Flt3 ligand augments immune responses to anti-DEC-205-NY-ESO-1 vaccine through expansion of dendritic cell subsets.

Generating responses to tumor antigens poses a challenge for immunotherapy. This phase II trial (NCT02129075) tested fms-like tyrosine kinase 3 (Flt3) ligand pre-treatment enhancement of responses to dendritic cell (DC)-targeting vaccines. We evaluated a regimen of Flt3L (CDX-301) to increase DCs and other antigen-presenting cells, poly-ICLC (TLR3 agonist that activates DCs) and a vaccine comprising anti-DEC-205-NY-ESO-1, a fusion antibody targeting CD205, linked to NY-ESO-1. High-risk melanoma patients were randomized to vaccine, with and without CDX-301. The end point was immune response to NY-ESO-1. Flt3L increased peripheral monocytes and conventional DCs (cDCs), including cross-presenting cDC1 and cDC2 and plasmacytoid DCs. Significant increases in humoral and T-cell responses and activation of DCs, natural killer cells and T cells were elicited. Transcriptional analyses revealed gene signatures associated with CDX-301 induction of an early, durable immune response. This study reveals in vivo effects of Flt3L on innate immune cells in the setting of vaccination, leading to an immunogenic vaccine regimen.

Examination of Patient-Reported Outcomes in Association with TNF-Inhibitor Treatment Response: Results from a US Observational Cohort Study.

INTRODUCTION: Implementation of a treat-to-target strategy is challenging when the patient and physician prioritize different goals. This study aimed to "translate" improvements in Clinical Disease Activity Index (CDAI) to concepts that resonate with patients (such as pain, fatigue, morning stiffness) by examining the association between changes in disease activity and patient-reported outcomes (PROs) in a national cohort of patients with rheumatoid arthritis (RA) initiating their first biologic treatment. METHODS: Patients in the Corrona registry with moderate or high disease activity (M/HDA) (defined by a CDAI score > 10), prior use of at least one conventional synthetic disease-modifying antirheumatic drug (csDMARD), 12-month follow-up, and initiating their first tumor necrosis factor inhibitor (TNFi) between 1 January 2006 through 1 November 2015 were identified. Patients were stratified on the basis of CDAI during follow-up, and changes in PROs were compared with a test of trend using CDAI-defined groups. RESULTS: Of 1570 patients, 37% achieved sustained remission or low disease activity (remission/LDA), 15% had improving remission/LDA, 12% had worsening M/HDA, and 35% were in sustained M/HDA during 12-month follow-up. Those in sustained remission/LDA had greater magnitude of improvement in physical functioning, pain, fatigue, morning stiffness, patient's global assessment, and quality of life compared with patients in sustained M/HDA (p < 0.001). CONCLUSION: Reduction in disease activity was associated with improvements in PROs, with the greatest improvements seen in those who achieved sustained remission/LDA. These results reinforce the benefits of a treat-to-target approach to RA care and may improve dialogue between patients and providers, support shared decision-making, and reduce "clinical inertia." FUNDING: Corrona, LLC.