Clinical Trials /

CAR-T Cell Immunotherapy for Advanced Lung Cancer

NCT03330834

Description:

The NSCLC patients who failed the standard treatments, with positive Programmed Death-Ligand 1 (PD-L1) expression, were enrolled into this trial. About 22 advanced NSCLC patients will be screened according to the criteria. The qualified patients will be recruited and sign the informed consent.Participants will be hospitalized and undergo clinical examinations. Appropriate volume of peripheral blood will be draw (from 66 ml to 360 ml, depend on the body weight and blood routine test), using Ficoll method to centrifuge peripheral blood cell and collected T cells. PD-L1 CAR gene is cloned in a lenti-viral vector that was composed of T cell activation molecules (Cluster of Differentiation 137 (CD137/4-1BB) and Cluster of Differentiation 3(CD3) zeta intracellular domains) and PD-L1 single-chain variable fragment(scFv) derived from the variable regions of a PD-L1 monoclonal antibody.Then, investigators packaged pseudo-lentiviral particles in human embryonic kidney (293T) cells that will be used to transduce autologous T cells isolated from the patients. CAR positive T lymphocytes will be determined by FACS with florescence labeled goat anti-human F(ab')2. The plasmids, pseudo-lentiviral particles and transduced T cells will be subject to the stipulated tests by a third party. Patients will receive leukodepletion chemotherapy (cyclophosphamide: 250mg/m^2 × 3 days; fludarabine: 25mg/m^2× 3 days). One day later, the chemotherapeutic effects would be assessed. PD-L1 CAR-T cells will be infused on day 0 with 10%, day 3 with 30% and day 7 with 60% (total number is (1-2)×10^6/kg). The patients will be observed closely for any adverse reactions and if happened, given supportive treatments. The patients will be discharged on day 14 and will be followed up for two years according to the study scheme, i.e. once a month for the first three months; once every two months in the first year; since then, once a quarter in the second year. The persistence of PD-L1 CAR-T cells in the circulation will be monitored by fluorescent activated cell sorting (FACS) and polymerase chain reaction (PCR). If the patients undergo core needle biopsy, the infiltration of CAR positive cells in the tumor tissue will be evaluated by immunohistochemistry (IHC). The safety profile and anti-tumor efficacy of the CAR-T cells immunotherapy will be assessed during the whole process based on CTCAE v4.1 and RECIST v1.1.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: CAR-T Cell Immunotherapy for Advanced Lung Cancer
  • Official Title: Safety and Toxicity of CAR-T Cell Immunotherapy in Patients With Advanced Lung Cancer After Standard Treatment Failure: A Single-Arm and Single-Center Phase I Clinical Study

