EGFR mutation subtypes and response to immune checkpoint blockade treatment in non-small-cell lung cancer.

BACKGROUND: Although EGFR mutant tumors exhibit low response rates to immune checkpoint blockade overall, some EGFR mutant tumors do respond to these therapies; however, there is a lack of understanding of the characteristics of EGFR mutant lung tumors responsive to immune checkpoint blockade. PATIENTS AND METHODS: We retrospectively analyzed de-identified clinical and molecular data on 171 cases of EGFR mutant lung tumors treated with immune checkpoint inhibitors from the Yale Cancer Center, Memorial Sloan Kettering Cancer Center, University of California Los Angeles, and Dana Farber Cancer Institute. A separate cohort of 383 EGFR mutant lung cancer cases with sequencing data available from the Yale Cancer Center, Memorial Sloan Kettering Cancer Center, and The Cancer Genome Atlas was compiled to assess the relationship between tumor mutation burden and specific EGFR alterations. RESULTS: Compared with 212 EGFR wild-type lung cancers, outcomes with programmed cell death 1 or programmed death-ligand 1 (PD-(L)1) blockade were worse in patients with lung tumors harboring alterations in exon 19 of EGFR (EGFRΔ19) but similar for EGFRL858R lung tumors. EGFRT790M status and PD-L1 expression did not impact response or survival outcomes to immune checkpoint blockade. PD-L1 expression was similar across EGFR alleles. Lung tumors with EGFRΔ19 alterations harbored a lower tumor mutation burden compared with EGFRL858R lung tumors despite similar smoking history. CONCLUSIONS: EGFR mutant tumors have generally low response to immune checkpoint inhibitors, but outcomes vary by allele. Understanding the heterogeneity of EGFR mutant tumors may be informative for establishing the benefits and uses of PD-(L)1 therapies for patients with this disease.

A dormant TIL phenotype defines non-small cell lung carcinomas sensitive to immune checkpoint blockers.

The biological determinants of sensitivity and resistance to immune checkpoint blockers are not completely understood. To elucidate the role of intratumoral T-cells and their association with the tumor genomic landscape, we perform paired whole exome DNA sequencing and multiplexed quantitative immunofluorescence (QIF) in pre-treatment samples from non-small cell lung carcinoma (NSCLC) patients treated with PD-1 axis blockers. QIF is used to simultaneously measure the level of CD3+ tumor infiltrating lymphocytes (TILs), in situ T-cell proliferation (Ki-67 in CD3) and effector capacity (Granzyme-B in CD3). Elevated mutational load, candidate class-I neoantigens or intratumoral CD3 signal are significantly associated with favorable response to therapy. Additionally, a "dormant" TIL signature is associated with survival benefit in patients treated with immune checkpoint blockers characterized by elevated TILs with low activation and proliferation. We further demonstrate that dormant TILs can be reinvigorated upon PD-1 blockade in a patient-derived xenograft model.

Evaluation of a risk score for interhospital transport of critically ill patients.

BACKGROUND: Interhospital transfer imposes essential risk for critically ill patients. The Risk Score for Transport Patients (RSTP) scale can be used as a triage tool for patient severity. METHODS: In total, 128 transfers of critically ill patients were classified in two groups of severity according to the RSTP. Statistical analysis was performed using the receiver operating characteristic (ROC) curve and goodness of fit statistics. RESULTS: In total, 66 patients (51.5%) were classified as group I and 62 (48.4%) as group II. Major en route complications were more common in group II patients (19.3% v 3%, p<0.001). Haemodynamic instability was the most common complication. There were significant differences in the mean risk scores between group I and II patients (mean (SD) 4.48 (1.01) v 11.04 (3.47), p<0.001). Discrimination power of RSTP was acceptable (area under the ROC curve 0.743; cutoff value > or =8). Goodness of fit was adequate (p = 0.390). CONCLUSION: The RSTP had acceptable discrimination and adequate goodness of fit and could be considered as a triage tool. Haemodynamic instability is the most common problem encountered during transfer.

Oncogenes come of age.

