Tumor-Immune Signatures of Treatment Resistance to Brentuximab Vedotin with Ipilimumab and/or Nivolumab in Hodgkin Lymphoma.

To investigate the cellular and molecular mechanisms associated with targeting CD30-expressing Hodgkin lymphoma (HL) and immune checkpoint modulation induced by combination therapies of CTLA4 and PD1, we leveraged Phase 1/2 multicenter open-label trial NCT01896999 that enrolled patients with refractory or relapsed HL (R/R HL). Using peripheral blood, we assessed soluble proteins, cell composition, T-cell clonality, and tumor antigen-specific antibodies in 54 patients enrolled in the phase 1 component of the trial. NCT01896999 reported high (>75%) overall objective response rates with brentuximab vedotin (BV) in combination with ipilimumab (I) and/or nivolumab (N) in patients with R/R HL. We observed a durable increase in soluble PD1 and plasmacytoid dendritic cells as well as decreases in plasma CCL17, ANGPT2, MMP12, IL13, and CXCL13 in N-containing regimens (BV + N and BV + I + N) compared with BV + I (P < 0.05). Nonresponders and patients with short progression-free survival showed elevated CXCL9, CXCL13, CD5, CCL17, adenosine-deaminase, and MUC16 at baseline or after one treatment cycle and a higher prevalence of NY-ESO-1-specific autoantibodies (P < 0.05). The results suggest a circulating tumor-immune-derived signature of BV ± I ± N treatment resistance that may be useful for patient stratification in combination checkpoint therapy. SIGNIFICANCE: Identification of multi-omic immune markers from peripheral blood may help elucidate resistance mechanisms to checkpoint inhibitor and antibody-drug conjugate combinations with potential implications for treatment decisions in relapsed HL.

Case Management in Prevention of 30-Day Readmission in Post-Coronary Artery Bypass Graft Surgery.

PURPOSE OF STUDY: Thirty-day readmission is associated with increased morbidity and mortality among postoperative coronary artery bypass graft (CABG) surgery patients. Interventions such as case management and follow-up care may reduce 30-day readmission. The purpose of this article is to report a study on modifiable factors that may have significant implications for case management in the prevention of readmission after CABG surgery. PRIMARY PRACTICE SETTINGS: The study population included all the adult patients who underwent first-time CABG surgery from January 1, 2013, to January 1, 2016, from a Mid-South hospital. METHODOLOGY AND SAMPLE: A retrospective case-control study was employed to examine 1,712 patients who underwent CABG surgery. RESULTS: The results revealed that patients readmitted within 30 days had a significantly shorter length of stay (LOS) (6 days vs. 10 days; p < .0001), more days in intensive care unit (6 days vs. 4 days; p = .0391), and significantly higher diabetes/renal (4% vs. 1%), infection (17% vs. 2%), and respiratory-related diagnoses (10% vs. 1%; p < .0001). IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: Among these factors, hospital LOS is a major factor that can be addressed through case management in addition to other modifiable risk factors. Understanding modifiable factors associated with higher readmission risk is crucial for effective intervention and case management planning.

Multi-omics Analysis Reveals Immune Features Associated with Immunotherapy Benefit in Patients with Squamous Cell Lung Cancer from Phase III Lung-MAP S1400I Trial.

PURPOSE: Identifying molecular and immune features to guide immune checkpoint inhibitor (ICI)-based regimens remains an unmet clinical need. EXPERIMENTAL DESIGN: Tissue and longitudinal blood specimens from phase III trial S1400I in patients with metastatic squamous non-small cell carcinoma (SqNSCLC) treated with nivolumab monotherapy (nivo) or nivolumab plus ipilimumab (nivo+ipi) were subjected to multi-omics analyses including multiplex immunofluorescence (mIF), nCounter PanCancer Immune Profiling Panel, whole-exome sequencing, and Olink. RESULTS: Higher immune scores from immune gene expression profiling or immune cell infiltration by mIF were associated with response to ICIs and improved survival, except regulatory T cells, which were associated with worse overall survival (OS) for patients receiving nivo+ipi. Immune cell density and closer proximity of CD8+GZB+ T cells to malignant cells were associated with superior progression-free survival and OS. The cold immune landscape of NSCLC was associated with a higher level of chromosomal copy-number variation (CNV) burden. Patients with LRP1B-mutant tumors had a shorter survival than patients with LRP1B-wild-type tumors. Olink assays revealed soluble proteins such as LAMP3 increased in responders while IL6 and CXCL13 increased in nonresponders. Upregulation of serum CXCL13, MMP12, CSF-1, and IL8 were associated with worse survival before radiologic progression. CONCLUSIONS: The frequency, distribution, and clustering of immune cells relative to malignant ones can impact ICI efficacy in patients with SqNSCLC. High CNV burden may contribute to the cold immune microenvironment. Soluble inflammation/immune-related proteins in the blood have the potential to monitor therapeutic benefit from ICI treatment in patients with SqNSCLC.

Immune determinants of CAR-T cell expansion in solid tumor patients receiving GD2 CAR-T cell therapy.

Chimeric antigen receptor T cells (CAR-Ts) have remarkable efficacy in liquid tumors, but limited responses in solid tumors. We conducted a Phase I trial (NCT02107963) of GD2 CAR-Ts (GD2-CAR.OX40.28.z.iC9), demonstrating feasibility and safety of administration in children and young adults with osteosarcoma and neuroblastoma. Since CAR-T efficacy requires adequate CAR-T expansion, patients were grouped into good or poor expanders across dose levels. Patient samples were evaluated by multi-dimensional proteomic, transcriptomic, and epigenetic analyses. T cell assessments identified naive T cells in pre-treatment apheresis associated with good expansion, and exhausted T cells in CAR-T products with poor expansion. Myeloid cell assessment identified CXCR3+ monocytes in pre-treatment apheresis associated with good expansion. Longitudinal analysis of post-treatment samples identified increased CXCR3- classical monocytes in all groups as CAR-T numbers waned. Together, our data uncover mediators of CAR-T biology and correlates of expansion that could be utilized to advance immunotherapies for solid tumor patients.

Food allergy and asthma.

Food allergies (FA) and asthma commonly coexist in patients, with asthma affecting 14% of school-age children and with FA affecting up to 8% of children in the United States. Compared with children without FA, children with FA are two to four times more likely to have asthma. The timings of food sensitization and FA seem to be strong predictors of asthma onset in childhood; results of studies show that food sensitization in the first few years of life is associated with increased odds of developing early wheeze. Having multiple FAs as opposed to a single FA further compounds the risk of asthma. Reciprocally, there is a strong association between the presence of food sensitization and/or FA and poor asthma control, including increased asthma-related healthcare utilization and emergency medication use. Asthma is a risk factor in ~75% of fatal food-related anaphylaxis cases. Therefore, besides FA education and management, patients with FA and with asthma should optimize medical therapy of their asthma and receive asthma education, including identifying possible asthma triggers. Furthermore, allergists should ensure that asthma must be well controlled before conducting oral food challenges. Timely administration of epinephrine is lifesaving and remains the firstline treatment during food-induced anaphylaxis, especially in patients with asthma. Among those biologic therapies that have been highly effective in treating asthma, omalizumab and dupilumab are now also being studied as treatments for FA.