A Phase 1 interventional study of NY-ESO-1 TCR redirected autologous T cell product and Low-dose irradiation in Advanced Melanoma, Melanoma Metastatic and Sarcoma, sponsored by Centre Hospitalier Universitaire Vaudois. Recruiting at 2 sites in Switzerland. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-05-15.
Sponsored by Centre Hospitalier Universitaire Vaudois · Phase 1, Interventional, and Treatment
A single center, dose escalaion, Phase I clinical trial to demonstrate safety and efficacy of LauT-1, autologous "New York Esophageal Squamous Cell Carcinoma-1 T-Cell Receptor (NY-ESO-1 TCR)-directed T cells in combination with non-myeloablative (NMA) lymphodepleting chemotherapy and low dose irradiation (LDI) in patients with NY-ESO-1 positive sarcoma and melanoma.
In this study, the investigators target the cancer testis antigen NY-ESO-1, which is highly expressed in a subset of sarcoma and melanoma but is largely absent in normal tissues. The affinity enhanced, Human Leukocyte Antigen - A2 (HLA-A2) restricted I53F T-cell receptor (TCR) used in this study is derived from a TCR originally isolated from a melanoma patient and recognizes the 157-165 epitope of the NY-ESO-1 protein with high affinity. The patients' own T-cells will be isolated, then genetically modified to express the I53F NY-ESO-1 TCR and expanded to generate the product "LauT-1", which is reinfused into the patients following lymphodepleting chemotherapy (LDCT) and low dose tumor irradiation (LDTI). LDCT allows maximal expansion of the infused T cells, and LDTI has been shown to inflame the tumor microenvironment in preliminary clinical data from recent studies, which may be useful to enhance T-cell infiltration and provide co-stimulatory signals within the tumor microenvironment, thereby maximising the chance to detect and potentially eliminate NY-ESO-1 expressing tumor cells.
In the current phase I study, the investigators assess the safety, maximum tolerated dose (MTD) and feasibility of adoptive transfer of LauT-1 after LDCT and LDTI in HLA-A*0201 and/or HLA-A*0205 positive patients with advanced melanoma or sarcoma expressing NY-ESO-1. The experimental products are given initially to a group of 3 patients (safety cohort; cohort 1). If safe, the next 6 patients will be enrolled using a rule-based 3-patient cohort dose-escalation design using split-dosing to determine the MTD of LauT-1 (cohorts 2 and 3).
Procedures:
After confirming the expression of the NY-ESO-1 protein in at least 50% of the tumor cells and the presence of a permissive HLA allele during the pre-screeening procedure, patients eligible for the study will be undergo medical screening and registration to the study, followed by leukapheresis for the collection of autologous white blood cells (T lymphocytes) for the production of the gene-modified LauT-1 product. After successful leukapheresis, patients are allowed to receive a bridging therapy at the discretion of the PI/treating physician.
If all conditions are met and LauT-1 production is completed, the patient will start intravenous (IV) non-myeloablative lymphodepleting chemotherapy (LDCT) composed of fludarabine and cyclophosphamide. Both treatments will be started on the same day. Fludarabine will be given for four days, and cyclophosphamide for 2 days. LDTI will be administered as a single dose on Day 0 to all irradiable lesions using tomotherapy.
On D0, patients will receive NY-ESO-1 TCR T cell infusion, intravenously. Supportive care will be given as needed during the whole treatment period, and patients will be discharged according to institutional practice standards once they have achieved hematologic recovery, in the absence of other reasons for hospitalization. Patients will then be followed weekly in the outpatient clinic until the end of the Treatment-Limiting Toxicity (TLT) period. For cohort 1, the TLT period which extends from the first day of lymphodepleting chemotherapy to D30 after LauT-1 infusion. For cohorts 2 and 3, the TLT period extends from the first day of lymphodepleting chemotherapy to D45 after the first LauT-1 infusion, but no less than 30 days after the second LauT-1 infusion (which may extend the 45-day period by 6 days). After the end of treatment visit, patients will be followed at the outpatient clinic by clinical \& laboratory examination, as well as tumor assessment according to study schedule.
Inclusion criteria at pre-screening
1) Patients with histologically confirmed advanced or metastatic cutaneous melanoma or any type of sarcoma.
