Abstract 1633P
Background
While the majority of gastrointestinal stromal tumors (GIST) at diagnosis harbours KIT/PDGFRA mutations (Mut) and are sensitive to imatinib (IM), a minority of cases may be KIT/PDGFRA wild type (WT). An imprecise rate of GIST may further convert to WT along their clinical history and medical treatments. Within this setting we aimed at: a) evaluating the rate of Mut to WT conversion, b) generating a preclinical patient-derived model of IM-resistant wtGIST to functionally explore novel therapeutic strategies. We focused on the composite effects of interferons (IFNs) along with an HLA-independent adoptive immunotherapy with cytokine induced killer lymphocytes (CIK).
Methods
We assessed the KIT/PDGFRA mutational status of surgical GIST samples and set corresponding cell cultures from WT cases. The functional activity by IFNs and CIK immunotherapy was explored in vitro.
Results
We found 18 wtGIST in a cohort of 38 GIST, 5 (13%) at baseline while for 13/25 (52%) the original Mut could no longer be detectable after treatment with IM (mean time 26 months).We generated 11 wtGIST-derived cultures (wtGISTc), confirmed consistent with the original surgical sample. All the wtGISTc resulted resistant in vitro to IM (IC50 17 μM) and moderately sensitive to sunitinib (SU) (IC50 6 μM). Treatment with IFNα (72h, 104 IU/ml) exerted a direct cytotoxicity in vitro (mean mortality 44%) against 4/ 6 wtGISTc, while all of them (6/6) were resistant to IFNγ (72h, 103 IU/ml). No synergism was observed by the association of IFNs with IM or SU. Both IFNα and IFNγ determined indirect immunomodulatory effects, with significant membrane upregulation of PD-L1/2 (2.1 fold, p< 0.05, 6/6) and the HLA-I/β2M complex (mean 2.1 fold). WTGISTc consistently expressed NKG2D ligands, targets of CIK lymphocytes. Adoptive immunotherapy in vitro with patient-derived CIK significantly killed wtGISTc resistant to both IM and IFNs (50% killing at effector:target ratio 10:1 n=4).
Conclusions
We report a relevant GIST conversion rate from Mut to WT, following medical treatment, underscoring the need for longitudinal mutational assessment in the clinic. Preclinical evidence supports the exploration of CIK adoptive immunotherapy as novel approach for wtGIST resistant to medical treatments.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
“Associazione Italiana Ricerca sul Cancro” (AIRC), IG-2017 n. 20259 (DS).
Disclosure
All authors have declared no conflicts of interest.