NY-ESO-1-redirected T Cells in Patients With Advanced Melanoma and Sarcoma (LauT1)

A Phase I Study Evaluating Safety and Feasibility of Redirected Autologous T Cells Expressing a High Affinity TCR Specific for NY-ESO-1 (LauT-1) in Patients With Advanced Melanoma and Sarcoma

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.

Study Overview

• Status: Recruiting
• Conditions: Sarcoma; Advanced Melanoma; Melanoma Metastatic
• Intervention / Treatment: Biological: NY-ESO-1 TCR redirected autologous T cell product; Radiation: Low-dose irradiation; Drug: Non-myeloablative lymphodepleting chemotherapy

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 9
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Virginie Zimmer, Study Coordinator; Phone Number: +41 21 314 97 09; Email: virginie.zimmer@chuv.ch
• Study Contact Backup: Name: Bernhard Gentner, MD; Phone Number: +4179 556 90 20; Email: Bernhard.Gentner@chuv.ch

Study Locations

• Switzerland
  • Canton of Vaud
    • Lausanne, Canton of Vaud, Switzerland, 1011
      • Recruiting
      • Centre Hospitalier Universitaire Vaudois
      • Contact: Bernhard Gentner, MD; Phone Number: +41 79 556 90 20; Email: bernhard.gentner@chuv.ch
      • Contact: Virginie Zimmer, Study Coordinator; Phone Number: +41795566947; Email: virginie.zimmer@chuv.ch
      • Principal Investigator: Bernhard Gentner, MD
    • Lausanne, Canton of Vaud, Switzerland, 1011
      • Not yet recruiting
      • Centre Hospitalier Universitaire Vaudois (CHUV)
      • Contact: Bernhard Gentner, MD; Phone Number: +41 79 556 90 20; Email: bernhard.gentner@chuv.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion criteria at pre-screening

1) Patients with histologically confirmed advanced or metastatic cutaneous melanoma or any type of sarcoma.

Inclusion criteria at screening

1. Patients with sarcoma, who have received at least one line of standard therapy (if available) and failed to respond, progressed or were intolerant to that therapy, will be eligible. If the participant refuses or is, in the opinion of the investigator, ineligible for these treatments, the reason must be documented in the medical record.

2. Patients with metastatic melanoma:

   1. Without proto-oncogene B-Raf (BRAF) mutation who have received at least one line of standard therapy and failed to respond, progressed or were intolerant to that therapy, will be eligible. If the participant refuses or is, in the opinion of the investigator, ineligible for these treatments, the reason must be documented in the medical record.
   2. With BRAF mutation who have received at least two lines of standard therapy and failed to respond, progressed or were intolerant to that therapy, will be eligible. If the participant refuses or is, in the opinion of the investigator, ineligible for these treatments, the reason must be documented in the medical record.
3. Patient must have immunohistochemically documented NY-ESO-1 expression, defined as ≥ 1+ expression on either archival or fresh tumor tissue by immunohistochemistry, in ≥50% of the sampled tumor tissue AND HLA-A*0201 and/or HLA-A*0205 positive, as identified by high-resolution genomic deoxyribonucleic acid (DNA) typing of the HLA-A locus.
4. Age ≥ 18 years
5. Able to undergo apheresis
6. At least one lesion accessible to biopsy for translational research (TR) at D30, without putting the patient at unusual risk.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
8. Life expectancy of greater than 12 weeks.
9. Radiologically measurable disease (as per RECIST v1.1).
10. Adequate organ function

Exclusion Criteria:

1. Patients with an active second malignancy
2. Patients with symptomatic and/or untreated brain metastases, as well as leptomeningeal carcinomatosis. Patients with definitively treated brain metastases will be considered for enrolment after agreement with the Principal Investigator, as long as lesions are stable, there are no new brain lesions, and the patient does not require chronic corticosteroid treatment.
3. History of idiopathic pulmonary fibrosis or evidence of active pneumonitis (any origin). History of radiation pneumonitis in the radiation field (fibrosis) is allowed.
4. History of recent myocardial infarction, or unstable angina, within six months prior to enrolment
5. Patients with prior allogeneic stem cell transplantation or organ transplantation
6. Active severe systemic infections within 2 weeks prior to apheresis
7. Patient requiring regular systemic immunosuppressive therapy. All immunosuppressive medications including but not limited to steroids, mycophenolate mofetil, azathioprine, methotrexate, thalidomide, and anti-Tumor Necrosis Factor-alpha (TNF-alpha) agents must have been discontinued at least 2 weeks before apheresis .
8. History of severe immediate hypersensitivity reaction to any of the agents/ excipients of the study products.
9. Women who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.
10. Subjects, for whom there are concerns that they will not reliably comply with the requirements for contraception, should not be enrolled into the study.
11. Any serious underlying medical condition that could interfere with study medication and potential adverse events.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: Single arm study

Biological: NY-ESO-1 TCR redirected autologous T cell product; 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.; Other Names: LauT-1; Radiation: Low-dose irradiation; 1Gy will be administered using tomotherapy (Accuray) to all irradiable lesions, to all cohorts before the (first) LauT-1 infusion.; Drug: Non-myeloablative lymphodepleting chemotherapy; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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	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.	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)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	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.	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.	24 months
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).	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.	90 days for each patient

