Search

Therapeutic antibodies to immune checkpoints show promising results. Programmed death-ligand 1 (PD-L1), an immune checkpoint ligand, blocks the cancer immunity cycle by binding the PD-L1 receptor (programmed death 1). We investigated PD-L1 protein expression and messenger RNA (mRNA) levels in SCLC.PD-L1 protein expression and mRNA levels were determined by immunohistochemistry (IHC) with SP142 and Dako 28-8 PD-L1 antibodies and in situ hybridization in primary tumor tissue microarrays in both tumor cells and tumor-infiltrating immune cells (TIICs) obtained from a limited-disease SCLC cohort of 98 patients. An additional cohort of 96 tumor specimens from patients with extensive-disease SCLC was assessed for PD-L1 protein expression in tumor cells with Dako 28-8 antibody only.The overall prevalence of PD-L1 protein expression in tumor cells was 16.5%. In the limited-disease cohort, the prevalences of PD-L1 protein expression in tumor cells with SP142 and Dako 28-8 were 14.7% and 19.4% (tumor proportion score cutoff ≥1%) and PD-L1 mRNA ISH expression was positive in 15.5% of tumor samples. Increased PD-L1 protein/mRNA expression was associated with the presence of more TIICs (p0.05). The extensive-disease cohort demonstrated a 14.9% positivity of PD-L1 protein expression in tumor cells with Dako 28-8 antibody.A subset of SCLCs is characterized by positive PD-L1 and/or mRNA expression in tumor cells. Higher PD-L1 and mRNA expression correlate with more infiltration of TIICs. The prevalence of PD-L1 in SCLC is lower than that published for NSCLC. The predictive role of PD-L1 expression in SCLC treatment remains to be established.

Meeting abstracts The majority of lung cancer in the U.S. is treated in the community. A prospective cohort study of stage IV NSCLC and extensive disease (ED) SCLC is being conducted in 70 U.S. community practices to assess outcomes during the pre- and post-immunotherapy eras of lung cancer

Background: The current study explores T-cell (TC) clonality and molecular factors associated with this metric. Tumors employ multiple mechanisms to evade antitumor immune responses. One process involves TC inhibition via upregulation of immune checkpoint (IC) ligands in the tumor microenvironment (TME). Gradual upregulation of inhibitory receptor at their cellular surface results in a decreased capacity to proliferate and activate cytotoxic pathways against tumor cells presenting antigenic peptides.1 In melanoma, this subset of exhausted TCs has been described as highly clonal, where the majority of PD-1-expressing TC population shares the same TCR sequence specific against the same antigenic fragment.2 Previous studies have demonstrated that a clonal TCR repertoire appears to be associated in part with therapeutic responses during IC blockade.3 Methods: We performed TCR sequencing on 82 blood and 73 archival tumor tissue samples collected from ED SCLC patients (pts) in an ongoing longitudinal cohort study in US community oncology practices. Of these, 82 blood and 48 tissue samples had sufficient material available to quantify a clonality metric. To quantify TC abundance as a fraction of total nucleated cells, 82 blood and 58 tissue samples had sufficient material available. Results: Within the subset of 48 tumor samples, a more clonal (ie, less diverse) TCR repertoire was associated with less necrosis (P≤0.012) and lower levels of inflammatory cell infiltration in the local TME (P≤0.021). When pts were divided into 2 equal groups according to the median clonality level, pts with a less clonal TCR repertoire (n = 24/48) who were treated with non-immune-targeted therapy trended toward a longer overall survival (OS; 446 vs 301 days; P≤0.039). In contrast, the percentage of TCs in the TME did not correlate with improved survival (P≤0.412), necrosis (P≤0.131), and inflammation (P≤0.615). This observation differs from results in melanoma describing the impact of IC blockade where pts responding to therapy were associated with a more clonal TME TC population and increased CD8 TCs in the tumor compartment and at the invasive margin.3 In blood, while a less clonal TCR repertoire was associated with a similar but non-significant trend toward longer survival (P≤0.148), pts with increased TC abundance had longer OS (P≤0.025). No association was observed between clonality in TME and clonality (P≤0.571) or TC abundance (P≤0.965) in blood. Conclusion: We hypothesize that a diverse TCR repertoire in the TME and increased peripheral TC abundance are 2 predictors of longer OS in ED SCLC. To further explore factors that may influence TC responses in ED SCLC, the current TCR sequencing results will be integrated with transcriptome and whole genome sequencing analyses. References 1. Wherry EJ. Nat Immunol. 2011;12:492-99. 2. Gros A, et al. J Clin Invest. 2014;124:2246-59. 3. Tumeh PC, et al. Nature. 2014;515:568-71. Citation Format: Maen Hussein, Sharon Wilks, Marc Monte, Donald A. Richards, Jerome H. Goldschmidt, David Waterhouse, Lisu Wang, Saumya Pant, Erik Yusko, Ryan O. Emerson, Darin M. Taverna, Kaushal Desai, Spyro Mousses, Zhenhao Qi, Jason D. Hipp, Harlan Robins, Kimary Kulig, Cory Batenchuk. Characterization of the T-cell receptor (TCR) repertoire in extensive disease small cell lung cancer (ED SCLC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4159.

We observed increased hemoglobin A2 (HbA2) levels in an asymptomatic human immunodeficiency virus-1 (HIV1) patient with no previous history of beta-thalassemia. He was treated only with zidovudine (AZT). In an attempt to understand this observation, a retrospective study was initiated to determine whether mean HbA2 levels are higher in AZT-treated patients than in subjects not receiving this drug and to assess if other hematologic alterations are associated with elevated HbA2. One hundred fifty-one HIV-positive cases were investigated; AZT was administered to 81 of them. The mean value of HbA2 was 0.032 (SD +/- 0.005) for the treated group vs. 0.027 (SD +/- 0.004) for the controls. This difference was highly significant (P < 0.001). Twenty-four patients (31%) in the treated group had elevated HbA2 levels vs. none in the controls. Bone marrow toxicity seemed to be more significant in patients with heightened HbA2 values, and HbA2 levels did not increase with CDC clinical stage. We conclude that AZT may be linked to high HbA2 levels in some patients.

Two homosexual HIV1-positive male patients with thrombotic thrombopenic purpura (TTP) were found to have past history of immune thrombocytopenia (ITP). The first patient had ITP 10 months prior to TTP and was successfully treated by splenectomy. The second patient had ITP 32 months before TTP. No specific treatment was given for his asymptomatic ITP. Association of HIV infection to TTP seems to be frequent. These two types of purpura have different pathogenic mechanisms but share a common altered immune response to antigenic challenge. The occurrence of ITP and TTP in HIV-positive patients may lead to errors in diagnosis and therapy.