Faculty Bibliography

Therapeutic cancer vaccines can generate measurable antigen-specific immune responses in humans, yet tumor regression is often incomplete, inconsistent, or short-lived. In immunologically cold tumors, this pattern may reflect not an absolute inability to prime immunity, but difficulty advancing induced immunity through the full sequence required for tumor control. Peripheral blood responses may be real and still be biologically inadequate if they contract early, fail to acquire productive trafficking programs sufficient for tissue entry, lose functional competence under chronic antigen stress, or remain constrained by the suppressive tumor microenvironment. The manuscript advances a sequential, feedback-guided adjuvant framework in which peptide vaccination remains the backbone but is preceded and followed by distinct support phases. A Phase 0 immune-readiness step, potentially using IL-7 (e.g., CYT107), is intended to improve the baseline substrate before antigen exposure. Phase 1 priming uses peptide vaccination on a commonly used adjuvant backbone such as Montanide ISA-51 or poly-ICLC (Hiltonol), while radiation and/or STING-based strategies are treated as context-dependent enhancers rather than replacements for priming. IL-15-centered consolidation is then used to support expansion and persistence. A formal trafficking assessment follows so that blood-only success is not overinterpreted. IL-21 is positioned later as a persistence- and quality-support cytokine when response quality declines. The framework also addresses why otherwise rational protocols can fail at the chemokine-trafficking step: CXCR3-dependent tumor entry is not interchangeable with generic inflammation, CCR5 biology is context dependent, and IL-12, although biologically attractive and previously tested as a vaccine adjuvant, is best viewed here as an optional, context-specific amplifier rather than a universal backbone. Although organized as sequential phases, the framework is intended as a bottleneck-guided and iterative design logic in which phases may overlap, repeat, or be entered in partial parallel depending on the dominant biologic constraint. The central hypothesis is that vaccine programs that progress beyond priming into trafficking-competent and functionally sustained states are predicted to correlate more closely with disease control than programs judged mainly by early blood immunogenicity.

Chronic kidney disease (CKD) is associated with increased coronary artery disease (CAD) and coronary artery calcification. We hypothesized that the osteogenic factor, bone morphogenetic protein-4 (sBMP-4), is elevated in subjects with both CKD and CAD. Serum was collected from 79 subjects undergoing diagnostic angiography and stratified according to CAD and CKD status. Subjects with both CAD and CKD had significantly elevated sBMP-4 compared to those with only one or no disease. sBMP-4 continued to be associated with the presence of both diseases after adjustment for other risk factors. To determine if sBMP-4 is associated with coronary artery calcification, we compared coronary artery calcium scores (CAC) to sBMP-4 in 22 subjects. A positive correlation between CAC and sBMP-4 was seen. In conclusion, sBMP-4 is elevated in patients with both CAD and CKD and positively correlates with CAC, suggesting a role for sBMP-4 in the increased CAD seen in CKD patients.

BACKGROUND: Critical limb ischemia, a manifestation of severe peripheral atherosclerosis and compromised lower-extremity blood flow, results in a high rate of limb loss. We hypothesized that adenoviral delivery of a constitutively active form of the transcription factor hypoxia-inducible factor-1alpha (ie, Ad2/HIF-1alpha/VP16 or HIF-1alpha) into the lower extremity of patients with critical limb ischemia would be safe and might result in a durable clinical response. METHODS AND RESULTS: This phase I dose-escalation program included 2 studies: a randomized, double-blind, placebo-controlled study and an open-label extension study. In total, 34 no-option patients with critical limb ischemia received HIF-1alpha at doses of 1x10(8) to 2x10(11) viral particles. No serious adverse events were attributable to study treatment. Five deaths occurred: 3 in HIF-1alpha and 2 in placebo patients. In the first (randomized) study, 7 of 21 HIF-1alpha patients met treatment failure criteria and had major amputations. Three of the 7 placebo patients rolled over to receive HIF-1alpha in the extension study. No amputations occurred in the 2 highest-dose groups of Ad2/HIF-1alpha/VP16 (1x10(11) and 2x10(11) viral particles). The most common adverse events included peripheral edema, disease progression, and peripheral ischemia. At 1 year, limb status observations in HIF-1alpha patients included complete rest pain resolution in 14 of 32 patients and complete ulcer healing in 5 of 18 patients. CONCLUSIONS: HIF-1alpha therapy in patients with critical limb ischemia was well tolerated, supporting further, larger, randomized efficacy trials.

OBJECTIVE: To examine duplex ultrasound (US) criteria for carotid in-stent restenosis (ISR). BACKGROUND: Carotid artery stent (CAS) placement is an alternative to surgery for the treatment of carotid stenosis in high surgical risk patients. US is the primary method used to follow carotid stent patency. This study investigates US velocity measurements in carotid ISR. METHODS: Two hundred sixty consecutive patients with CAS placement from June 2000 to June 2004 were followed with serial US. ISR was determined by using the standard US velocity criteria for nonstented carotid artery using peak systolic velocity (PSV), end-diastolic velocity (EDV), and internal carotid artery to common carotid velocity ratio (ICA/CCA ratio). Patients suspected of having carotid ISR > or =50% by US, underwent invasive angiography with stenosis graded by NASCET criteria. Results were compared to patients with nonstented carotid artery stenosis using Two-tailed Student's t-test. RESULTS: PSV and ICA/CCA ratio increased to a greater degree in ISR. In 50-69% stenotic arteries, the mean ICA/CCA ratio was 2.76 +/- 0.7 in the ISR group compared to 2.04 +/- 0.3 in the nonstented carotid group (P < 0.05). In > or =70% stenotic arteries, there were increases in PSV (520 +/- 93 vs. 362 +/- 60, P < 0.05) and ICA/CCA ratio (7.58 +/- 2 vs. 4.51 +/- 1.3, P < 0.05) in ISR versus nonstented carotid arteries, respectively. CONCLUSION: PSV and ICA/CCA ratio in ISR increased to a greater extent for angiographic stenosis > or =50%. PSV 240 cm/sec and ICA/CCA ratio 2.45 are optimal thresholds for > or =50% ISR, and PSV 450 cm/sec and ICA/CCA ratio 4.3 are optimal thresholds for > or =70% ISR.