Clinical Trials /

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

NCT03354390

Description:

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. Sponsoring Institute: National Heart, Lung, and Blood Institute ...

Related Conditions:
  • Clear Cell Renal Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: HERV-E TCR Transduced Autologous T Cells in People With Metastatic Clear Cell Renal Cell Carcinoma
  • Official Title: A Phase I Study of HERV-E TCR Transduced Autologous T Cells in Patients With Metastatic Clear Cell Renal Cell Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: 180012
  • SECONDARY ID: 18-H-0012
  • NCT ID: NCT03354390

Conditions

  • Kidney Cancer

Interventions

DrugSynonymsArms
cell infusion1

Purpose

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. Sponsoring Institute: National Heart, Lung, and Blood Institute

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 7 days.

      The primary endpoint is safety by day 21. Secondary endpoints will include overall response
      rate, progressionfree survival and overall survival. We will also evaluate for the
      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.
    

Trial Arms

NameTypeDescriptionInterventions
1Experimental1 x 10e6 HERV-E TCR transduced CD8/CD34 cells per kg body weight
    2Experimental5 x 10e6 HERV-E TCR transduced CD8/CD34 cells per kg body weight
      3Experimental1 x 10e7 HERV-E TCR transduced CD8/CD34 cells per kg body weight
        4Experimental5 x 10e7 HERV-E TCR transduced CD8/CD34 cells per kg body weight

          Eligibility Criteria

                  -  INCLUSION CRITERIA:
          
                    -  Patients must have histologically confirmed RCC with clear-cell component by the
                       Laboratory of Pathology of 43T The National Institutes of Health43T (NIH) 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 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) (2-week washout from antiangiogenic drug therapy and 4-week
                       washout from immunecheckpoint inhibitor is required) 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 with 3 or fewer brain metastases that have been treated with stereotactic
                       radiosurgery and remained stable on MRI for at least 2 months after treatment without
                       evidence for CNS progression, steroids or antiepileptic medications are eligible.
                       Patients with surgically resected brain metastases are eligible. These patients may be
                       enrolled at the discretion of the Principal Investigator.
          
                    -  Patients must be between the ages of 18 and 70 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.
          
                    -  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 1000/ microL
          
                         -  WBC greater than or equal to 3000/microL
          
                         -  Platelet count greater than or equal to 100.000/microL (without transfusional
                            support)
          
                         -  Hemoglobin greater than or equal to 8gr/dl (without transfusional support)
          
                         -  Chemistry
          
                         -  Serum AST/ALT less than or equal to 2.5 x upper limit of normal (ULN)
          
                         -  Serum ALP less than or equal to 2 x 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
          
                         -  Calculated creatinine clearance by the method of CKI-EPI greater than or equal to
                            50 ml/min/1.73m2
          
                         -  INR < 1.5
          
                         -  Cardiology
          
                         -  Estimated left ventricular ejection fraction by echocardiography greater than or
                            equal to 45%
          
                         -  Respiratory
          
                         -  Predicted DLCO by PFT > 45%
          
                    -  Patients with favorable, intermediate and poor risk categories will be eligible for
                       the study. Patients must be categorized prior to study enrollment using the following
                       poor prognostic factors categorization as per International Metastatic RCC Database
                       Consortium (IMDC):
          
                         -  KPS equal to 70 or less
          
                         -  Less than 1 year from diagnosis to treatment
          
                         -  Hemoglobin less than the LLN
          
                         -  Corrected calcium concentration greater than 10 mg/dL
          
                         -  Absolute neutrophil count greater than the ULN
          
                         -  Platelet count greater than the ULN
          
                    -  Patients must have the ability to provide written informed consent prior to study
                       specific screening procedures, with the understanding that the patient has the right
                       to withdraw from the study at any time.
          
                  EXCLUSION CRITERIA:
          
                    -  Patients that require immediate therapy due to tumor mass effects or spinal cord
                       compression.
          
                    -  Lack of evidence for progressive disease or measurable disease over the 6 months or
                       measurable disease preceding study enrollment.
          
                    -  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), radiotherapy, or major
                       surgery within the last 2 weeks prior to entering the study. For PD-1/PD-L1 inhibitors
                       or CTLA-4 inhibitors, a 4-week period must have elapsed before commencing protocol
                       treatment. 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). These patients will be excluded from this
                       clinical trial because of their poor prognosis and because they often develop
                       progressive neurologic dysfunction that would confound the evaluation of neurologic
                       and other adverse events.
          
