HERV-E TCR Transduced Autologous T Cells in People With Metastatic Clear Cell Renal Cell Carcinoma

A Phase I Study of HERV-E TCR Transduced Autologous T Cells in Patients With Metastatic Clear Cell Renal Cell Carcinoma

Background:

Gene transfer is a new cancer therapy takes white blood cells from a person and grows them in a lab. The cells are changed with a virus to attack tumor cells, then returned to the person. Researchers want to see if this therapy fights kidney cancer cells.

Objective:

To see if gene transfer is safe and causes tumors to shrink.

Eligibility:

People at least 18 years old with certain kidney cancer

Design:

Participants will be screened with blood and urine tests. They may have:

• Scans
• Heart, lung, and eye tests
• Lab tests
• Tumor samples taken

Participants will have leukapheresis. Blood will be removed by a needle in an arm. It will go through a machine that removes white blood cells. Plasma and red cells will be returned through a needle in the participant s other arm.

Participants cells will be grown in the lab and genetically changed.

Participants will stay in the hospital 2-3 weeks. There they will:

• Get 2 chemotherapy drugs by catheter (thin plastic tube) inserted into a vein in the chest.
• Get the changed cells via catheter.
• Get a drug to increase white blood cell count and one to make the cells active.
• Recover for about a week.
• Have lab and blood tests.

After leaving the hospital, participants will:

• Take an antibiotic for several months.
• Have leukapheresis.
• Have one- or two-day clinic visits every few weeks for 2 years, and then as determined by their doctor. These will include blood and lab tests, imaging studies, and physical exam.

Participants will have follow-up checks for up to 15 years.

Study Overview

• Status: Active, not recruiting
• Conditions: Kidney Cancer
• Intervention / Treatment: Biological: cell infusion

Detailed Description

Metastatic renal cell carcinoma (RCC) is an incurable condition. Current therapy for this disease consists of the serial administration of agents such as VEGF, mTOR inhibitors and immunotherapy (high-dose (HD) IL-2 or immune-checkpoint inhibitors). Long-term survival can be achieved with high-doses IL-2 or immune-checkpoint inhibitors. However, of those patients treated with immunotherapy, three quarters will not respond at all and only 5-8% will achieve a complete and durable response.

Allogeneic hematopoietic stem cell transplantation is also capable of inducing prolonged disease regression in patients with metastatic clear cell RCC (ccRCC). In vitro studies have established that transplanted donor T-cells targeting antigens expressed on RCC cells mediate these anti-tumor effects. However, hematopoietic stem cell transplantation can be toxic and associated with a 10-20% risk of procedure-related mortality. The observation that transplanted donor T-cells have the potential to cure a subset of patients with metastatic disease forms the basis for continued efforts in our laboratory to harness the power of T-cells to cure this disorder.

Our team isolated a tumor-specific cytotoxic T lymphocyte (CTL) line from peripheral blood mononuclear cells (PBMCs) obtained after an allogeneic transplant from a patient who showed prolonged tumor regression. Using limiting dilution cloning, we identified an allogeneic (derived from the stem cell donor) CD8+ T-cell clone that killed ccRCC cells in an HLA A11 restricted fashion. Using cDNA expression cloning, we identified a HERV-E derived antigen expressed in the patient s ccRCC cells to be the target of this T-cell clone. Remarkably, we found this HERV-E was expressed in the majority of ccRCC cells with no expression in normal tissues. Based on the identification of the antigenicity of the HERV-E transcripts in ccRCC, our team in collaboration with Dr. Nishimura s laboratory (Loyola University Cardinal Bernardin Cancer Center) has cloned, expressed and characterized the TCR from this CD8+ T-cell clone that recognizes an HLA A11 restricted HERV-E antigen.

This research protocol is therefore designed to evaluate the safety and effectiveness of infusion of HERV-E TCR transduced CD8+/CD34+ enriched T cells in HLA-A*11:01 positive patients with metastatic clear cell RCC. Subjects will receive a novel non-myeloablative immunosuppressive conditioning regimen of cyclophosphamide and fludarabine followed by an infusion of HERV-E TCR transduced CD8+/CD34+ enriched T cells. To mediate T cell survival and sustain function, moderate-doses of IL-2 (aldesleukin) will be administered intravenously twice a day for 14 doses.

