Antibody targeting of the immune checkpoint receptor PD1 produces therapeutic activity in a variety of solid tumors, but most patients exhibit partial or complete resistance to treatment for reasons that are unclear. In this study, we evaluated tumor specimens from 65 patients with melanoma, lung nonsquamous, squamous cell lung or head and neck cancers who were treated with the approved PD1-targeting antibodies pembrolizumab or nivolumab. Tumor RNA before anti-PD1 therapy was analyzed on the nCounter system using the PanCancer 730-Immune Panel, and we identified 23 immune-related genes or signatures linked to response and progression-free survival (PFS). In addition, we evaluated intra- and interbiopsy variability of PD1, PD-L1, CD8A, and CD4 mRNAs and their relationship with tumor-infiltrating lymphocytes (TIL) and PD-L1 IHC expression. Among the biomarkers examined, PD1 gene expression along with 12 signatures tracking CD8 and CD4 T-cell activation, natural killer cells, and IFN activation associated significantly with nonprogressive disease and PFS. These associations were independent of sample timing, drug used, or cancer type. TIL correlated moderately (∼0.50) with PD1 and CD8A mRNA levels and weakly (∼0.35) with CD4 and PD-L1. IHC expression of PD-L1 correlated strongly with PD-L1 (0.90), moderately with CD4 and CD8A, and weakly with PD1. Reproducibility of gene expression in intra- and interbiopsy specimens was very high (total SD <3%). Overall, our results support the hypothesis that identification of a preexisting and stable adaptive immune response as defined by mRNA expression pattern is reproducible and sufficient to predict clinical outcome, regardless of the type of cancer or the PD1 therapeutic antibody administered to patients. .

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Summary:A simplified cryopreservation method for bone marrow (BM) and peripheral blood progenitor cells (PBPC) was utilized in hematopoietic cell transplantation of 213 patients with hematological or solid neoplasms after ablative chemotherapy (187 with peripheral blood progenitor cells and 26 with bone marrow). Cells were cryopreserved, after addition of autologous fresh plasma with DMSO, without HES, by freezing to ؊80؇C in a methanol bath and non-programmed freezer. For the patients autotransplanted with PBPC, the median period necessary for recovery of more than 0.5 × 10 9 /l granulocytes was 11 days (range 6-44), and 15 (8-204) days were required to obtain more than 20 × 10 9 /l platelets. For the patients autotransplanted with BM, the median period necessary to recover Ͼ0.5 × 10 9 /l granulocytes was 12 days (range 9-33), and 24 (12-57) days to obtain more than 20 × 10 9 /l platelets. These results support this method as being very effective in achieving high-quality cryopreservation. The procedure, which uses a non-programmed freezer, simplifies and reduces enormously the cost of the technical measures currently in use, enabling its adoption in almost any clinical oncological institution. Keywords: hematopoietic cell transplantation; cryopreservation; plasma and DMSO; non-programmed freezing; methanolThe transplantation of hematopoietic progenitor cells, derived both from bone marrow and peripheral blood, is an ever more frequent procedure in the treatment of numerous neoplastic diseases. The technology for this type of therapeutic procedure requires, in the majority of cases, the freezing and storage of these cells for variable periods of time. The freezing procedure is traditionally carried out using machinery which incorporates pre-established, comCorrespondence: Dr F Hernández-Navarro, Servicio Hematología y Hemoterapia, Hospital La Paz, Paseo de la Castellana 261, 28046, Madrid, Spain Received 7 July 1997; accepted 21 October 1997 puterized freezing programs. 1-4 Experience using direct or non-programmed freezing systems for hemotopoietic progenitor cells and their transplant is less widespread. [5][6][7][8][9][10][11] In this article, we summarize our experience using a simple, non-programmed freezing method for the transplant of hematopoietic cells in patients with neoplastic disease. Two different in vitro experiments were designed to analyze the reproducibility and the effect of the methanol bath on freezing rates. Finally, a limited comparative study of in vitro cell viability following programmed and non-programmed freezing is also presented. Materials and methods Cooling ratesIn order to analyze the reproducibility of the cooling rates with the methanol system and the impact of this technique on the standardization of the freezing, two different in vitro experiments were performed.In the first (Figure 1), four different bags containing 160 ml of hematopoietic cells in 10% DMSO and autologous plasma were cryopreserved using a mechanical freezer at Ϫ80°C in a methanol bath as previously describe...

ratio [HR] 20.1, 95% confidence interval [CI] 5.5-73.9, p < 0.001), presence of liver metastasis (HR 5.5, 95% CI 2.1-14.6, p ¼ 0.001), and CNS metastasis (HR 2.9, 95% CI 1.1-7.4, p ¼ 0.027) were independent predictive factors for short PFS. Conclusion: Clinical factors including post-treatment NLR at 6 week might be predictive of clinical benefits from anti-PD-1 antibody therapy in lung cancer.

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