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MA13 - Going Back to the Roots! (ID 139)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
MA13.09 - Cisplatin Sustains Lung Cancer Metastasis Through the Systemic Activation of SDF-1/CXCR4 Axis (Now Available) (ID 2821)
14:00 - 15:30 | Author(s): Valeria Cancila
Standard chemotherapy regimens have limited long-term efficacy in lung cancer patients due to chemoresistance and inefficacy in controlling metastatic disease. In pre-clinical models we have shown that cisplatin treatment enriches for the chemoresistant fraction of CD133+CXCR4+ lung cancer metastasis initiating cells (MICs), increasing distant metastasis development that can be prevented by CXCR4 blockade. Therefore, we hypothesize that the SDF-1/CXCR4 axis, implied in MICs maintenance/migration and in immune and stromal cells trafficking, could play a critical role in cisplatin-induced pro-metastatic effects.Method
To study the effects of cisplatin in promoting a pre-metastatic niche, naïve SCID mice were treated with cisplatin plus/minus peptide R (5mg/kg), a novel inhibitor of CXCR4 and after 72h injected intravenously with metastatic H460 cell line. To assess the effect of the combination treatment in pre-clinical model, H460 subcutaneous xenografts were treated with cisplatin alone or with peptide R for three weeks. Content of MICs in xenografts, number and phenotype of lung metastasis and immune cells modulationt were evaluated by FACS and IHCResult
We showed that cisplatin treatment of naïf SCID mice resulted in a rapid BM expansion of the subset of CCR2+CXCR4+Ly6Chigh inflammatory monocytes (IM), concomitantly with their recruitment to murine lungs guided by increased level of SFD-1 released by PDGFRβ+ stromal cells in response to cisplatin. Peptide R partially prevented these effects.
Tail-vein injection of H460 human lung cancer cells 72h after cisplatin administration resulted in augmented number of lung metastases (p=0.003), that showed a 3.5-fold enrichment in CD133+CXCR4+ MICs (p=0.005) and increase of IM and derived macrophages. Pre-treatment with peptide R abolished these effects. We verified that the abundance of CXCR4+CCR2+IM together with increased endothelial permeability caused by cisplatin may favor tumor cells extravasations and expansion of MICs through SDF-1/CXCR4 axis activation which determined metastasis overgrowth.
SDF-1 was also increased in cisplatin-treated subcutaneous H460 xenografts that expanded the subset of chemoresistant CD133+CXCR4+ MICs and recruited CXCR4+tumor associated macrophages which may allow MICs to escape primary tumor. At the metastatic site cisplatin treatment of H460 xenografts caused an increase in stromal SDF-1 and recruitment of both CXCR4+ inflammatory monocytes/macrophages (1.6-fold change p=0.01) and MICs subset (1.8-fold change p=0,04), overall resulting in a boost in micrometastases. CXCR4 inhibition prevented the co-recruitment and cross-talk of MICs and IM at distant site, counteracting the pro-metastatic effects of cisplatin.
Matched case series of stage III chemo-naive NSCLC patients and cisplatin-based neo-adjuvant treated patients demonstrated a significant increased in SDF-1 after chemotherapy (p=0,0001). An high expression of tumoral SDF-1 ( Score: staining intensity x % positive tumor cells >6) induced by cisplatin neo-adjuvant treatment was associated with a shorter DFS (p=0,0056) and poor OS (p=0,029).Conclusion
Conclusions: Our data reveal a paradoxical pro-metastatic effect of cisplatin that fosters MIC-IM recruitment and cross-talk via SDF-1/CXCR4 axis activation. A new combination strategy based on CXCR4 inhibition may disrupt these interactions, providing more effective and long-lasting results for lung cancer treatment
OA14 - Update of Phase 3 Trials and the Role of HPD (ID 148)
- Event: WCLC 2019
- Type: Oral Session
- Track: Immuno-oncology
- Presentations: 1
- Now Available
OA14.06 - Hyperprogressive Disease in Advanced Non–Small Cell Lung Cancer Patients Treated with Immune Checkpoint Inhibitors (Now Available) (ID 1835)
11:30 - 13:00 | Author(s): Valeria Cancila
Hyperprogressive disease (HPD) is a paradoxical boost in tumour growth described in a subset of cancer patients treated with immune checkpoint inhibitors (ICIs).Method
We retrospectively collected data about all consecutive patients with advanced Non-Small Cell Lung Cancer (aNSCLC) treated with ICIs at our Institution between 04/2013 and 12/2018. Patients were classified according to our previously published clinical/radiological criteria for HPD (Lo Russo G, Clin Canc Res 2018). (Table). All ICIs administered for ≥1 cycle were admitted. Chi-square test was used to compare qualitative variables. Survival was estimated with Kaplan-Meier method. Log-rank test was used to compare curves. Multivariate analyses were performed with Cox hazard model.
Table HPD definition on the basis of 3 concomitant out of the five possible criteria
HPD CLINICAL & RADIOLOGICAL CRITERIA
Time-to-treatment failure < 2 months
Increase of ≥ 50% in the sum of target lesions major diameters between baseline and first radiological evaluation
Appearance of at least two new lesions in an organ already involved between baseline and first radiological evaluation
Spread of the disease to a new organ between baseline and first radiological evaluation
Clinical deterioration with decrease in ECOG performance status ≥ 2 during the first 2 months of treatment
We reviewed 301 cases and 257 were evaluable for response. We identified four categories: responders (R, 57 cases, 22.2%), patients with stable disease as best response (SD, 69 cases, 26.8%), patients with progressive disease as best response (P, 78 cases, 30.4%) and patients with HPD (53 cases, 20.6%). Clinical/pathological variables were uniformly distributed among groups, except for a higher rate of patients with Eastern Cooperative Oncology Group Performance Status (ECOG-PS) >1 in HPD group (p = 0.0141). After a median follow-up of 23.49 months (IQR 10.72–44.21 months), median Progression-Free Survival (mPFS) and median Overall Survival (mOS) were 14,2 vs 6,5 vs 2,3 vs 1,5 months ( p < 0.0001) and 32,5 vs 17,8 vs 7,8 vs 4,1months (p < 0.0001) in R, SD, P and HPD group, respectively. The multivariate analyses, between P and HPD groups, adjusted for ICIs line, number of metastatic sites and ECOG-PS according to PFS (HR 2.448, 95% CI 2.137-2.899, p<0.0001) and OS (HR 2.481, 95%CI 2.092-2.950, p < 0.0001) confirmed the worse outcome of HPD group.Conclusion
Our updated analysis confirmed patients with HPD as a distinct category that performs significantly worse than other groups, including P patients. The incidence of HPD in our cohort is relevant. The ICIs’ detrimental effect has to be taken into account and further investigated.