Phase I/II Study Evaluating AUTO4 in Patients With T Cell Receptor Beta Constant (TRBC)1 Positive T Cell Lymphoma

A Single Arm, Open Label, Multi-centre, Phase I/II Study Evaluating the Safety and Clinical Activity of AUTO4, a CAR T-cell Treatment Targeting TRBC1, in Patients With Relapsed or Refractory TRBC1 Positive Selected T Cell Non-Hodgkin Lymphoma

The purpose of this study is to test the safety and efficacy of AUTO4 a chimeric antigen receptor (CAR) T cell treatment targeting TRBC1 in patients with relapsed or refractory TRBC1 positive selected T-Non-Hodgkin Lymphoma (NHL).

Study Overview

• Status: Terminated
• Conditions: Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; T Cell Non-Hodgkin Lymphoma; Peripheral T-Cell Lymphoma, Not Otherwise Specified
• Intervention / Treatment: Biological: AUTO4

Detailed Description

The study will consist of 2 phases, a Phase I/dose escalation phase and a Phase II/expansion phase. Patients with relapsed or refractory TRBC1 positive selected T-NHL will be enrolled in both phases of the study. Eligible patients will undergo leukapheresis to harvest T cells, the starting material for the manufacture of the autologous CAR-T product AUTO4. Following preconditioning by a chemotherapeutic regimen, the patient will receive AUTO4 intravenously as a single dose following which they will then enter a 24-month follow-up period

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain
    • Vall d'Hebron Institute of Oncology
• United Kingdom
  • Glasgow, United Kingdom
    • Queen Elizabeth University Hospital
  • London, United Kingdom
    • University College London Hospitals NHS Foundation Trust
  • Manchester, United Kingdom
    • Manchester Royal Infirmary Hospital
  • Newcastle upon Tyne, United Kingdom
    • Freeman Hospital, The Newcastle upon Tyne Hospitals NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male or female, aged ≥ 18 years.
2. Willing and able to give written, informed consent to be screened for TRBC1 positive T-NHL and to enter the main study.

3. Confirmed diagnosis of selected T-NHL, including:

   1. Peripheral T cell lymphoma not otherwise specified, or
   2. Angioimmunoblastic T cell lymphoma, or
   3. Anaplastic large cell lymphoma
4. Confirmed TRBC1 positive tumour.
5. Relapsed or refractory disease and have had ≥1 prior lines of therapy.
6. Positron emission tomography (PET)-positive measurable disease per Lugano classification.
7. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1.
8. Adequate bone marrow function without the requirement for ongoing blood products.
9. Adequate renal, hepatic, pulmonary, and cardiac function.
10. For females of childbearing potential (defined as < 2 years after last menstruation or not surgically sterile), a negative serum or urine pregnancy test must be documented at screening, prior to pre-conditioning and confirmed before receiving the first dose of study treatment. For females who are not postmenopausal (< 24 months of amenorrhea) or who are not surgically sterile (absence of ovaries and/or uterus), a highly effective method of contraception together with a barrier method must be used from the start of the pre-conditioning stage and for at least 12 months after the last dose of AUTO4 (study treatment). They must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for 12 months after receiving the last dose of study drug
11. For males, it must be agreed that 2 acceptable methods of contraception are used.
12. No contra-indications for leukapheresis, or the pre-conditioning regimen.

Exclusion Criteria:

Patients meeting any of the following exclusion criteria must not be enrolled into the study:

1. Patients with T cell leukaemia.
2. Females who are pregnant or lactating.
3. Prior treatment with investigational gene therapy or approved gene therapy or genetically engineered cell therapy product or allogeneic stem cell transplant.
4. Known history or presence of clinically relevant central nervous system (CNS) pathology. Patients with a known history or prior diagnosis of optic neuritis or other immunologic or inflammatory disease affecting the CNS.
5. Current or history of CNS involvement by malignancy.
6. Clinically significant, uncontrolled heart disease.
7. Patients with evidence of uncontrolled hypertension or with a history of hypertension crisis or hypertensive encephalopathy.
8. Patients with a history (within 3 months) or evidence of deep vein thrombosis or pulmonary embolism requiring ongoing therapeutic anticoagulation at the time of pre-conditioning.
9. Patients with active gastrointestinal bleeding.
10. Active infectious bacterial, viral disease or fungal disease (hepatitis B virus, hepatitis C virus, human immunodeficiency virus, human T cell lymphotropic virus or syphilis) requiring treatment.
11. Active autoimmune disease requiring immunosuppression.
12. History of other neoplasms unless disease free for at least 2 years (adequately treated carcinoma in situ, curatively treated non-melanoma skin cancer, breast or prostate cancer on hormonal therapy are allowed).
13. Prior treatment with programmed cell death protein 1, programmed death ligand 1, or cytotoxic T lymphocyte-associated protein 4 targeted therapy, or tumour necrosis factor (TNF) receptor superfamily agonists including cluster of differentiation (CD)134 (OX40), CD27, CD137 (41BB), and CD357 (glucocorticoid induced TNF receptor family related protein) within 6 weeks prior to AUTO4 infusion.
14. Research participants receiving any other investigational agents, or concurrent biological, chemotherapy, or radiation therapy.
15. Use of rituximab (or rituximab biosimilar) within the last 6 months prior to AUTO4 infusion.
16. Patients, who in the opinion of the Investigator, may not be able to understand or comply with the safety monitoring requirements of the study.

