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/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.
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
Interventions
Drug | Synonyms | Arms |
---|
CAR-T cells to treat advanced lung cancer | | Single 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/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.
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
Name | Type | Description | Interventions |
---|
Single Arm | Experimental | 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. | - CAR-T cells to treat advanced lung cancer
|
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: | 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 |
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.
No statistical analysis was performed becuase the study was terminated after only 1 patient received treatment. |
Secondary Outcome Measures
Measure: | Number of Participants Experiencing a Complete (CR) or Partial (PR) Tumor Response |
Time Frame: | Every three month through study completion, average 2 years |
Safety Issue: | |
Description: | 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. |
Details
Phase: | Phase 1 |
Primary Purpose: | Interventional |
Overall Status: | Terminated |
Lead Sponsor: | Sun Yat-sen University |
Trial Keywords
- CAR-T
- advanced lung cancer
- single-arm
- phase I clinical study
Last Updated
July 13, 2020