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire Vaudois

Publications and helpful links

General Publications

• Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, Jungbluth A, Gnjatic S, Thompson JA, Yee C. Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med. 2008 Jun 19;358(25):2698-703. doi: 10.1056/NEJMoa0800251.
• Dudley ME, Wunderlich JR, Yang JC, Hwu P, Schwartzentruber DJ, Topalian SL, Sherry RM, Marincola FM, Leitman SF, Seipp CA, Rogers-Freezer L, Morton KE, Nahvi A, Mavroukakis SA, White DE, Rosenberg SA. A phase I study of nonmyeloablative chemotherapy and adoptive transfer of autologous tumor antigen-specific T lymphocytes in patients with metastatic melanoma. J Immunother. 2002 May-Jun;25(3):243-51. doi: 10.1097/01.CJI.0000016820.36510.89.
• Robbins PF, Kassim SH, Tran TL, Crystal JS, Morgan RA, Feldman SA, Yang JC, Dudley ME, Wunderlich JR, Sherry RM, Kammula US, Hughes MS, Restifo NP, Raffeld M, Lee CC, Li YF, El-Gamil M, Rosenberg SA. A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T-cell receptor: long-term follow-up and correlates with response. Clin Cancer Res. 2015 Mar 1;21(5):1019-27. doi: 10.1158/1078-0432.CCR-14-2708. Epub 2014 Dec 23.
• Herrera FG, Ronet C, Ochoa de Olza M, Barras D, Crespo I, Andreatta M, Corria-Osorio J, Spill A, Benedetti F, Genolet R, Orcurto A, Imbimbo M, Ghisoni E, Navarro Rodrigo B, Berthold DR, Sarivalasis A, Zaman K, Duran R, Dromain C, Prior J, Schaefer N, Bourhis J, Dimopoulou G, Tsourti Z, Messemaker M, Smith T, Warren SE, Foukas P, Rusakiewicz S, Pittet MJ, Zimmermann S, Sempoux C, Dafni U, Harari A, Kandalaft LE, Carmona SJ, Dangaj Laniti D, Irving M, Coukos G. Low-Dose Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy. Cancer Discov. 2022 Jan;12(1):108-133. doi: 10.1158/2159-8290.CD-21-0003. Epub 2021 Sep 3.
• Ramachandran I, Lowther DE, Dryer-Minnerly R, Wang R, Fayngerts S, Nunez D, Betts G, Bath N, Tipping AJ, Melchiori L, Navenot JM, Glod J, Mackall CL, D'Angelo SP, Araujo DM, Chow WA, Demetri GD, Druta M, Van Tine BA, Grupp SA, Abdul Razak AR, Wilky B, Iyengar M, Trivedi T, Winkle EV, Chagin K, Amado R, Binder GK, Basu S. Systemic and local immunity following adoptive transfer of NY-ESO-1 SPEAR T cells in synovial sarcoma. J Immunother Cancer. 2019 Oct 24;7(1):276. doi: 10.1186/s40425-019-0762-2.
• Park TS, Groh EM, Patel K, Kerkar SP, Lee CC, Rosenberg SA. Expression of MAGE-A and NY-ESO-1 in Primary and Metastatic Cancers. J Immunother. 2016 Jan;39(1):1-7. doi: 10.1097/CJI.0000000000000101.
• Chen JL, Stewart-Jones G, Bossi G, Lissin NM, Wooldridge L, Choi EM, Held G, Dunbar PR, Esnouf RM, Sami M, Boulter JM, Rizkallah P, Renner C, Sewell A, van der Merwe PA, Jakobsen BK, Griffiths G, Jones EY, Cerundolo V. Structural and kinetic basis for heightened immunogenicity of T cell vaccines. J Exp Med. 2005 Apr 18;201(8):1243-55. doi: 10.1084/jem.20042323.
• Derre L, Bruyninx M, Baumgaertner P, Ferber M, Schmid D, Leimgruber A, Zoete V, Romero P, Michielin O, Speiser DE, Rufer N. Distinct sets of alphabeta TCRs confer similar recognition of tumor antigen NY-ESO-1157-165 by interacting with its central Met/Trp residues. Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):15010-5. doi: 10.1073/pnas.0807954105. Epub 2008 Sep 22.
• Gnjatic S, Nishikawa H, Jungbluth AA, Gure AO, Ritter G, Jager E, Knuth A, Chen YT, Old LJ. NY-ESO-1: review of an immunogenic tumor antigen. Adv Cancer Res. 2006;95:1-30. doi: 10.1016/S0065-230X(06)95001-5.
• Raza A, Merhi M, Inchakalody VP, Krishnankutty R, Relecom A, Uddin S, Dermime S. Unleashing the immune response to NY-ESO-1 cancer testis antigen as a potential target for cancer immunotherapy. J Transl Med. 2020 Mar 27;18(1):140. doi: 10.1186/s12967-020-02306-y.
• Cornetta K, Yao J, Jasti A, Koop S, Douglas M, Hsu D, Couture LA, Hawkins T, Duffy L. Replication-competent lentivirus analysis of clinical grade vector products. Mol Ther. 2011 Mar;19(3):557-66. doi: 10.1038/mt.2010.278. Epub 2010 Dec 21.

Study record dates

Study Major Dates

• Study Start (Actual): March 24, 2025
• Primary Completion (Estimated): June 1, 2029
• Study Completion (Estimated): June 1, 2029

Study Registration Dates

• First Submitted: March 17, 2025
• First Submitted That Met QC Criteria: March 20, 2025
• First Posted (Actual): March 21, 2025

Study Record Updates

• Last Update Posted (Actual): May 15, 2026
• Last Update Submitted That Met QC Criteria: May 12, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: metastatic melanoma; Sarcoma; NY-ESO-1; LauT-1; TCR redirected T cell; autolog T-cell
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Skin Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Neoplasms, Connective and Soft Tissue; Nevi and Melanomas; Skin Neoplasms; Skin and Connective Tissue Diseases; Melanoma; Sarcoma; Physical Phenomena; Radiation
• Other Study ID Numbers: CHUV-DO-0026-NYESO1-2023

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No