Phase I/II Study of Autologous T Cells to Express T-Cell Receptors (TCRs) in Subjects With Solid Tumors

Phase I/II Study of Autologous T Cells Engineered Using the Sleeping Beauty System to Express T-Cell Receptors (TCRs) Reactive Against Cancer-specific Mutations in Subjects With Solid Tumors

A Phase I/II study of autologous T cells engineered using the Sleeping Beauty transposon/transposase system to express TCR(s) reactive against neoantigens in subjects with relapsed/refractory solid tumors

Study Overview

• Status: Terminated
• Conditions: Gynecologic Cancer; Colorectal Cancer; Pancreatic Cancer; Ovarian Cancer; Cholangiocarcinoma; Adenocarcinoma of Lung; Endometrial Cancer; Non-small Cell Lung Cancer; Ovarian Carcinoma; Squamous Cell Lung Cancer; Ovary Neoplasm; Adenosquamous Cell Lung Cancer
• Intervention / Treatment: Biological: Neoantigen specific TCR-T cell drug product; Biological: Aldesleukin (IL-2)

Detailed Description

A Phase I/II study of autologous T cells engineered using the Sleeping Beauty transposon/transposase system to express TCR(s) reactive against neoantigens in subjects with relapsed/refractory solid tumors.

An HLA Typing and Tumor Neoantigen Mutation Testing Protocol (Protocol # TCR001-002) has been used to identify patients for potential enrollment into this Study Protocol. Subjects who have completed the HLA Typing and Tumor Neoantigen Mutation Testing Protocol, i.e., subjects for whom a TCR matching the subject's somatic mutation(s) and HLA type restriction combination is available in Alaunos' TCR library will be eligible for enrollment on this study.

The Phase I part of this study is a prospective, open-label, dose-escalation study of TCR-T cell drug product in patients with progressive or recurrent solid tumors who have failed standard therapy. The Phase II part is a prospective, open-label, single dose portion of the study. The Phase II part will begin once the MTD/RP2D in the Phase I part has been determined.

Subjects with one of the following histologically confirmed solid tumors will be included:

• Cohort 1: Gynecologic cancer (e.g., ovarian, endometrial)
• Cohort 2: Colorectal cancer
• Cohort 3: Pancreatic cancer
• Cohort 4: Non-small cell lung cancer (NSCLC); NSCLC includes but is not limited to squamous cell carcinoma, adenosquamous carcinoma or adenocarcinomas
• Cohort 5: Cholangiocarcinoma

Subject must have a tumor mutation and HLA typing combination that matches to at least one of the following TCRs in the Alaunos' library (mutation & HLA type):

• KRAS G12D & HLA-A*11:01
• KRAS G12D & HLA-C*08:02
• KRAS G12V & HLA-A*11:01
• KRAS G12V & HLA-C*01:02
• TP53 R175H & HLA-A*02:01
• TP53 R175H & HLA-DRB1*13:01
• TP53 R248W & HLA-A*68:01
• TP53 Y220C & HLA-A*02:01
• TP53 Y220C & HLA-DRB3*02:02
• EGFR E746-A750del & HLA-DPA1*02:01, DPB1*01:01

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Patients who have completed the HLA Typing and Tumor Neoantigen Identification Protocol (TCR001-002) and for whom a TCR(s) matching the subject's somatic mutation(s) and HLA type restriction combination is available in Alaunos' Clinical TCR library

2. Patients who have previously received at least one line of standard systemic therapy for their advanced/metastatic cancer and have either progressed, recurred, or were intolerant to the previous treatment. Specifically:

   • Subgroup 1. Gynecologic cancers (i.e., ovarian or endometrial):

     1. Ovarian cancer
     2. Endometrial cancer
   • Subgroup 2. Colorectal cancer
   • Subgroup 3. Pancreatic cancer
   • Subgroup 4. Non-small cell lung cancer (NSCLC)
   • Subgroup 5. Cholangiocarcinoma
3. Patients must have evaluable or measurable disease per RECIST 1.1 with at least one lesion that can be measured that is not the biopsied lesion.
4. Patients must be able to provide written informed consent.
5. Patients must be age ≥ 18 years.
6. Clinical Performance Status of ECOG 0 or 1. Approval from the Alaunos Medical Monitor is required for ECOG of 2.
7. Patient must be willing and able to provide written informed consent for the long-term follow-up protocol (TCR001-202) for up to 15 years post TCR-T Cell drug product infusion per FDA requirements.
8. Adequate bone marrow reserves as assessed by the following hematology laboratory criteria:
9. Adequate major organ system function
10. A washout period must have elapsed since completion of any prior systemic therapy, and apheresis with guidelines as follows (windows other than what is listed below should be allowed only after consultation with the Medical Monitor); subjects' non-hematologic toxicities from any prior systemic therapy must have recovered to ≤ Grade 1 (with the exception of neuropathy and alopecia) or baseline prior to starting the protocol's therapy.
11. Patients may have undergone minor surgical procedures or limited-field radiotherapy provided any major organ toxicities have recovered to ≤ Grade 1.
12. Female patients must not be pregnant or breastfeeding.

