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.

      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, 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
  • cell infusion
2Experimental5 x 10e6 HERV-E TCR transduced CD8/CD34 cells per kg body weight
  • cell infusion
3Experimental1 x 10e7 HERV-E TCR transduced CD8/CD34 cells per kg body weight
  • cell infusion
4Experimental5 x 10e7 HERV-E TCR transduced CD8/CD34 cells per kg body weight
  • cell infusion

Eligibility Criteria

        -  INCLUSION CRITERIA:

          -  Patients must have histologically confirmed RCC with clear-cell component by the
             Laboratory of Pathology of 43T the 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) 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 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 (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 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)

               -  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 / Alveolar Volume Adjusted by PFT > 45%

          -  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.

          -  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 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 single brain metastases of <1cm treated with either stereotactic or
                  gamma knife radiotherapy and remained stable on MRI for 2 weeks are eligible.

               2. Patients with 3 or fewer brain metastases of <1cm treated with either
                  stereotactic or gamma knife radiotherapy and remained stable on MRI for 4 weeks
                  are eligible.

               3. Patients with surgically resected brain metastases and no evidence of active
                  disease in the CNS at the time of screening evaluation are eligible.

               4. These patients may be enrolled at the discretion of the Principal Investigator

          -  Patients with hypercalcemia (>10 mg/dL) of malignancy.

          -  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 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 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/or
             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, endocrine, renal, gastrointestinal, genitourinary or immune system,
             active obstructive or restrictive pulmonary disease, active autoimmune diseases such
             as rheumatoid arthritis.

          -  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 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:toxicity

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

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