The primary endpoint is safety by day 21. Secondary endpoints will include overall response rate, progression-free survival and overall survival. Exploratory studies will include persistence of circulating HERV-E TCR transduced CD8+/CD34+ enriched T cells, changes in immune cell subsets and activation status of T cells, as well as, other immunologic determinants with clinical outcomes at baseline, at different time points during treatment and at the time of disease progression.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

• INCLUSION CRITERIA:
• Patients must have histologically confirmed RCC with clear-cell component by the Laboratory of Pathology of the NIH and/or outside Pathology Department prior to entering this study.
• Patients must be HLA-A 11:01 positive (confirmed by HLA typing at the NIH DTM)
• Patients must have measurable disease per RECIST version 1.1 and have disease progression during or after the last treatment regimen and within 6 months before study enrollment
• Patients must have received at least one antiangiogenic drug and an immune-checkpoint inhibitor (i.e. nivolumab) unless the patient has contraindications to receiving these medications, the agents are not available to the patient, or the patient declines to receive these drugs due to personal preference.
• Patients must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, the duration of study participation and 180 days (female patients) or 90 days (male patients) after the end of the treatment if sexually active and able to bear or beget children. In addition, male patients must refrain from sperm donation for 90 days after the final dose of investigational product. Female patients must refrain from egg cell donation for 180 days after the final dose of investigational product
• Patients must be between the ages of 18 and 75 years.
• Patient must have an anticipated life expectancy of at least 3 months.
• Patients must have a performance status of 0 or 1 ECOG performance status (PS) scale.
• Patients must have a caregiver willing to stay with them during the first month of treatment (30 days +/- 7 days).
• Patients receiving treatment with bisphosphonates or denosumab are eligible for enrollment if on a stable dose for greater than or equal to 4 weeks

• Serology:

  • Seronegative for HIV antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune-competence and thus be less responsive to the experimental treatment and more susceptible to its toxicities.)
  • Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then patient must be tested for the presence of antigen by RT-PCR and be HCV RNA negative.

• Organ Function

  • Hematology
  • Absolute neutrophil count greater than or equal to 500/ microL
  • WBC greater than or equal to 1500/microL
  • Platelet count greater than or equal to 75.000/microL (without transfusional support
  • Chemistry
  • Serum AST/ALT less than or equal to 2.5 x upper limit of normal (ULN)
  • Total bilirubin less than or equal to 1.5 mg/dl except for patients with Gilbert s syndrome who must have a total bilirubin less than or equal to 3 mg/dl
  • Creatinine clearance greater than or equal to 50 ml/min/1.73m^2 by the method of CKI-EPI or >=50 ml/min by the method of 24h Clearence of Creatinine Calculation
  • INR < 1.5
  • Cardiology
  • Estimated left ventricular ejection fraction by echocardiography greater than or equal to 45%
  • Respiratory
  • Predicted DLCO / Alveolar Volume Adjusted by PFT >= 45%

EXCLUSION CRITERIA:

• Patients that require immediate therapy due to tumor mass effects or spinal cord compression.
• Patients must not have had standard of care anti-VEGFR therapy (mean half-life around 30 hours), mTOR inhibitors (mean half-life around 30 hours), at least for the last 7 days prior to T-cell infusion and radiotherapy, or major surgery within the last 2 weeks prior to T-cell infusion. For PD-1/PD-L1 inhibitors or CTLA-4 inhibitors, a 4-week period must have elapsed before T-cell infusion. For recent experimental therapies a 28-day period must have elapsed before infusing expanded T-cells.

• Patients with active CNS involvement by malignancy either by imaging or cerebrospinal fluid involvement or biopsy-proven (due to poor prognosis and potential for neurological dysfunction that would confound evaluation of neurological and other adverse events) except for:

  1. Patients with 3 or fewer brain metasteses of <1cm treated with either stereotactic or gamma knife radiotherapy and remained stable on MRI for 2 weeks are eligible.
  2. Patients with surgically resected brain metastases and no evidence of active disease in the CNS at the time of screening evaluation are eligible.
• Patients with hypercalcemia (>10 mg/dL) of malignancy.
• Any prior Grade greater than or equal to 3 immune-related adverse event (irAE) while receiving immunotherapy, including anti-CTLA4 treatment that requires long-term immunosuppressive therapy. Note: Active or history of vitiligo or hypothyroidism will not be a basis for exclusion.
• Patients with second malignancies in addition to their clear cell RCC are not eligible if the second malignancy has required systemic treatment within the past 4 years or is not in complete remission. There are exceptions to this criterion: successfully treated non-metastatic basal cell, squamous cell skin carcinoma, in situ non-invasive cervical cancer and in situ non-invasive breast cancer.
• Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant.
• Active coagulation disorders or other major uncontrolled medical illnesses of the respiratory, endocrine, renal, gastrointestinal, genitourinary or immune system, uncontrolled systemic infection, active obstructive or restrictive pulmonary disease.
• Patients who have recent history of cerebrovascular accident, transient ischemic attack should be cleared by the neurology consult service before enrolling this study.
• Patients who have recent history of coronary artery disease or cardiac arrhythmia should be cleared by the cardiology consult service before enrolling this study.
• Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
• Patients with autoimmune diseases such as Crohn's disease, ulcerative colitis, rheumatoid arthritis, autoimmune hepatitis or pancreatitis, and systemic lupus erythematosus that requires treatment with chronic immunosuppressive therapy.
• Systemic corticosteroid steroid therapy of any dose is not allowed within 2 days prior to enrollment.