Exclusion Criteria:

1. Patients with known active CNS metastases
2. Concurrent systemic steroid therapy
3. Any form of primary immunodeficiency
4. Patients who have decreased immune competence
5. History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine, aldesleukin or bendamustine
6. Severe chronic respiratory condition
7. History of a bleeding disorder or unexplained major bleeding diathesis
8. Arm B Criteria only: Clinically significant patient history which in the judgment of the principal investigator (PI) would compromise the subject's ability to tolerate high-dose aldesleukin;
9. Any major bronchial occlusion or bleeding not amenable to palliation.
10. Patients with psychiatric illness/social situations at the time of treatment that would limit compliance with study requirements.
11. Participants with known active, uncontrolled bacterial, fungal, or viral infection
12. Patients with a prior history or concurrent malignancy
13. Active unstable or clinically significant medical condition
14. History of any major cardiovascular conditions within the past 6 months

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TCR-T Cell Drug Product; Phase I: Dose-escalation of TCR-T Cell Drug Product Phase II: Single dose of TCR-T Cell Drug Product after MTD/RP2D determine in Phase I portion of the study	Biological: Neoantigen specific TCR-T cell drug product; Phase I: Ascending dose, single Infusion of TCR+ Cells Phase II: Single infusion at the RP2D
Experimental: TCR-T Cell Drug Product with Aldesleukin (IL-2); Phase I: Dose-escalation of TCR-T Cell Drug Product with Aldesleukin (IL-2) Phase II: Single dose of TCR-T Cell Drug Product with Aldesleukin (IL-2) after MTD/RP2D determine in Phase I portion of the study	Biological: Neoantigen specific TCR-T cell drug product; Phase I: Ascending dose, single Infusion of TCR+ Cells Phase II: Single infusion at the RP2D; Biological: Aldesleukin (IL-2); To support growth and activation of TCR-T cell drug product

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Emergent Adverse Events	Treatment-emergent adverse events (TEAEs) were defined as any adverse event that began or worsened after initiation of lymphodepletion and up to 28 days following TCR-T cell infusion. TEAEs were coded using MedDRA and summarized by system organ class and preferred term, severity, and relationship to study treatment. Participants were followed for delayed or ongoing toxicities for up to 1 year.	From initiation of lymphodepletion through Day 28 after TCR-T cell infusion, and through long-term follow-up for up to 1 year.
Frequency of Dose Limiting Toxicities	Number of participants experiencing DLTs, defined as specific adverse events attributable to the TCR-T cell drug product occurring within the first 28 days of infusion. DLTs include, but are not limited to, Grade 4 neutropenia lasting ≥ 14 days, Grade 4 thrombocytopenia, Grade 3 thrombocytopenia with significant bleeding, and ≥ Grade 3 febrile neutropenia with hemodynamic compromise. Non-hematologic DLTs include Grade 3 or 4 Cytokine Release Syndrome (CRS) that does not improve to Grade ≤ 2 within 72 hours, and Grade 3 Immune-effector cell-associated neurotoxicity syndrome (ICANS) that does not resolve to Grade ≤ 2 within 7 days, among others. The severity of adverse events will be graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.	From Day 0 to Day 28 post TCR-T cell drug product infusion.
Determination of Maximum Tolerated Dose (MTD) or Recommended Phase II Dose (RP2D)	The MTD and/or RP2D was to be determined based on dose-limiting toxicities observed during the dose-escalation phase. The planned definition required ≥2 patients at a given dose level to experience a DLT to declare that dose not tolerated.	From Day 0 to Day 28 post TCR-T cell drug product infusion.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility of TCR-T Cell Drug Product Manufacturing	Feasibility will be assessed by the number of participants who met eligibility criteria at each step of the manufacturing process, including inability to undergo apheresis, failure of product manufacture, manufactured product not infused, and successful manufacture and infusion of TCR-T cell drug product.	From apheresis collection to the release of the final TCR-T cell drug product for infusion, estimated to be approximately 5 weeks
TCR-T Cell Persistence	Persistence of TCR-T cells in peripheral blood was assessed by quantitative PCR for vector copy number per 1 × 10⁶ cells at baseline (1 week prior to infusion), predose (Day 0), and multiple post-infusion time points through Month 18. Only quantifiable values are summarized. Samples with "Not Detected (ND)" or "Below the Limit of Quantitation (BLOQ)" are reported as NA and excluded from summary statistics.	Baseline through Month 18 post-infusion.
Percent Change in TCR-T Cell Count From Post Dose to Day 28	Assessed by comparing each participant's highest post-dose TCR-T cell count (copies per 1×10⁶ cells by qPCR) to the TCR-T cell count at Day 28. Percent change was calculated as: ((Day 28 - peak post-dose) / peak post-dose) × 100.	Post-dose through Day 28

