ALBERT

Description: Despite profound T-cell immunodeficiency, most patients treated with chemotherapy do not succumb to infection. The basis for residual protective immunity in lymphopenic patients is not known. We prospectively measured T-cell numbers, thymopoiesis, and T-cell memory in 73 children undergoing a 2-year chemotherapy regimen for acute lymphoblastic leukemia (ALL) and compared them to an age-matched cohort of 805 healthy children. Most patients had profound defects in CD4 and CD8 T-cell numbers at diagnosis that did not recover during the 2 years of therapy. Thymic output and the fraction of naive T cells were significantly lower than in healthy controls. However, the remaining T-cell compartment was enriched for antigen-experienced, memory T cells defined both by phenotype and by function. This relative sparing of T-cell memory may, in part, account for the maintenance of protective immunity in lymphopenic patients treated for ALL. Moreover, because the memory T-cell compartment is least affected by ALL and its treatment, strategies to induce immunity to pathogens or tumor antigens in cancer patients may be most successful if they seek to expand pre-existing memory T cells. (Blood. 2005; 106:1749-1754)

Description: CpG ODN are being actively investigated as cancer vaccine adjuvants because they mature plasmacytoid dendritic cells (pDC) into potent antigen-presenting cells. In addition, TLR ligands induce a broad range of other immunologic effects in pDC including the secretion of interferon α (IFNa) and chemokines which alter lymphocyte migration. Whether these CpG-ODN driven TLR ligand signals enhance antigen specific Immunity and/or trafficking In humans Is presently unknown. We evaluated the efficacy of the CpG-ODN, 1018-ISS, as a vaccine adjuvant given with GM-CSF to induce T cell immunity in humans to the tumor antigen hTERT. Seventeen patients with advanced solid tumors were treated with 6 cycles of GM-CSF (x 3d), CpG-ODN (escalating from 3mg - 100mg × 1d) followed by a peptide vaccine (a CD8 epitope from hTERT), in a Phase I dose escalation study. Surprisingly, only one of seventeen patients showed a detectable hTERT-specific tetramer T cell response. However, the majority of patients developed marked peripheral blood (PB) lymphopenia after CpG-ODN. Time-course flow cytometry analysis of PB revealed that CD8, CD4, NK and B cell counts were all depressed immediately after CpG-ODN. The effect was transient, with normal counts returning after a week, suggesting that CpG-ODN induced alteration in cell migration rather than cell death. To find further evidence for altered migration we examined vaccine sites. Clinically, vaccine sites showed significant swelling/induration within hours of CpG-ODN administration, though none was dose-limiting. Immunohistochemistry of vaccine biopsies showed significant, perivascular accumulation of CD4 and CD8 T cells clustered around CD123+ pDC. Biopsies after CpG-ODN, but not after GM-CSF, showed a marked increase in expression of MxA, an interferon-inducible gene suggesting that the local activation of pDC with resultant IFNa secretion. qRT-PCR confirmed significant increases in a panel of IFNa-inducible genes in the PB after CpG-ODN, indicating a systemic effect of IFNa secretion. Lastly, we showed directly that CpG-ODN markedly increased the ability of purified pDC to induce T cell migration in an in vitro transwell assay, demonstrating that CpG-ODN stimulation of human pDC not only induces IFNa, but also other chemokines that are sufficient to chemoattract T cells. Our results show that CpG-ODN with GM-CSF may not be an effective adjuvant strategy for peptide tumor vaccines; but sequenced GM-CSF/CpG-ODN causes a chemokine response that effects T cell migration to the peripheral tissues. These findings suggest a role for CpG beyond that of a vaccine adjuvant as a mediator of lymphocyte migration, targeting immune responses to specific peripheral tissues. Therapeutic intratumoral GM-CSF/CpG-ODN injection could profoundly alter the local immunologic milieu, recruiting activated pDC and T cells to the tumor site, and tipping the balance towards an effective tumor-specific immune response.

Description: Abstract 2553 Background: Inferior Vena Cava (IVC) filter placement has increased significantly over the past few decades, due to expanding indications for filter placement. Indications for filter placement vary widely depending on which professional society recommendations are followed. Our objectives were to record the number of IVC filters placed in our medium sized metropolitan teaching hospital, assess the effect of medical specialty on placement and evaluate compliance with accepted standards as set by the American College of Chest Physicians (ACCP) and the Society of Interventional Radiology (SIR). Methods: Single-center, retrospective medical record review of all patients who received an IVC filter over 26 months (01/30/2008 - 4/5/2010). Inclusion criteria included patients from both sexes, all ages, filter placement within the aforementioned dates and inpatient procedures performed by interventional radiology. A total of 443 IVC filters were placed in our institution over the time period studied. 48.1% (213) of these filters were placed by interventional radiology. Of these, 187 were reviewed with 26 excluded do to incomplete patient records available at the time of review (July 2010). Medical records were reviewed for patient demographics, clinical course, and compliance with accepted guidelines set by the ACCP and SIR. Results: The average age was 75.3 years and 43.9% of the patients were males. 76.2% of patients were on the medical service (internal medicine and its subspecialties) whereas 22.8% were on non medical services. 87.2 % of filters were recommended by medicine and its subspecialties and 12.8% by non medical specialties. 43.3% of filters placed met guidelines established by the ACCP (Table 1). 79.1% of filters placed met SIR guidelines (Table 2). No documentation was available to assess compliance for 20.9% of filters. 46% of filters placed by internal medicine and its subspecialties met ACCP criteria whereas only 25% of filters recommended by non medicine specialties were compliant with criteria (p value=0.039, 95% CI). Physicians within internal medicine and its subspecialties were compliant with SIR guidelines for 84% of the filters placed, whereas only 46% of non medicine physicians met these indications (p=0.001, 95% CI). 35.8% of filters placed met SIR criteria but did not meet ACCP guidelines. Conclusions: Indications for IVC filter placement varied significantly in this study, less than half of filters placed met ACCP guidelines, yet over three-fourths met criteria set by the SIR, especially when comparing medicine and non medicine specialties. In analyzing the filters which meet indications set by SIR but not ACCP it becomes apparent that most of these are placed for patients classified as “fall risks”, failures of anticoagulation, limited cardiopulmonary reserve and medication noncompliance. Further research needs to be guided towards evaluating if these indications truly merit the placement of an IVC filter. This study strongly suggests a need for harmonization of current guidelines espoused by professional societies. A limitation of our study was that 230 filters placed by vascular surgery and interventional cardiology were not reviewed. Disclosures: No relevant conflicts of interest to declare.

Description: Although memory lymphocytes in CD4, CD8 and B cell lineages are characterized by a strikingly diverse array of functions and phenotypes, they share common properties of longevity, lowered response threshold and the ability to self-renew. The development of these memory functions is essential for immunity to pathogens and tumors, but it is not known how diverse lineages acquire these same properties. We therefore studied the transcriptional profile of memory differentiation to determine whether the development of memory in disparate lineages involves a common differentiation program. To identify a core signature of memory differentiation, we used cross-species genomic analysis to identify genes differentially expressed by both human and murine memory CD8 T cells compared to their naive precursors. We identified 220 genes significantly increased in human memory-phenotype cells, and found this signature to be highly conserved in two different TCR transgenic murine models of memory differentiation (P