Background: Intravenous TTI-621 (SIRPα-IgG1 Fc) was previously shown to have activity in relapsed or refractory haematological malignancies. This phase 1 study evaluated the safety and activity of TTI-621 in patients with percutaneously accessible relapsed or refractory mycosis fungoides, Sézary syndrome, or solid tumours. Here we report the clinical and translational results among patients with mycosis fungoides or Sézary syndrome., Methods: This multicentre, open-label, phase 1 study was conducted at five academic health-care and research centres in the USA. Eligible patients were aged 18 years or older; had injectable, histologically or cytologically confirmed relapsed or refractory cutaneous T-cell lymphoma (CTCL) or solid tumours; Eastern Cooperative Oncology Group performance status of 2 or less; and adequate haematological, renal, hepatic, and cardiac function. TTI-621 was injected intralesionally in a sequential dose escalation (cohorts 1-5; single 1 mg, 3 mg, or 10 mg injection or three 10 mg injections weekly for 1 or 2 weeks) and in expansion cohorts (cohorts 6-9; 2 week induction at the maximum tolerated dose; weekly continuation was allowed). In cohort 6, patients were injected with TTI-621 in a single lesion and in cohort 7, they were injected in multiple lesions. In cohort 8, TTI-621 was combined with pembrolizumab 200 mg injections per product labels. In cohort 9, TTI-621 was combined with the standard labelled dose of subcutaneous pegylated interferon alpha-2a 90 μg. The primary endpoint was the incidence and severity of adverse events. The study is registered with ClinicalTrials.gov, NCT02890368, and was closed by the sponsor to focus on intravenous studies with TTI-621., Findings: Between Jan 30, 2017, and March 31, 2020, 66 patients with mycosis fungoides, Sézary syndrome, other CTCL, or solid tumours were screened, 35 of whom with mycosis fungoides or Sézary syndrome were enrolled and received intralesional TTI-621 (escalation, n=13; expansion, n=22). No dose-limiting toxicities occurred; the maximum tolerated dose was not established. In the dose expansion cohorts, the maximally assessed regimen (10 mg thrice weekly for 2 weeks) was used. 25 (71%) patients had treatment-related adverse events; the most common (occurring in ≥10% of patients) were chills (in ten [29%] patients), injection site pain (nine [26%]), and fatigue (eight [23%]). No treatment-related adverse events were grade 3 or more or serious. There were no treatment-related deaths. Rapid responses (median 45 days, IQR 17-66) occurred independently of disease stage or injection frequency. 26 (90%) of 29 evaluable patients had decreased Composite Assessment of Index Lesion Severity (CAILS) scores; ten (34%) had a decrease in CAILS score of 50% or more (CAILS response). CAILS score reductions occurred in adjacent non-injected lesions in eight (80%) of ten patients with paired assessments and in distal non-injected lesions in one additional patient., Interpretation: Intralesional TTI-621 was well tolerated and had activity in adjacent or distal non-injected lesions in patients with relapsed or refractory mycosis fungoides or Sézary syndrome, suggesting it has systemic and locoregional abscopal effects and potential as an immunotherapy for these conditions., Funding: Trillium Therapeutics., Competing Interests: Declaration of interests CQ reports research grants from Celgene; is a clinical investigator for Trillium Therapeutics, MiRagen, Bioniz, and Kyowa Kirin; and reports participation in advisory boards for Helsinn, miRagen, Bioniz, Trillium Therapeutics, and Kyowa Kirin. JAT reports research grants from Merck, Hoffmann-LaRoche, Pfizer, Five Prime, Novartis, Incyte, Trillium Therapeutics, and Xencor; and participation in advisory boards for Neoleukin, AVEO Oncology, and Regeneron. MHT reports research funding to their institution from Bristol Myers Squibb, Merck, Pharmacyclics, AstraZeneca, Eisai, Incyte, EMD Serono, Novartis, Seattle Genetics, AbbVie, Genentech, Eli Lilly, Roche, Acerta Pharma, Genzyme Corporation, and Pfizer; consulting or participation in advisory boards for Bristol Myers Squibb, Eisai, Novartis, Bayer, Sanofi/Genzyme, Array BioPharma, LOXO oncology, Blueprint Medicines, and Arqule; and participation in speakers' bureaus for Bristol Myers Squibb and Eisai. JAD reports speaker fees from Helsinn; and consultant fees from Regeneron. JMZ reports participation in advisory boards for Kyowa Kirin, Secura Bio, Mudi Pharma, Seattle Genetics, Legend Bio tech, and Ono Pharma; and research funding to their institution from Seattle Genetics, AbbVie, Karyopharm, and CRSPR. ARS has been a consultant for Acrotech, Bristol Myers Squibb-Celgene, Kyowa-Hakko-Kirin, and Portolla. SM has been a sub-investigator for Trillium Therapeutics, Bioniz, Kyowa Kirin, Affimed, Galderma, Soligenix, Helsinn, and Eisai; and been on the nurse advisory board for Kyowa Kirin. GHYL, PSP, RAU, NM, and YS report employment by and stock ownership in Trillium Therapeutics. OEA reports research grants from Trillium Therapeutics, Pfizer, and Kyowa Kirin; has been a clinical investigator for Trillium Therapeutics, Bioniz, Kyowa Kirin, Affimed, Galderma, Soligenix, Helsinn, and Eisai; and reports participation in advisory boards for Bioniz, Trillium Therapeutics, Kyowa Kirin, Medivir, and Almirall. CJ declares no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)