Background: Novel immunotherapy approaches have changed the treatment landscape of patients (pts) with high-risk cancers like melanoma, Merkel cell carcinoma (MCC) and cutaneous squamous cell carcinoma (cSCC). However, despite the widespread use of checkpoint inhibitors (CPI) in these indications, most pts either fail to respond or eventually have progressed. NT-I7 (efineptakin alfa) is a long-acting human IL-7 that can increase the number and functionality of T-cells in peripheral blood and within the tumors. NT-I7 in combination with atezolizumab (atezo), may augment the efficacy in high-risk skin cancers. Methods: This is a phase 1b/2a study to evaluate the safety and efficacy of NT-I7 in combination with atezo in pts with CPI- naïve or relapsed/refractory (R/R) high-risk skin cancers. Phase 1b dose escalation followed a 3+3 design, in which pts who received NT-I7 IM every 3 weeks (Q3W) at 3 dose levels (DL1-3): 120, 360, and 840 µg/kg or Q6W at DL4 1200 µg/kg, and atezo IV 1200 mg Q3W. The objectives of the phase 1b were to evaluate dose-limiting toxicity (DLT), determine the MTD and the recommended phase 2 dose (RP2D), pharmacokinetics (PK), pharmacodynamics and preliminary antitumor activity. Results: As of January 14, 2022, 16 pts were enrolled in phase 1b: DL1 (n = 3), DL2 (n = 3), DL3 (n = 7), and DL4 (n = 3). The median age was 66 years [46-86], with ECOG PS 0 in 6 (37%), 1 in 7 (44%) and 2 in 3 (19%), and median number of prior therapies 1 [1-2]. One pt had a DLT at DL3 [Grade (G)3 confusion and G3 increased AST] but no DLTs were reported at DL4 and MTD was not reached. The RP2D was 1200 µg/kg Q6W of NT-I7 plus atezo 1200 mg Q3W. All pts had drug related AEs. Most AEs were G 1- 2 in 11(69%) pts; 5 (31%) in G3. There were no related G4/G5 AEs. Eleven pts had stable disease and the disease control rate was 69% (11/16). Preliminary PK analysis of DL1- 3 showed dose dependent C_max, with T_max at ̃24hr and T½ ranging ̃75hr to 125hr. NT-I7 dose-dependent expansion of the absolute lymphocyte count, CD3⁺, CD4⁺ and CD8⁺ T-cells peaked after one dose and the increase was maintained by repeat dosing until the end of treatment. Immunophenotyping of memory T-cell subsets showed a 5-fold expansion in most T-cell subsets and a 30-fold expansion of the stem cell memory CD8+ T-cell subset (Tscm) at DL4. Conclusions: This trial is the first time an IL-7 cytokine-based therapy and CPI has been assessed in UV induced high-risk skin cancers including in IO refractory pts. The combination of NT-I7 and atezo showed favorable safety and anticancer activity. NT-I7 significantly increased total lymphocyte and the T-cell compartment, with a greatest expansion of the CD8+ Tscm, a vital population for eliciting antitumor activity. Additional safety and efficacy updates will be provided by the ongoing phase 2a trial in CPI-naïve cSCC and MCC and CPI R/R MCC, cSCC and melanoma. Clinical trial information: NCT03901573.