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

Experimental: AUTO4; Relapsed or refractory T cell non-Hodgkin Lymphoma patients

Biological: AUTO4; AUTO4 (Ritux-QBEND/10-Ritux-CD8 sort-suicide gene generated as a marker/suicide gene for T cells [RQR8]/anti-T cell receptor beta constant [aTRBC]1 CAR T cells). Following pre-conditioning with chemotherapy (cyclophosphamide and fludarabine), patients will be treated with doses from 25 to 900 x 10^6 RQR8/anti-TRBC1 CAR T cells in Phase I. Following dose determination patients will be treated with the selected doses of RQR8/aTRBC1 CAR T cells (AUTO4) in Phase II.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Numbers of Patients With Grade 3 to 5 Toxicity Occurring Within 60 Days of AUTO4 Infusion.	To assess the safety and tolerability of AUTO4 administration. The incidence of Grade 3-5 toxicities occurring within 60 days of AUTO4 infusion.	60 days of AUTO4 infusion
Frequency of Dose-limiting Toxicity (DLT) of AUTO4 Within 28 Days of AUTO4 Infusion.	To identify the recommended Phase II dose and maximum tolerated dose (MTD), if an MTD exists, of AUTO4 by monitoring the frequency of DLT of AUTO4 within 28 days of AUTO4 infusion.	28 days of AUTO4 infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency and Severity of All Adverse Events (AEs) and Serious Adverse Events (SAEs).	All AEs/SAEs were recorded from admission for pre-conditioning chemotherapy (Day -6 relative to AUTO4). Due to the long period between consent and AUTO4 treatment, any AEs/SAEs related to bridging chemotherapy not associated with study procedures did not require reporting as study AEs/SAEs. Any significant events were added to the patient's medical history. All AEs/SAEs related to study procedures (leukapheresis, bone marrow assessments) were reported.	24 months post treatment
To Assess the Overall Safety and Tolerability of AUTO4.	Incidence and severity of opportunistic infections following AUTO4 infusion.	24 months post treatment
Feasibility of Generating AUTO4: Number of Patients Whose Cells Achieve Successful AUTO4 Manufacture as a Proportion of the Number of Patients Undergoing Leukapheresis.	Feasibility of product generation was examined by assessing the number of AUTO4 successfully manufactured as a fraction of the number of patients undergoing leukapheresis (all patients enrolled).	Up to 8 weeks post leukapheresis
Determine the Complete Response (CR) Rate Following Treatment With AUTO4.	Participants achieving CR per Lugano criteria based on independent central radiology review. The Lugano classification of response by 18F (Fluorine isotope 18)-2-fluoro-2-deoxy-D-glucose fluorodeoxyglucose (FDG) positron emission tomography (PET)-computed tomography (CT): no uptake or no residual uptake (when used interim); slight uptake, but below blood pool (mediastinum); uptake above mediastinal, but below or equal to uptake in the liver; uptake slightly to moderately higher than liver; markedly increased uptake or any new lesion (on response evaluation) Non-progressive diseasecomplete metabolic response - score of 1, 2 or 3 in nodal or extranodal sites with or without a residual masspartial metabolic response - score of 4 or 5 with reduced uptake compared with baseline and residual mass(es) of any sizestable disease or no metabolic response - score of 4 or 5 with no obvious change in FDG uptake Progressive disease score 4 or 5 in any lesion	Up to 24 months
Evaluate Duration of Response (DOR) Following Treatment With AUTO4.	DOR was defined as the time from the first observed CR or partial response (PR) to documented disease progression or death due to any cause, for patients who were considered as responders. Patients who received protocol specified anti-cancer treatment post AUTO4 infusion were ignored in the main analysis. Patients who proceeded to stem cell transplantation (SCT) after AUTO4 infusion were censored at the time of SCT (including the conditioning regimen for SCT). Patients who received new non-protocol anticancer therapies other than SCT were censored at the date of last adequate assessment prior to the new therapy. Patients who experienced event after missing two or more scheduled disease assessments were censored at the date of last adequate assessment prior to the event. Data for DOR were pooled for analysis because the number of patients was <5 for all of the groups and the intended model cannot be built with such a small sample size.	Up to 24 months
Evaluate Progression-free Survival (PFS) Following Treatment With AUTO4.	PFS was defined as the time from the first treatment of AUTO4 to documented disease progression/relapse or death due to any cause. If a patient did not have relapse or death due to any reason prior to data cut-off, PFS was censored at the date of the last adequate assessment by default. Patients who received protocol specified anti-cancer treatment post AUTO4 infusion were ignored in the main analysis. Patients who proceeded to SCT after AUTO4 infusion were censored at the time of SCT (including the conditioning regimen for SCT). Patients who received new non-protocol anticancer therapies other than SCT were censored as the date of last adequate assessment prior to the new therapy. Patients who experienced event after missing two or more scheduled disease assessments were censored at the date of last adequate assessment prior to the event	Up to 24 months
Evaluate Overall Survival (OS) Following Treatment With AUTO4.	OS was defined as the time from the first treatment of AUTO4 to death due to any cause. Patients who had not died prior to data cut-off or database finalization were censored at the last contact date. Patients who received SCT after AUTO4 infusion were ignored in the main analysis.	Up to 24 months
Time to Response (PR and CR)	Time taken for participants achieving PR or CR per Lugano criteria based on independent central radiology review. The Lugano classification of response by 18F FDG PET-CT: no uptake or no residual uptake (when used interim); slight uptake, but below blood pool (mediastinum); uptake above mediastinal, but below or equal to uptake in the liver; uptake slightly to moderately higher than liver; markedly increased uptake or any new lesion (on response evaluation) Non-progressive disease: Complete metabolic response - score of 1, 2, or 3 in nodal or extranodal sites with or without a residual mass; Partial metabolic response - score of 4 or 5 with reduced uptake compared with baseline and residual mass(es) of any size	24 months post treatment
Evaluate Time to CR Following Treatment With AUTO4.	The time taken for participants achieving CR per Lugano criteria based on independent central radiology review. The Lugano classification of response by 18F-2-fluoro-2-deoxy-D-glucose FDG PET-CT: no uptake or no residual uptake (when used interim); slight uptake, but below blood pool (mediastinum); uptake above mediastinal, but below or equal to uptake in the liver; uptake slightly to moderately higher than liver; markedly increased uptake or any new lesion (on response evaluation) Non-progressive disease: • Complete metabolic response - score of 1, 2, or 3 in nodal or extranodal sites with or without a residual mass	Up to 24 months
To Determine the Expansion and Persistence of AUTO4 Following Infusion.	RQR8/aTRBC1-CAR positive T cells as determined by polymerase chain reaction at a range of time points in the peripheral blood.	Up to 24 months
Duration of TRBC1 Positive T Cell Aplasia.	Enumeration of circulating T cell receptor beta constant 1 positive T cells assessed by flow cytometry at a range of time points in the peripheral blood.	Up to 24 months