Mutations of proto-oncogenes are common events in the pathogenesis of cancers, as shown in a wide range of studies during the 30 years since the discovery of these genes. The benefits of novel therapies that target the products of mutant alleles in human cancers, and the demonstrated dependence of cancers in mouse models on continued expression of initiating oncogenes, are especially promising signs that revolutionary improvements in cancer care are possible. Full realization of the promise of targeted therapies, however, will require better definitions of the genotypes of human cancers, new approaches to interrupt the biochemical consequences of oncogenic mutations, and a greater understanding of drug resistance and tumor progression. In this paper, we summarize recent efforts toward these goals in our laboratory and others.

Retinoic acid down-regulation of fibronectin and retinoic acid receptor alpha proteins in NIH-3T3 cells. Blocks of this response by ras transformation.

All-trans-retinoic acid (RA) markedly reduced the level of intracellular fibronectin (FN) in a time- and concentration-dependent fashion in NIH-3T3 cells, but not in NIH-3T3 cells transformed by an activated Ha-ras oncogene. Pulse/chase experiments indicated that RA affects FN biosynthesis rather than its turnover rate. Steady state levels of FN transcripts did not change after treatment of the cells with RA for various times or concentrations, suggesting that RA acts at the translational level. Similar effects were observed in other fibroblasts. In NIH-3T3 cells, RA had distinct effects on different receptors; it down-modulated retinoic acid receptor (RAR) a protein and transcript levels, it up-regulated RAR beta transcripts, and it had no effect on RAR gamma. Transformation of NIH-3T3 cells with an activated Ha-ras oncogene down-modulated RAR expression and abolished responsiveness to RA. We identified the retinoid signal transduction pathways responsible for the effects of RA on FN and RAR alpha proteins by the use of the retinoid X receptor-selective compound, SR11237, by stable over-expression of a truncated form of the RAR alpha gene, RAR alpha 403 with strong RAR dominant negative activity, and by overexpression of RAR alpha. We conclude that: 1) RA-dependent FN down-modulation is mediated by RARs, 2) retinoid X receptors mediate the observed reduction of RAR alpha by RA, and 3) the block of RA responsiveness in Ha-ras cells cannot be overcome by overexpression of RAR alpha. These studies have defined fibronectin and RAR alpha as targets of RA in fibroblast cells and have shown that oncogenic transformation renders the cells resistant to RA action.

Evaluation of methods of pre-vaccination screening for markers of hepatitis B infection.

The prevalence of serologic evidence of hepatitis B virus infection in various populations in Greece was examined to provide data for formulating cost-effective strategies for prevaccination screening. Markers were detected in 17.5% of 320 healthy persons, 73.3% of 273 multiply transfused patients and 61.0% of 146 haemodialysis patients. In multiply transfused patients, antibody to hepatitis B surface antigen (anti-HBs) was significantly more common than antibody to core antigen (anti-HBc) (67.0%, 44.3%), while the opposite was true for haemodialysis patients (43.8%, 57.5%). These data suggest that it may be most cost-effective to screen only for anti-HBs in multiply transfused patients and only anti-HBc in haemodialysis patients. Vaccination without screening may be more cost-effective for healthy persons. Anti-HBs and anti-HBc were detected with similar frequencies (14.7%, 15.9%), thus neither offers an advantage in screening healthy persons, although use of anti-HBc may facilitate detection of chronic carriers. These data indicate that the choice of marker for pre-vaccination screening should depend on the population under consideration.

Defective phagocytic and bactericidal function of polymorphonuclear leucocytes in patients with beta-thalassaemia major.

The phagocytic and bactericidal activity of polymorphonuclear leucocytes (PMNL) obtained from 50 non-splenectomised patients with homozygous beta-thalassaemia was studied. Polymorphonuclear leucocytes suspended in the serum of patients from whom they were derived ingested fewer Escherichia coli, 72.2 +/- 21.8 (mean +/- s.d.) per 50 PMNLs compared with 144.5 +/- 36.8 bacteria phagocytosed by PMNLs from healthy volunteers and suspended in normal serum (P less than 0.01). Killing of ingested bacteria by the PMNLs from patients was also significantly reduced. These abnormalities are in part serum-associated and are due to the presence of heat-labile inhibitor(s) in the patients' serum. When PMNLs from patients were suspended in patients' heat-inactivated serum, phagocytosis increased to 99.2 +/- 29.2 (P less than 0.01). Similar improvement was noted in PMNL bactericidal activity. These abnormalities provide additional information that helps to explain the increased susceptibility to bacterial infections of patients with homozygous beta-thalassaemia.