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase I: To evaluate the objective response rate (ORR) (RECIST and iRECIST criteria) of subjects with solid cancers who receive TCR-T cell drug product.	Determine the Objective response rate (ORR) per RECIST v1.1 and iRECIST	Up to 2 years
Phase I: To explore translational hypotheses related to molecular signatures, mechanism of action, immunogenicity, and serum cytokine profiles associated with TCR-T cell drug product infusion without IL-2 (Arm A) or with IL-2 (Arm B).	TCR-T cellular persistence in peripheral blood (e.g., Cmax, Tmax, AUCD0-D28, etc.) over time determined by VCN.	Up to 2 years
Phase I: To explore translational hypotheses related to molecular signatures, mechanism of action, immunogenicity, and serum cytokine profiles associated with TCR-T cell drug product infusion without IL-2 (Arm A) or with IL-2 (Arm B).	Insertion-site clonality of TCR-T cell drug product will be measured by tracking the transposon insertion-site(s) of gene-modified cells in peripheral blood samples.	Up to 2 years
Phase I: To explore translational hypotheses related to molecular signatures, mechanism of action, immunogenicity, and serum cytokine profiles associated with TCR-T cell drug product infusion without IL-2 (Arm A) or with IL-2 (Arm B).	Serum cytokine concentrations including, but not limited to IFN-γ, IL-6, TNF-α, GM-CSF, IL-2, IL-7, and IL-15 will be determined by multiplex immunoassay.	Up to 2 years
Phase I: To explore translational hypotheses related to molecular signatures, mechanism of action, immunogenicity, and serum cytokine profiles associated with TCR-T cell drug product infusion without IL-2 (Arm A) or with IL-2 (Arm B).	Immunogenicity elicited against the transgenic components of the TCR therapy (i.e., anti-drug antibody and T-cell responses) will be assessed by immunoassay of peripheral blood and serum samples.	Up to 2 years
Phase II: To explore anti-tumor and immunotherapy response of TCR-T cell drug product without IL-2 (Arm A) or with IL-2 (Arm B)	Objective Response Rate (ORR) is defined as the proportion of FAS subjects achieving a confirmed PR or CR according to iRECIST during study.	Up to 2 years
Phase II: To explore translational hypotheses related to molecular signatures, mechanism of action, immunogenicity, and serum cytokine profiles associated with TCR-T cell drug product infusion without IL-2 (Arm A) or with IL-2 (Arm B).	The collection of tumor tissue samples is to enable the investigation of all T cells (T cell and TCR-T cell infiltration) in the tumor.	Up to 2 years
Phase II: To explore translational hypotheses related to molecular signatures, mechanism of action, immunogenicity, and serum cytokine profiles associated with TCR-T cell drug product infusion without IL-2 (Arm A) or with IL-2 (Arm B).	To evaluate the levels of blood-based tumor neoantigen biomarkers, peripheral blood samples collected from all subjects according to the schedule shown in may be analyzed.	Up to 2 years
Phase II: To evaluate anti-tumor activity (ORR) (iRECIST) of TCR-T cell drug product without IL-2 (Arm A) or with IL-2 (Arm B) in each of the tumor types.	An estimate of the ORR is determined by the proportion of confirmed objective responses and will be summarized separately for each of the tumor type subgroup.	Up to 2 years

Collaborators and Investigators

• Sponsor: Alaunos Therapeutics
• Investigators: Principal Investigator: Scott Kopetz, MD, PhD, MD Anderson

Publications and helpful links

General Publications

• Levy PL, Gros A. Fast track to personalized TCR T cell therapies. Cancer Cell. 2022 May 9;40(5):447-449. doi: 10.1016/j.ccell.2022.04.013. Epub 2022 May 9.

Study record dates

Study Major Dates

• Study Start (Actual): April 4, 2022
• Primary Completion (Actual): August 14, 2023
• Study Completion (Actual): August 14, 2023

Study Registration Dates

• First Submitted: December 6, 2021
• First Submitted That Met QC Criteria: January 3, 2022
• First Posted (Actual): January 18, 2022

Study Record Updates

• Last Update Posted (Estimated): November 7, 2025
• Last Update Submitted That Met QC Criteria: October 23, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: immunotherapy; cell therapy; IL-2; Gene therapy; T lymphocyte; neoantigen; adoptive cell therapy; T cell receptor; TCR-engineered T cells
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Endocrine System Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Intestinal Diseases; Respiratory Tract Diseases; Neoplasms by Histologic Type; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Uterine Diseases; Genital Diseases, Female; Lung Diseases; Endocrine Gland Neoplasms; Pancreatic Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Respiratory Tract Neoplasms; Thoracic Neoplasms; Colonic Diseases; Lung Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Neoplasms, Female; Gonadal Disorders; Carcinoma; Carcinoma, Bronchogenic; Bronchial Neoplasms; Uterine Neoplasms; Adenocarcinoma of Lung; Colorectal Neoplasms; Ovarian Neoplasms; Pancreatic Neoplasms; Carcinoma, Non-Small-Cell Lung; Cholangiocarcinoma; Endometrial Neoplasms; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Intercellular Signaling Peptides and Proteins; Cytokines; Interleukins; Lymphokines; Interleukin-2; aldesleukin
• Other Study ID Numbers: TCR001-201

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: Yes
• Studies a U.S. FDA-regulated device product: No