Inclusion criteria at screening
Patients with metastatic melanoma:
Exclusion Criteria:
Biological: NY-ESO-1 TCR redirected autologous T cell product · Radiation: Low-dose irradiation · Drug: Non-myeloablative lymphodepleting chemotherapy
Ex vivo expanded autologous CD4+/CD8+ cells expressing the transgenic TCR I53F recognizing NY-ESO-1 peptides presented on tumor cells in the context of HLA-A\*02. Cohort 1: The LauT-1-ACT infusion contains a minimum of 3x10\^8 transduced cells (i.e. CD3+vβ13.1+) and a maximum of 1x10\^10 total cells. Cohort 2 : Patients will receive a fixed dose of 3x10\^8 transduced LauT-1 cells (i.e. CD3+vβ13.1+) split over 2 administrations. Cohort 3: Patients will receive a fixed dose of 6x10\^8 transduced LauT-1 cells (i.e. CD3+vβ13.1+) split over 2 administrations.
Also known as: LauT-1
1Gy will be administered using tomotherapy (Accuray) to all irradiable lesions, to all cohorts before the (first) LauT-1 infusion.
Cohort 1: Fludarabine (30 mg/m2 per day, from D-6 to D-3) and cyclophosphamide (2400 mg/ m2 x 2 days, on days -6 and -5) are administered as an IV infusion. The cyclophosphamide dose may be reduced to 1800mg/m2 on days -6 and -5, if the patient has previously been exposed to significant cumulative doses of chemotherapy). Cohorts 2 and 3: Fludarabine (30 mg/m2 per day, from D-6 to D-3) and cyclophosphamide (900 mg/ m2 x 2 days, on days -6 and -5) are administered as an IV infusion.
Safety as measured by the incidence of treatment emergent adverse events
Safety of LauT-1 plus LDI after lymphodepleting chemotherapy will be established by classifying the observed toxicities by the MedDRA system and grading them using the National Cancer Institute (NCI) Common Toxicity Criteria (CTCAE Version 5.0), American Society for Transplantation and Cellular Therapy (ASTCT) Cytokine Release Syndrom (CRS) or European Hematology Association (EHA) / European Society for Blood and Marrow Transplantation (EBMT) consensus grading for immune effector cell-associated hematotoxicity (ICAHT) , as applicable.
Time frame: 90 days following (first) LauT-1 infusion
Feasibility as measured by the rates of production failure and drop-outs before infusion
Feasibility of LauT-1 production and administration will be evaluated as the number of patients who receive LauT-1 at the intended dose according to the assigned dose-level, among all registered patients
Time frame: From start of LauT-1 production to administration of intended dose (Cohort 1: 3 weeks after start of LauT-1 production; Cohorts 2-3: second administration of LauT-1 - up to 9 weeks of start of LauT-1 production)
Maximum tolerated dose (MTD) for LauT-1 (applies to Cohorts 2 and 3)
Defined as the highest LauT-1 dose where no TLTs are observed in at least 3 treated patients, or a maximum of 1 non-lethal TLT is observed in a minimum of 5 treated patients.
Time frame: End of TLT period (which extends from the first day of lymphodepleting chemotherapy to D45 after the first LauT-1 infusion, but no less than 30 days after the second LauT-1 infusion (which may extend the 45-day period by 6 days)
Long term safety as measured by the incidence of TEAE
Evaluated by documenting clinical and laboratory abnormalities, absence of replication-competent lentivirus, absence of abnormal clonal proliferation and organ toxicity using the MedDRA classification and the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v5.0).
Time frame: 24 months
Objective response rate (ORR)
Evaluated according to Response Evaluation Criteria In Solid Tumors 1.1 (RECIST 1.1), overall and by cohort. ORR is defined as the rate of patients with best overall response objective response (Complete Response (CR) or Partial Response (PR)) within the first 90 days following LauT-1 infusion.
Time frame: 90 days for each patient
Disease control rate (DCR)
Evaluated according to RECIST 1.1, overall and by cohort. DCR is defined as the rate of patients with best overall response stable disease (for at least 3 months) or objective response (CR or PR) across all assessment time-points during the period from enrollment to termination of follow-up or progression (if it occurs before the end of follow-up).
Time frame: 2 years
Progression-free survival (PFS)
Is evaluated at 6, 12 and 24 months, where PFS is defined as the time from enrolment until objective tumor progression (using RECIST criteria) or death, if not documented progression.
Time frame: 24 months
Overall survival (OS)
OS rate is defined as the time from enrolment until death from any cause. If there is no death date, the patient will be censored at the last day the patient was known to be alive.
Time frame: 24 months
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Centre Hospitalier Universitaire Vaudois