Clinical Trial IDs

  • ORG STUDY ID: CART-YY2017
  • NCT ID: NCT03330834

Conditions

  • Advanced Lung Cancer

Interventions

DrugSynonymsArms
CAR-T cells to treat advanced lung cancerSingle Arm

Purpose

The NSCLC patients who failed the standard treatments, with positive Programmed Death-Ligand 1 (PD-L1) expression, were enrolled into this trial. About 22 advanced NSCLC patients will be screened according to the criteria. The qualified patients will be recruited and sign the informed consent.Participants will be hospitalized and undergo clinical examinations. Appropriate volume of peripheral blood will be draw (from 66 ml to 360 ml, depend on the body weight and blood routine test), using Ficoll method to centrifuge peripheral blood cell and collected T cells. PD-L1 CAR gene is cloned in a lenti-viral vector that was composed of T cell activation molecules (Cluster of Differentiation 137 (CD137/4-1BB) and Cluster of Differentiation 3(CD3) zeta intracellular domains) and PD-L1 single-chain variable fragment(scFv) derived from the variable regions of a PD-L1 monoclonal antibody.Then, investigators packaged pseudo-lentiviral particles in human embryonic kidney (293T) cells that will be used to transduce autologous T cells isolated from the patients. CAR positive T lymphocytes will be determined by FACS with florescence labeled goat anti-human F(ab')2. The plasmids, pseudo-lentiviral particles and transduced T cells will be subject to the stipulated tests by a third party. Patients will receive leukodepletion chemotherapy (cyclophosphamide: 250mg/m^2 × 3 days; fludarabine: 25mg/m^2× 3 days). One day later, the chemotherapeutic effects would be assessed. PD-L1 CAR-T cells will be infused on day 0 with 10%, day 3 with 30% and day 7 with 60% (total number is (1-2)×10^6/kg). The patients will be observed closely for any adverse reactions and if happened, given supportive treatments. The patients will be discharged on day 14 and will be followed up for two years according to the study scheme, i.e. once a month for the first three months; once every two months in the first year; since then, once a quarter in the second year. The persistence of PD-L1 CAR-T cells in the circulation will be monitored by fluorescent activated cell sorting (FACS) and polymerase chain reaction (PCR). If the patients undergo core needle biopsy, the infiltration of CAR positive cells in the tumor tissue will be evaluated by immunohistochemistry (IHC). The safety profile and anti-tumor efficacy of the CAR-T cells immunotherapy will be assessed during the whole process based on CTCAE v4.1 and RECIST v1.1.

Detailed Description

      The morbidity and mortality of lung cancer ranks the first in all malignancies. Although
      targeted therapy such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors
      (TKI) and activated lymphocyte kinase (ALK)-TKI can prolong non-small cell lung cancer
      (NSCLC) patients' survival, drug resistance almost occurs inevitably.

      In recent years, PD-L1/PD-1 antibodies like Nivolumab and Pembrolizumab, show satisfactory
      therapeutic potential in the treatment of cancers like melanoma and lung cancer. Latest
      clinical investigations show that anti-PD-1 or PD-L1 antibody therapy can prolong patients'
      survival but actually only 20% of patients benefited from it.

      Chimeric antigen receptor T-Cell (CAR-T) was genetically modified T lymphocytes by
      pseudo-lentiviral transduction to provide them with high binding affinity and specificity to
      the tumor antigen. That affinity was provided by CAR, independent from major
      histocompatibility complex (MHC).

      CAR-T cell immunotherapy had shown tremendous success in the treatment of acute lymphocytic
      leukemia (ALL). Cluster of Differentiation (CD)-19 CAR-T cell treatment archived as high as
      92% complete response rate for refractory and recurrent ALL. When the CAR-T cells targeting
      Her2/neu were given to the patients, mortality was observed from cardiopulmonary failure due
      to the weak expression of Her2/neu on the pulmonary epithelial cells. In contrast, Her2/neu
      antibody (trastuzumab) is widely applied safely in clinic to treat breast cancer patients. It
      strongly suggests that the CAR-T cells are more potent.

      Thus investigators hypothesized that the CAR targeting tumor cell PD-L1 would significantly
      improve the efficacy of CAR-T cells and extend their application in the treatment of solid
      tumors, especially lung cancer. Investigators designed and cloned a PD-L1 CAR gene that
      targets the PD-L1 expressed on tumor cells. Given that PD-L1 CAR-T cells can effectively kill
      not only PD-L1 positive tumor cells in vivo but also immunosuppressive cells (like
      myeloid-derived suppressor cells (MDSCs)) inside tumors, they can remarkably improve
      immunosuppressive tumor microenvironment. Accordingly they can restore the function of tumor
      infiltrated T-lymphocytes(TILs) to achieve the synergistic effect of killing tumor cells that
      can greatly enhance the killing effects of PD-L1 CAR-T cells on tumor cells, even eliminate
      tumors.

      The preclinical studies showed that PD-L1 CAR-T cells could be activated by and had
      significant killing effects on PD-L1 positive tumor cells in vitro. They inhibited tumor
      growth, while no obvious toxicity have been observed in mouse xenograft models. Investigators
      decide to explore the safety and efficacy of the new CAR-T cells in the phase I clinical
      study in the treatment of advanced NSCLC patients.
    

