Dermal dendritic cells and epidermal Langerhans cells are APCs that migrate from skin to draining lymph nodes (LN) to drive peripheral tolerance and adaptive immunity. Their migration requires the chemokine receptor CCR7, which directs egress from the skin via dermal lymphatic vessels and extravasation into the LN parenchyma from lymph in the subcapsular sinus. CCR7 is activated by two chemokines: CCL19 and CCL21. CCL21 alone is sufficient for the migration of APCs from skin to LN. CCL19 and CCL21 also bind atypical chemokine receptor (ACKR) 4. ACKR4-mediated CCL21 scavenging by lymphatic endothelial cells lining the subcapsular sinus ceiling stabilizes interfollicular CCL21 gradients that direct lymph-borne CCR7+ APCs into the parenchyma of mouse LN. In this study, we show that ACKR4 also aids APC egress from mouse skin under steady-state and inflammatory conditions. ACKR4 plays a particularly prominent role during cutaneous inflammation when it facilitates Langerhans cell egress from skin and enables the accumulation of dermal dendritic cells in skin-draining LN. Stromal cells in mouse skin, predominantly keratinocytes and a subset of dermal lymphatic endothelial cells, express ACKR4 and are capable of ACKR4-dependent chemokine scavenging in situ. ACKR4-mediated scavenging of dermal-derived CCL19, rather than CCL21, is critical during inflammation, because the aberrant trafficking of skin-derived APCs in Ackr4-deficient mice is completely rescued by genetic deletion of Ccl19. Thus, ACKR4 on stromal cells aids the egress of APCs from mouse skin, and, during inflammation, facilitates CCR7-dependent cell trafficking by scavenging CCL19.

3103 Background: CDC7, a protein with key roles in regulating cell-cycle progression is often over-expressed in malignant cells, particularly those with TP53 mutations. LY3143921, an orally administered ATP-competitive CDC7 inhibitor, demonstrated favorable pre-clinical anti-cancer activity in colorectal cancer (CRC) and squamous non-small cell lung cancer (sqNSCLC), particularly in TP53 mutant models. Methods: Phase Ia (dose escalation) recruited patients (pts) with advanced solid tumors enriched for malignancies associated with TP53 mutation. Pts received LY3143921 OD or BD continuously on a 21-day schedule, using an accelerated 3+3 escalation design, starting at 30 mg OD. Phase Ib recruited pts with CRC or sqNSCLC treated continuously at RP2D, or pts with other advanced tumors treated at RP2D on days 1-3 every 7 days. Radiological assessment was performed every 2 cycles initially. Pts in phase Ib could consent to pre- and on-treatment skin +/- tumor biopsies. Primary objectives: assess safety/tolerability and determine MTD and RP2D of LY3143921. Secondary objectives: evaluate preliminary efficacy and pharmacokinetic (PK) profile of LY3143921. Exploratory objective: correlate efficacy to baseline molecular/genetic alterations, including TP53 mutation and measure markers including pMCM2 in pre- and on- treatment tumor and skin samples. Results: 68 pts were recruited and 67 treated (38 phase Ia, 29 phase Ib). Most frequent drug-related CTCAEs (all grades): nausea (75%), orthostatic hypotension (50%), vomiting (47%), fatigue (45%) & diarrhea (44%). Grade 3-4 LY3143921 related AEs occurred in 17 pts. In phase Ia 8 DLTs occurred in 5 pts (G3 nausea, vomiting, fatigue & hyponatraemia and G2 diarrhea, anorexia & lethargy). RP2D was 360 mg BD (continuous non-fasted dosing schedule). 37 pts were evaluable for radiological response with no complete or partial responses seen, and stable disease (SD) was observed in 24 pts (65%). In phase Ia 3 pts achieved long term SD of 1, 2.5 and 3+ years duration. For evaluable pts treated in phase Ib, SD was seen in 8/12 CRC pts, 1/2 sqNSCLC pts and 2/2 pts treated with the intermittent schedule (median duration 15 weeks, range 6-18+). 2 pts remain on-study. Recruitment ceased due to lack of radiological response according to RECIST. Dose-dependent increases in LY3143921 exposure (Cmax & AUC0-24) were seen. IHC analyses of skin biopsies demonstrated reductions in pMCM2, indicating on-target activity of LY3143921. Pre-clinical testing of combination with standard of care agents is ongoing. Additional PD and PK data will be presented. Conclusions: LY3143921 is well tolerated, exhibits dose-dependent increases in plasma exposure and demonstrates evidence of target inhibition. Significant monotherapy clinical activity was not observed; further analyses should investigate potential predictive response biomarkers and rational combination approaches. Clinical trial information: NCT03096054.