• The following are exceptions to this criterion:

  • Intranasal, inhaled, and topical steroids
  • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent
  • Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
• History of severe immediate hypersensitivity reaction to any of the agents used in this study.
• Unable to understand the investigational nature of the study or give informed consent and does not have a legally authorized representative or surrogate that can provide informed consent.
• Any condition that, in the opinion of the investigator, would interfere with evaluation of the investigational product or interpretation of subject safety or study results.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Level 1 is 1 x 10^6 HERV-E TCR transduced CD8+/CD34+ enriched T-cells per kg body weight; Participants with Metastatic Clear Cell Renal Cell Carcinoma will receive a lymphodepleting chemotherapy with cyclophosphamide and fludarabine followed by an infusion of 1 x 10^6 HERV-E TCR transduced CD8+/CD34+ enriched T-cells per kg body weight. Following infusion of HERV-E T-cells, participants will receive IL-2 (aldesleukin) which will be administered intravenously twice a day for 14 doses.	Biological: cell infusion; This is a phase 1 trial of HERV-E TCR transduced CD8+/CD34+ T cells in HLA-A*11:01 positive patients with metastatic ccRCC. The study is planned based on a Phase 1 3+3 dose escalation design. The maximum tolerated dose (MTD) is defined as the highest dose at which 0 or 1 patient in six has experienced a dose limiting toxicity (DLT). Patients with evaluable advanced/metastatic ccRCC will be recruited in up to 4 dose levels.
Experimental: Level 2 is 5 x 10^6 HERV-E TCR transduced CD8+/CD34+ enriched T-cells per kg body weight; Participants with Metastatic Clear Cell Renal Cell Carcinoma will receive a lymphodepleting chemotherapy with cyclophosphamide and fludarabine followed by an infusion of 5 x 10^6 HERV-E TCR transduced CD8+/CD34+ enriched T-cells per kg body weight. Following infusion of HERV-E T-cells, participants will receive IL-2 (aldesleukin) which will be administered intravenously twice a day for 14 doses.	Biological: cell infusion; This is a phase 1 trial of HERV-E TCR transduced CD8+/CD34+ T cells in HLA-A*11:01 positive patients with metastatic ccRCC. The study is planned based on a Phase 1 3+3 dose escalation design. The maximum tolerated dose (MTD) is defined as the highest dose at which 0 or 1 patient in six has experienced a dose limiting toxicity (DLT). Patients with evaluable advanced/metastatic ccRCC will be recruited in up to 4 dose levels.
Experimental: Level 3 is 1 x 10^7 HERV-E TCR transduced CD8+/CD34+ enriched T-cells per kg body weight; Participants with Metastatic Clear Cell Renal Cell Carcinoma will receive a lymphodepleting chemotherapy with cyclophosphamide and fludarabine followed by an infusion of 1 x 10^7 HERV-E TCR transduced CD8+/CD34+ enriched T-cells per kg body weight. Following infusion of HERV-E T-cells, participants will receive IL-2 (aldesleukin) which will be administered intravenously twice a day for 14 doses.	Biological: cell infusion; This is a phase 1 trial of HERV-E TCR transduced CD8+/CD34+ T cells in HLA-A*11:01 positive patients with metastatic ccRCC. The study is planned based on a Phase 1 3+3 dose escalation design. The maximum tolerated dose (MTD) is defined as the highest dose at which 0 or 1 patient in six has experienced a dose limiting toxicity (DLT). Patients with evaluable advanced/metastatic ccRCC will be recruited in up to 4 dose levels.
Experimental: Level 4 is 5 x 10^7 HERV-E TCR transduced CD8+/CD34+ enriched T-cells per kg body weight; Participants with Metastatic Clear Cell Renal Cell Carcinoma will receive a lymphodepleting chemotherapy with cyclophosphamide and fludarabine followed by an infusion of 5 x 10^7 HERV-E TCR transduced CD8+/CD34+ enriched T-cells per kg body weight. Following infusion of HERV-E T-cells, participants will receive IL-2 (aldesleukin) which will be administered intravenously twice a day for 14 doses.	Biological: cell infusion; This is a phase 1 trial of HERV-E TCR transduced CD8+/CD34+ T cells in HLA-A*11:01 positive patients with metastatic ccRCC. The study is planned based on a Phase 1 3+3 dose escalation design. The maximum tolerated dose (MTD) is defined as the highest dose at which 0 or 1 patient in six has experienced a dose limiting toxicity (DLT). Patients with evaluable advanced/metastatic ccRCC will be recruited in up to 4 dose levels.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Adverse Events at Least Possible Attributed to Treatment Regime for Each Dose Level Using the Common Terminology Criteria for Adverse Events Version 5.0 Except for Hematological Toxicities	Toxicity profile at least possible attributed to treatment regime for each dose level using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 except for hematological toxicities Toxicity profile as measured by using the Common Terminology Criteria for Adverse Events (CTCAE version 5.0) for grade 2 and above. According to https://ctep.cancer.gov/, CTCAE is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term. CTCAE grades are defined as: Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate instrumental activities of daily living. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4 Life-threatening consequences; urgent intervention indicated.	21 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate Based on the Revised Response Evaluation Criteria in Solid Tumors (RECIST) Guideline (Version 1.1)	The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The participant's best response assignment will depend on the achievement of both measurement and confirmation criteria. Partial Response (PR): > 30% decrease in SUL peak; minimum 0.8 unit decrease. Verification with follow-up study if anatomic criteria indicate disease progression. Progressive Disease (PD): > 30% increase in SUL peak (minimum 0.8 unit increase in SUL peak), > 75% increase in TLG of the 5 most active lesions, Visible increase in extent of FDG uptake, or new lesions. Verification with follow-up study if anatomic criteria indicate complete or partial response. Stable Disease (SD): Does not meet other criteria.	Baseline until date of first documented disease progression or date of death from any cause, whichever comes first, assessed up to Day 127
Overall Duration of Response (Days) Based on the Revised Response Evaluation Criteria in Solid Tumors (RECIST) Guideline (Version 1.1)	Overall duration of response (days) based on the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) The duration of overall response is measured from the time measurement criteria are met for Complete Response or Partial Response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).	Baseline until date of first documented response assessed up to Day 127
Median In Weeks to Progression-free Survival	Median in weeks of Progression-free survival. Progression-free survival is defined as from the time of initiation of treatment to the occurrence of disease progression or death, whichever occurs first. Disease progression is defined using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (RECIST 1.1), at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression.	Baseline up to Day 192
Median Overall Survival	Median Overall Survival. Overall survival is defined as the time from treatment initiation to death from any cause.	ongoing