Trial Arms

NameTypeDescriptionInterventions
Single ArmExperimentalCAR-T cells to treat advanced lung cancer. This study has only one arm. All participators will attend the screening and meet the set criteria for the clinical treatment. PD-L1 CAR-T cells are infused on day 0 with 10%, day 3 with 30% and day 7 with 60% , (1-2)×10^6/kg PD-L1 CAR-T cells total.

    Eligibility Criteria

            Inclusion Criteria:
    
              1. Subjects were diagnosed with NSCLC by pathology and at clinical stages ⅢB/Ⅳ based on
                 the 8th Union for International Cancer Control/American Joint Committee on Cancer
                 (UICC/AJCC) Staging System or the disease has recurred or progressed after multi-mode
                 therapy (radiotherapy, surgical excision or radical radiotherapy/chemotherapy to treat
                 local advanced lesions ).
    
              2. Subjects whose recurrent or advanced NSCLC has progressed after standard treatments
                 (operation, radiotherapy and targeting therapy, not including PD-1/PD-L1 checkpoint
                 inhibition therapy) or who are reluctant to receive chemotherapy.
    
              3. Subjects should undertake core needle biopsy again to collect at least one fresh
                 biopsy specimen and at least 10 non-stained sections before recruitment.
    
              4. TKI or chemotherapeutic should be discontinued at least 21 days before Day 0 of the
                 clinical trial while radiotherapy of lung cancer at least 6 months before Day 0 of the
                 clinical trial . Subjects should receive baseline imaging scan after the previous
                 treatments are suspended.
    
              5. Lesions must be detected by CT or MRI according to RECIST 1.1 Criteria. Tumor imaging
                 should be performed at least within 28 days before the beginning of the clinical
                 study.
    
              6. Age>=18 years old and weight >=40kg.
    
              7. PD-L1 is positive by IHC in tissue biopsies of progressive lung cancer after standard
                 treatments(>10%).Ventana PD-L1 (SP142) approved by FDA is used to detect PD-L1
                 expression level on participated patients' lung cancer sections.
    
              8. Life expectancy>=12 weeks
    
              9. Eastern Cooperative Oncology Group (ECOG) score≤ 2
    
             10. Blood pregnancy tests should be negative within 14 days before the woman of
                 childbearing age starts treatment and agrees to take contraceptive methods with a
                 failure rate of no more than 1% per year until the final follow-up.Contraceptive
                 methods with a failure rate of no more than 1% per year include tubal ligation,
                 vasectomy, hormonal contraceptives, intrauterine hormone release system and copper
                 intrauterine device (IUDs).
    
             11. Hematology and liver and kidney functions should meet the following laboratory values.
                 These laboratory tests should be completed in 7 days before the first therapeutic cell
                 infusion.
    
                 Tests and Laboratory Values:
    
                 Hematology:
    
                   1. White Blood Cell (WBC): >=3.5*10^9/L;
    
                   2. Absolute Neutrophil Count (ANC): >=1.5*10^9/L;
    
                   3. Hemoglobin (HGB): >=90g/L;
    
                   4. Platelet (PLT): >=80*10^9/L;
    
                 Blood Coagulation Function:
    
                 PT、APTT、FIB、TT: within normal limits;
    
                 Liver Function:
    
                   1. Aspartic Transaminase (AST): <2.5*upper normal limits(ULN)(hepatic metastasis
                      subjects with 0-1 ECOG score < 5*ULN);
    
                   2. Alanine Aminotransferase (ALT): <2.5*ULN(hepatic metastasis subjects with 0-1
                      ECOG scorer < 5*ULN);
    
                   3. Total Bilirubin (TIBC): <1.5*ULN;
    
                 Kidney Function:
    
                 Serum Creatinine (CR): <1.0*ULN.
    
             12. Subjects are willing to participate in this study and agree to sign the Informed
                 Consent.
    
            Exclusion Criteria:
    
              1. Subjects who are receiving systematic steroid treatments 3 days before the first cell
                 treatment.
    
                 Notice:
    
                   1. Corticosteroids can be used to treat adverse event (AE) and serious adverse event
                      (SAE) after the experimental cell treatment.
    
