Immune checkpoint	PD-L1 expression	Modulates T cell activity; high levels can inhibit immune responses but may predict immunotherapy success	[7,52]
Immune checkpoint	Indoleamine 2,3-dioxygenase	Depletes tryptophan, suppressing T cell function and fostering immune tolerance in the tumor microenvironment	[52-54]]
Immune checkpoint	Tim-3/Gal-9 axis	Tim-3 promotes T cell exhaustion; Gal-9 association linked to reduced CD8+ T cell infiltration	[51]
Tumor antigens	Cancer-testis antigens (NY-ESO-1, MAGE-A3)	Trigger immune responses but are linked to poor TKI response and aggressive tumor behavior	[54,55]
Chemokine biomarker	CXCL13 expression	Attracts B cells to tumor sites, facilitating TLS formation and enhancing immune response	[59]
Immune profiling	Immune clusters (Im-I to Im-IV)	High T cell presence in clusters improves survival; Im-I cluster shows immune evasion via CD276 expression	[47]
Molecular pathway	ERK1/ERK2 pathway activation	Drives tumor proliferation and is linked to immune-poor, aggressive GIST subtypes	[42]
Immune evasion marker	CD276 (B7-H3) expression	Inhibits CD8+ T cell activity, contributing to immune evasion and tumor progression	[43]

GIST: Gastrointestinal stromal tumors; TKI: Tyrosine kinase inhibitors; TLS: Tertiary lymphoid structures.