Collaborators and Investigators

• Sponsor: Autolus Limited

Publications and helpful links

General Publications

• Cwynarski K, Iacoboni G, Tholouli E, Menne T, Irvine DA, Balasubramaniam N, Wood L, Shang J, Xue E, Zhang Y, Basilico S, Neves M, Raymond M, Scott I, El-Kholy M, Jha R, Dainton-Smith H, Hussain R, Day W, Ferrari M, Thomas S, Lilova K, Brugger W, Marafioti T, Lao-Sirieix P, Maciocia P, Pule M. TRBC1-CAR T cell therapy in peripheral T cell lymphoma: a phase 1/2 trial. Nat Med. 2025 Jan;31(1):137-143. doi: 10.1038/s41591-024-03326-7. Epub 2024 Nov 11.

Study record dates

Study Major Dates

• Study Start (Actual): August 30, 2018
• Primary Completion (Actual): December 12, 2024
• Study Completion (Actual): December 12, 2024

Study Registration Dates

• First Submitted: July 7, 2018
• First Submitted That Met QC Criteria: July 7, 2018
• First Posted (Actual): July 18, 2018

Study Record Updates

• Last Update Posted (Actual): March 16, 2026
• Last Update Submitted That Met QC Criteria: February 23, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: T cell lymphoma; Relapsed T cell Non-Hodgkin Lymphoma; Refractory T cell Non-Hodgkin Lymphoma; AUTO4
• Additional Relevant MeSH Terms: Lymphadenopathy; Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Hemic and Lymphatic Diseases; Lymphoma, T-Cell; Lymphoma, Large-Cell, Anaplastic; Immunoblastic Lymphadenopathy
• Other Study ID Numbers: AUTO4-TL1; 2017-001965-26 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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