                   2. Subjects who receive steroid replacement therapy everyday can be included in the
                      clinical study. Prednisone therapy in a dose of 5-7.5mg/day is replacement
                      therapy.
    
                   3. Subjects who receive equivalent dose of hydrocortisone treatment as replacement
                      therapy are also allowed into the clinical trial.
    
              2. Subjects who have received systematic cytotoxic chemotherapy, biological therapy or
                 major operations in 3 weeks before the first dose of experimental cell therapy or
                 subjects who have received lung radiation more than 30 gray (Gy) in 6 months before
                 the first dose of experimental cell therapy.
    
              3. Subjects who have received previous cell treatments such as CAR-T and cytokine-induced
                 killer (CIK) cells or anti-PD-1 or anti- PD-L1 antibody treatment.
    
              4. Subjects with confirmed Central Nervous System (CNS) metastasis and/or carcinomatous
                 meningitis.
    
                 Notice:
    
                 Subjects who have received brain metastasis treatments are allowed in this study, in
                 the case that subjects' conditions are stable (no CNS symptoms) and no radiographic
                 evidence of new or extensive brain metastasis is found at least 4 weeks after the
                 treatments (such as operation or RT). Subjects should suspend hormone treatment at
                 least 3 days before the first dose of experimental cell treatment.
    
              5. Subjects with active autoimmune diseases who need systematic treatments (such as
                 disease improving drugs, corticosteroids and immunosuppressive drugs) in the last 2
                 years.
    
                 Notice:
    
                 Replacement therapy (thyroxine, insulin or physiological corticosteroid replacement
                 therapy to treat adrenal dysfunction or pituitary dysfunction) is not considered as
                 systematic therapy. Subjects who need inhalation corticosteroid therapy can be
                 included in this trial. Subjects with vitiligo or in long-term remission of pediatric
                 asthma or allergic diseases can be included in this trial.
    
              6. Subjects with interstitial pneumonia or a history of pneumonia with oral or
                 intravenous steroid treatments.
    
              7. Subjects whose lymphocytes are difficult to transduce (<20%) or can not proliferate
                 over 5 times.
    
              8. Subjects who have received allotransplantation or solid organ transplantation.
    
              9. Subjects who have received or will receive live vaccines in 30 days before the first
                 experimental cell treatment. Inactivated seasonal flu vaccination is allowed.
    
             10. Subjects with active infections who need intravenous systematic treatments.
    
             11. Subjects with a history of human immunodeficiency virus (HIV)(HIV 1/2 antibody
                 positive)infection.
    
             12. Subjects with known active hepatitis B or hepatitis C. Subjects with HBsAg positive
                 will be excluded. The definition of active hepatitis C is that hepatitis C antibody is
                 positive while quantitative hepatitis C virus (HCV) RNA results exceed the lower
                 detection limit.
    
             13. Subjects with a history of mental disorders or drug abuse that may influence treatment
                 compliance.
    
             14. Women in pregnancy or lactation or are expected to be pregnant during the study (from
                 the screening and to 60 days after the final experimental cell treatment) or men whose
                 wives are in pregnancy.
          
    Maximum Eligible Age:65 Years
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Safety of PD-L1 CAR-T cell treatment
    Time Frame:From the date of CAR-T cell infusion through study completion, average 2 years
    Safety Issue:
    Description:Assessed by the treatment-emergent adverse events as recorded on the case report form, vital signs, laboratory variables, physical examination, electrocardiogram. Treatment-emergent adverse events will be assessed and recorded according to CTCae v4.02.

    Secondary Outcome Measures

    Measure:Efficacy of PD-L1 CAR-T Cells
    Time Frame:Every three month through study completion, average 2 years
    Safety Issue:
    Description:Tumor response will be assessed according to RECIST V1.1

    Details

    Phase:Phase 1
    Primary Purpose:Interventional
    Overall Status:Not yet recruiting
    Lead Sponsor:Sun Yat-sen University

    Trial Keywords

    • CAR-T
    • advanced lung cancer
    • single-arm
    • phase I clinical study

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