Collaborators and Investigators

• Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Collaborators: Loyola University Medical Center (LUMC)
• Investigators: Principal Investigator: Richard W Childs, M.D., National Heart, Lung, and Blood Institute (NHLBI)

Publications and helpful links

General Publications

• Barisic S, Brahmbhatt EM, Cherkasova E, Spear TT, Savani U, Pierre S, Scurti GM, Chen L, Igboko M, Nadal R, Zeng G, Parry G, Stroncek DF, Highfill S, Dalheim AV, Reger R, Nishimura MI, Childs RW. Regression of renal cell carcinoma by T cell receptor-engineered T cells targeting a human endogenous retrovirus. J Immunother Cancer. 2024 Sep 11;12(9):e009147. doi: 10.1136/jitc-2024-009147.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): July 20, 2018
• Primary Completion (Actual): October 31, 2023
• Study Completion (Estimated): March 3, 2029

Study Registration Dates

• First Submitted: November 23, 2017
• First Submitted That Met QC Criteria: November 25, 2017
• First Posted (Actual): November 28, 2017

Study Record Updates

• Last Update Posted (Actual): April 28, 2026
• Last Update Submitted That Met QC Criteria: April 8, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: genetically modified lymphocytes; tumor antigens; T cell receptor immunotherapy; genomic retroviral elements
• Additional Relevant MeSH Terms: Urogenital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urologic Neoplasms; Kidney Neoplasms; Therapeutics; Drug Therapy; Surgical Equipment; Equipment and Supplies; Artificial Organs; Drug Delivery Systems; Infusion Pumps; Insulin Infusion Systems
• Other Study ID Numbers: 180012; 18-H-0012

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All IPD that underlie results in a publication
• IPD Sharing Time Frame: At the time of publication or by the end of the protocol, whichever comes first, and available indefinitely.
• IPD Sharing Access Criteria: Data will be shared through Figshare, which is an open access repository.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

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