                    -  Patients with hypercalcemia (>2.5 mmol/L) of malignancy.
          
                  -Any prior Grade greater than or equal to 3 immune-related adverse event (irAE) while
                  receiving immunotherapy, including anti-
          
                  CTLA4 treatment, or any unresolved irAE > Grade 1. Note: Active or history of vitiligo 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 treatment (including maintenance therapy) 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 uncontrolled systemic infections (defined as infections causing fevers and
                       infections requiring intravenous antibiotics when intravenous antibiotics have been
                       administered for less than 72 hours).
          
                    -  Active coagulation disorders or other major uncontrolled medical illnesses of the
                       respiratory (DLCO <45% predicted corrected), endocrine, renal, gastrointestinal,
                       genitourinary or immune system, active obstructive or restrictive pulmonary disease,
                       active autoimmune diseases such as rheumatoid arthritis.
          
                    -  History of cerebrovascular accident, transient ischemic attack within 1 year prior to
                       study enrollment.
          
                    -  Patients who have the following clinical conditions are at increased risk for cardiac
                       toxicities. Patients with any cardiac history of the following conditions within 2
                       years prior to study enrollment are excluded from the study:
          
                         -  Prior events including myocardial infarction, clinically significant pericardial
                            effusion, and myocarditis.
          
                         -  Prior cardiac arrhythmia including atrial fibrillation and atrial flutter, or
                            requiring concurrent use of drugs or biologics with pro-arrhythmic potential
                            (anticoagulants count as current treatment). Note: Resolved atrial fibrillation
                            not requiring current treatment is allowed.
          
                         -  NYHA Class II or greater heart failure.
          
                         -  If cardiac function assessment is clinically indicated or performed, an LVEF less
                            than normal per institutional guidelines, or <44%, if threshold for normal is not
                            otherwise specified by institutional guidelines
          
                         -  Mean QT interval corrected for heart rate (QTc) greater than or equal to 470 ms
                            calculated from 3 electrocardiograms (ECGs) using Frediricia s Correction or
                            other significant ECG abnormality noted within 14 days of treatment.
          
                         -  Hypertensive crisis or hypertensive encephalopathy.
          
                         -  Clinically significant peripheral vascular disease or vascular disease, including
                            rapidly growing aortic aneurysm or abdominal aortic aneurysm >5 cm or aortic
                            dissection.
          
                         -  Unstable angina.
          
                    -  Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency
                       Disease).
          
                    -  HIV-positive patients receiving anti-retroviral therapy are excluded from this study
                       due to the fact 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 are less responsive to the experimental treatment and more
                       susceptible to its toxicities.
          
                    -  HBV-or HCV-positive patients are ineligible because of potential reactivation of
                       hepatitis virus following non-myeloablative lymphocytic-depleting chemotherapy and
                       IL-2.
          
                    -  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 14 days
                       prior to the required leukapheresis, or the initiation of the conditioning
                       chemotherapy regimen. 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).
          
                  In the case of short term use of systemic corticosteroids (less than 24 hours within 28
                  days) of greater than 10 mg/day of prednisone or an equivalent corticosteroid, the required
                  washout period prior to starting the leukapheresis is 7 days.
          
                    -  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.
                
          Maximum Eligible Age:70 Years
          Minimum Eligible Age:18 Years
          Eligible Gender:All
          Healthy Volunteers:No

          Primary Outcome Measures

          Measure:Toxicity
          Time Frame:21 days
          Safety Issue:
          Description:

          Secondary Outcome Measures

          Measure:overall response rate
          Time Frame:ongoing
          Safety Issue:
          Description:
          Measure:progression-free survival
          Time Frame:ongoing
          Safety Issue:
          Description:
          Measure:overall survival
          Time Frame:ongoing
          Safety Issue:
          Description:

          Details

          Phase:Phase 1
          Primary Purpose:Interventional
          Overall Status:Recruiting
          Lead Sponsor:National Heart, Lung, and Blood Institute (NHLBI)

          Trial Keywords

          • genetically modified lymphocytes
          • tumor antigens
          • T cell receptor immunotherapy
          • genomic retroviral elements

          Last Updated

          January 25, 2018