A Phase 1 study evaluating NT-I7 (efineptakin alfa), a long-acting human IL-7, post-tisagenlecleucel (tisa-cel), post-axicabtagene ciloleucel (axi-cel), or post-lisocabtagene maraleucel (liso-cel) in Relapsed/Refractory large B-cell lymphoma

Abstract Autologous CD19 CAR T-cell therapy (CART19) for relapsed/refractory large B-cell lymphoma (r/r LBCL) enables high objective response rates (ORRs), 40-50% complete response (CR) rates and durable remissions. However, relapse post-CART19 is associated with poor prognosis. The degree of in vivo CART19 expansion is associated with improved response rates and duration of response (DoR). NT-I7 (efineptakin alfa) is a long-acting human IL-7 cytokine shown in pre-clinical studies to enhance CART19 proliferation and persistence, leading to improved anti-tumor efficacy. Here we report the results of a completed Phase 1 trial evaluating the safety, tolerability and preliminary anti-tumor activity of NT-I7 following CART19 for r/r LBCL, along with kinetics of CART19 expansion, extended immune-cell subset immunophenotyping, cytokine profiling and pharmacokinetics (PK) of NT-I7. This was a Phase 1, single-arm, open-label, multicenter trial (NCT05075603). Subjects ≥18 yrs with r/r LBCL eligible for standard of care CART19 (tisa-cel, axi-cel or liso-cel) were enrolled. NT-I7 was administered on Day 21 post-CART19 at 7 dose levels (DL) (60, 120, 240, 360, 480, 600 and 720 μg/kg; intramuscular) with 1 subject at DL1 and DL2, followed by a standard 3+3 dose escalation design. Treatment-emergent adverse events (TEAEs) were defined as AEs occuring post-NT-I7 to Day 100 post-CART19. Primary endpoint was safety/tolerability (AEs per CTCAE v5.0; CRS/ICANS per ASTCT) and incidence of dose-limiting toxicities (DLTs). Efficacy was assessed by ORR, DoR, progression-free survival (PFS) and overall survival (OS). Correlative assessments included CART19 expansion kinetics and immune-cell subset profiling by FACS; cytokine profiling; NT-I7 PK; and NT-I7 immunogenicity by anti-drug antibodies (ADA). Seventeen subjects were enrolled and evaluable for the primary endpoint. A protocol deviation occurred in 1 subject; thus, a per-protocol (PP) efficacy analysis was performed with n=16, per the statistical analysis plan. Median age was 64 years, 76.5% male, 76.5% white, 76.5% Stage III/IV, 58.5% bulky or extra-nodal disease and 23.5% double-hit/expressor. A total of 16/17 (94.1%) subjects reported ≥1 TEAE, with 8/17 (47.1%) reporting ≥1 TEAE related to NT-I7 (all Grade 1-2). CRS occurred in 10/17 (58.8%) subjects and ICANS in 2/17 (11.8%) subjects, but no CRS or ICANS was reported post-NT-I7 and no DLTs were observed at any DL. In the PP analysis, 14/16 (87.5%) achieved an ORR (CR 75.0%, PR 12.5%). Median DoR, PFS and OS were not estimable due to a limited follow-up period. Importantly, 7/8 (87.5%) subjects who received ≥480 μg/kg maintained a response at 6-months post-CART19, with 4/8 (50%) in CR. Whereas only 1/8 (12.5%) who received <480 μg/kg maintained a CR at 6-months post-CART19. The first 8 subjects at 60-360 μg/kg DLs received tisa-cel, while at 480-720 μg/kg DLs 1 subject received tisa-cel (480 μg/kg) and 7/8 (87.5%) received axi-cel (n=4) or liso-cel (n=3). CART19 and immune cell subset analyses demonstrated re-expansion of CART19 and endogenous CD4 and CD8 T-cells post-NT-I7, with evidence of proliferation by Ki67 in CART19 and endogenous T-cells as well as a 5-10% increase in stem-cell memory (Tscm) phenotype CART19. However, given differences in CART19 products and NT-I7 DLs, considerable patient-to-patient variability was observed. Cytokine profiling demonstrated increased TNF, IL-5 and IL-7, while IL-6 and IL-1β were not increased. PK analysis for NT-I7 demonstrated a mean Cmax of 1.0 ng/mL (60 μg/kg DL) to 27.3 ng/mL (720 μg/kg DL); mean AUC from time 0 to time of last quantifiable concentration ranged from 96.1 hr*ng/mL (60 μg/kg DL) to 4,765.2 hr*ng/mL (720 μg/kg DL). ADAs were detected at low titer in 3/16 (18.75%) subjects with no neutralizing ADAs. In this Phase 1, open-label, multi-center trial, NT-I7 on Day +21 post-CART19 was safe and well-tolerated. A total of 8/17 (47.1%) subjects reported TEAEs related to NT-I7, but all were Grade 1-2 with no DLTs and no CRS or ICANS post-NT-I7. Preliminary efficacy data suggests NT-I7 ≥480 μg/kg was associated with higher ORR and CR rates. However, subjects receiving NT-I7 at ≥480 μg/kg were also more likely to receive axi-cel or liso-cel, rather than tisa-cel. NT-I7 at 720 μg/kg was determined to be the RP2D. Correlative data suggest earlier NT-I7 administration post-CART19 infusion may better optimize CART19 expansion. Further studies investigating an earlier administration schema are needed.