CAR-T Cell Immunotherapy for Advanced Lung Cancer
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|ClinicalTrials.gov Identifier: NCT03330834|
Recruitment Status : Terminated (Serious adverse events)
First Posted : November 6, 2017
Results First Posted : July 13, 2020
Last Update Posted : July 13, 2020
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/CD28) 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.
|Condition or disease||Intervention/treatment||Phase|
|Advanced Lung Cancer||Biological: CAR-T cells to treat advanced lung cancer||Phase 1|
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||1 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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|
|Actual Study Start Date :||November 20, 2017|
|Actual Primary Completion Date :||April 14, 2020|
|Actual Study Completion Date :||April 14, 2020|
Experimental: Single Arm
CAR-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.
Biological: CAR-T cells to treat advanced lung cancer
Drug: fludarabine. On days -4 through -2, fludarabine (25mg/m2) will be infused for 3 consecutive days; Drug: cyclophosphamide. On days -4 through -2, cyclophosphamide (250mg/m2) will be infused for 3 consecutive days.
Patients will receive the above chemotherapy for lymphocyte-depletion followed by PD-L1 CAR-T cells.
- Number of Participants With Treatment-Emergent Adverse Events Associated With PD-L1 CAR-T Cell Treatment [ Time Frame: From the date of CAR-T cell infusion through study completion, average 2 years ]
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.
No statistical analysis was performed becuase the study was terminated after only 1 patient received treatment.
- Number of Participants Experiencing a Complete (CR) or Partial (PR) Tumor Response [ Time Frame: Every three month through study completion, average 2 years ]Tumor response will be assessed according to RECIST V1.1. The overall response rate calculated by the numbers of PR or CR / all patients received treatment. The disease control rate calculated by the numbers of CR PR and stable disease / all patients received treatment.
- Numbers of Patients Received Surveillance of PD-L1 CAR-T Cells in Vivo [ Time Frame: Day 7 after CAR-T cell infusion, and every 2 months up to 2 years ]Using flow cytometry to count of PD-L1 CAR-T cells, calculated the CAR-T cells existence by time after the infusion.
- Assessment of Count of the Functional B Cells in Peripheral Blood. [ Time Frame: Baseline, day 7 and 30 after the CAR-T cell infusion ]Exploring the correlation of the immune functions of pre- and post-CAR-T cell treatments with the treatment safety and efficacy.
- Assessment of Count of the Functional T Cells in Peripheral Blood. [ Time Frame: Baseline, day 7 and 30 after the CAR-T cell infusion ]Exploring the correlation of the immune functions of pre- and post-CAR-T cell treatments with the treatment safety and efficacy.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03330834
|Sun Yat-sen University Cancer Center|
|Guangzhou, Guangdong, China, 510060|
|Principal Investigator:||Li Zhang, M.D.||Sun Yat-sen University|