15 First-line platinum-based chemotherapy combined with PD-1/PD-L1 inhibitors (ICI) prevents hyperprogression in non-small cell lung cancer (NSCLC) patients by reducing circulating immature neutrophils
Authors: Roberto Ferrara, Giuseppe Lo Russo, Elena Jachetti, Giuseppina Calareso, Claudia Proto, Arsela Prelaj, Giulia Galli, Diego Signorelli, Marta Brambilla, Alessandro De Toma, Mario Occhipinti, Sara Manglaviti, Giulia Apollonio, Laura Mazzeo, Monica Ganzinelli, Antonia Martinetti, Filippo De Braud, Marina Garassino, Mario Paolo Colombo, Sabina Sangaletti
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Hyperprogression (HPD) has been described in ≃14–26% of NSCLC patients upon single-agent ICI 1 and has not been reported upon ICI and platinum-based chemotherapy (PCT) combinations. Both high circulating neutrophils 2 and senescent T-cells 3 correlated with HPD, however the exact neutrophils-T-cells interplay and the role of specific neutrophils subsets in driving HPD is unknown. Methods NSCLC patients treated with 1st line ICI as single-agent or in combination with PCT were assessed for HPD and circulating neutrophils’ phenotype. HPD required 3 assessment (2 before ICI, 1 upon ICI) and was defined as delta tumor growth rate (TGR) (TGR upon ICI – TGR before ICI) &gt;50% and/or TGR ratio (TGR upon ICI/TGR before ICI) ≥2. Circulating low density neutrophils (LDNs) subtypes were assessed by flow cytometry on peripheral blood mononuclear cells (PMBCs). LDNs were defined as CD66b+CD15+ cells among CD11b+ PBMCs. Immature subtypes were defined as CD10- LDNs. T-cells were isolated from healthy donors and cocultured with patients‘ LDNs to characterize the neutrophils-T-cells interplay. LDNs subtypes were isolated from patients and treated in-vitro with cisplatin to assess cell death. Results 46 NSCLC patients were treated with single-agent ICI and 17 with PCT+ICI (table 1). In the ICI single-agent cohort, PD and HPD occurred in 21 (41%) and 4 (9%) patients. Before ICI start, HPD patients had significantly higher median% of circulating immature CD10- LDNs neutrophils [43.5 (min 29.5; max 82.6) vs 10.3 (min 0.1; max 79.4), p=0.01] compared to PD patients (figure 1). In the ICI-PCT cohort no HPD was reported. 5 patients had baseline CD10- LDNs ≥ 43.5% (median% of CD10- LDNs in HPD patients upon single-agent ICI), 2 of them had stable disease and 3 PD upon ICI-PCT. In these 5 patients, CD10- LDNs significantly decreased during ICI-PCT compared to what observed in HPD patients upon single-agent ICI [median variation -43.4 (min -67.6, max -31.6) vs +6.9 (min -33, max +44), p= 0.03] (figure 2). After 7 days of coculture with T-cells, immature CD10- LDNs significantly reduced T-cells survival and promoted a T-cell senescent phenotype (CD28 loss, CD57 gain) impairing T-cells proliferation and increasing IFN-gamma production (figure 3). Cisplatin treatment significantly increased necrotic cell death among CD10- LDNs compared to CD10+ LDNs (figure 4). Abstract 15 Table 1 Patients characteristics in the single-agent ICI and PCT+ICI cohorts Abstract 15 Figure 1 Patterns of response, progression and hyperprogression to single-agent ICI and correlation with mature (CD10+) or immature (CD10-) LDNs’ subtypes Abstract 15 Figure 2 Neutrophils dynamic variation upon treatment (5 patients with high baseline CD10- LDNs and PD/SD to chemo-ICI vs 4 patients with HPD upon single-agent ICI) Abstract 15 Figure 3 Mature (CD10+) and immature (CD10-) LDNs in coculture with T-cells from an healthy donor differently influence CD8 and CD4 T-cells survival, proliferation, IFN-gamma production and expression of a senescent (CD28- CD57+) phenotype. Abstract 15 Figure 4 Cisplatin in-vitro treatment at different concentration (1 uM and 5 uM) increases necrotic (7AAD expression) cell death preferentially of immature (CD10-) rather than mature (CD10+) LDNs Conclusions Higher baseline immature CD10- LDNs impair T-cell survival and promote T-cell senescence being a circulating biomarker of HPD upon single-agent ICI. The addition of PCT prevents HPD by inducing immature neutrophils cell death. References Ferrara R, Mezquita L, Texier M, Lahmar J, Audigier-Valette C, Tessonnier L, et al . Hyperprogressive disease in patients with advanced non-small cell lung cancer treated with pd-1/pd-l1 inhibitors or with single-agent chemotherapy. JAMA Oncol 2018; 4 :1543–52. https://doi.org/10.1001/jamaoncol.2018.3676 Kim Y, Kim CH, Lee HY, Lee S-H, Kim HS, Lee S, et al. Comprehensive clinical and genetic characterization of hyperprogression based on volumetry in advanced non-small cell lung cancer treated with immune checkpoint inhibitor. J Thorac Oncol 2019; 14 :1608–18. https://doi.org/10.1016/j.jtho.2019.05.033 Ferrara R, Naigeon M, Auclin E, Duchemann B, Cassard L, Jouniaux JM, et al . Circulating T-cell immunosenescence in advanced non-small cell lung cancer patients treated with single agent PD-1/PD-L1 inhibitors or platinum-based chemotherapy. Clin Cancer Res 2020. https://doi.org/10.1158/1078-0432.CCR-20-1420. Ethics Approval Patients blood was obtained after signature of informed consent and within an observational prospective study (INT 22_15) approved by local Institutional Ethical Committee.