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SCIENCE CHINA Life Sciences, Volume 59 , Issue 5 : 468-479(2016) https://doi.org/10.1007/s11427-016-5023-8

Chimeric antigen receptor-modified T cells for the immunotherapy of patients with EGFR-expressing advanced relapsed/refractory non-small cell lung cancer

More info
  • ReceivedJan 16, 2016
  • AcceptedFeb 1, 2016
  • PublishedMar 10, 2016

Abstract


Funded by

Science and Technology Planning Project of Beijing City(Z151100003915076)

National Natural Science Foundation of China(31270820,81230061,81472612,81402566)

National Basic Science and Development Programme of China(2013BAI01B04)

Nursery Innovation Fund(15KMM50)


Acknowledgment

Acknowledgements This work was supported by the Science and Technology Planning Project of Beijing City (Z151100003915076), the National Natural Science Foundation of China (31270820, 81230061, 81472612, 81402566), the National Basic Science and Development Programme of China (2013BAI01B04), and the Nursery Innovation Fund (15KMM50).


Open access

This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.


Interest statement

Compliance and ethics The author(s) declare that they have no conflict of interest.


References

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  • Figure 1

    General characteristics of CAR-T-EGFR cells. A, Schematic representation of anti-EGFR CAR, not to scale. CAR contained anti-EGFR scFv, CD8a hinge and transmembrane region, CD137 costimulatory domain and CD3zeta T-cell activation domain. B, The CAR-T-EGFR cell products were produced by activated peripheral blood mononuclear cells (PBMCs) and released for infusion after 10 to 13 days in culture. C, Specific cytotoxicity of CAR-T-EGFR cells to the EGFR-expressing tumor cells. Results of a 4 h CCK8 analysis at effector/tumor cell (E:T) ratio of 5:1, 10:1, 20:1 and 40:1. The effector cells were CAR-T-EGFR, mock and NT cells. The target cells were A549 (EGFR+) human lung carcinoma cell line, MCF7 (EGFR+) human breast carcinoma cell line, HeLa (EGFR+) human cervical carcinoma cell line, and A2780 (EGFR) human ovarian cancer cell line. The EGFR expression in these tumor cells was detected by flow cytometry (Figure S2 in Supporting Information). Results are representative of all patients’ T cell products as means±SD (CAR-T-EGFR versus Mock and NT, P<0.001, two-way ANOVA test, GraphPad Prism 6.0). NT indicates non-viral transduction T cells. D, ELISA assay showing the level of cytokines, including IL-2, IL-4, IL-6, TNF-alpha, IFN-gamma, GM-CSF and Gram B, in supernatants from CAR-T-EGFR cells co-cultured with A549, MCF7, HeLa or A2780 cells at an E:T ratio of 20:1 for 24 h. Results are representative of all patients’ T cell products as means±SD (*, P<0.001 versus Mock and NT, two-way ANOVA test, GraphPad Prism 6.0).

  • Figure 2

    In vivo persistence of CAR-T-EGFR cells. A, The persistence of the infused CAR-T-EGFR cells in the peripheral blood. Q-PCR was used to assess the level of CAR-T-EGFR cells using the DNA obtained from the PBMCs of all patients, which were harvested before and at serial time points after CAR-T-EGFR cell infusion. B, Correlations of the CAR copy numbers in tumor biopsy versus peripheral blood collected at the same time. Q-PCR analyses showing the levels of CAR-T-EGFR cells using the DNA obtained from ultrasound-guided biopsy of malignant lymph nodes or tumor tissues. Malignant lymph nodes were separately collected at 26 weeks in patient 1 and at 16 weeks in patient 8 after CAR-T-EGFR cell infusion. Tumor tissues in the lung were separately collected at six weeks in patient 2, at six weeks in patient 6 and at 6 weeks and 16 weeks in patient 8 after CAR-T cell infusion. Ly indicates malignant lymph node, and Tu indicates tumor tissue from the lung.

  • Figure 3

    (color online) Outcome of anti-EGFR CAR-T cell infusion. A, Reduction of pleural effusion and slight shrinkage of metastatic hilar lymph node and pleural nodule in patient 1 were presented by computed tomography (CT) scans after the infusion of CAR-T cell (arrow). B, CT images showed the shrinkage of primary tumor in patient 8 (arrow). C, CT examination found the absorption of pleural effusion and remarkable regression of lung lesion in patient 9 after CAR-T treatment.

  • Figure 4

    Immunohistochemistry examination of tumor tissues after the infusion of CAR-T cells. A, Biopsied tissue obtained from patient 1 at the supraclavicular lymph node metastasis showed the enrichment of CD3+ cells and reduction of EGFR+ tumor cells, suggesting that the anti-EGFR CAR-T cells could traffic into the tumor tissues and might be related to the eradication of EGFR-expressing tumor cells. B, Patient 6 was biopsied at the same lesion in right lung one month after CAR-T cell infusion with a result of disappearance of EGFR expressing tumor cells and blast of cells without EGFR expression. C, Patient 8 was sampled one month and 3.5 months after the infusion of anti-EGFR CAR-T cells, immunohistochemistry examination of the biopsied tumor tissue presented a continuous reduction of EGFR positive tumor cells.

  • Table 1   Patient cinical caracteristics

    Patient

    NO.

    Age

    (years)

    Sex

    Histology

    Stage at diagnosis

    Prior treatment

    (regimens, response)

    Disease burden at

    CAR-T infusion

    Status at enrollment

    Condition

    regimens

    CAR-T Cells (×107 kg-1)

    Response*

    Type, Duration

    (months)

    Clinical outcome

    after infusion

    1

    55

    F

    Adeno-

    carcinoma

    Pemetrexed/DDP, PD

    Radiotherapy

    Gefitinib, SD (5months)

    Pleural effusion

    Bones

    Hilar lymph node

    Refractory

    None

    0.28

    SD 5.7

    AWD 15 months

    2

    66

    F

    Adeno-

    carcinoma

    Pemetrexed/CBP, PD

    Lungs, Bones

    Lymph nodes

    Pericardial effusion

    Adrenal gland

    Refractory

    CTX

    2.54

    PD

    DOD 2 months

    3

    60

    F

    Adeno-

    carcinoma

    Etoposide/DDP, SD

    Radiotherapy

    Doxetaxel/DDP, PD

    Bones, Lung

    Refractory

    CTX

    0.52

    PD

    AWD 14 months

    4

    59

    M

    Squamous

    cell

    carcinoma

    ⅡB

    Surgery

    Gemcitabine/DDP, adjuvant

    Right adrenal gland

    Relapsed

    None

    1.05

    PD

    AWD 12 months

    5

    47

    F

    Squamous

    cell carcinoma

    Doxetaxel/DDP, PD

    Gemcitabine/Xeloda, PD

    Abraxane/DDP, PD

    Sorafenib, PD

    Mediastinal lymph nodes, Bones

    Adrenal gland

    Soft tissues

    Refractory

    Pemetrexed/DDP/CTX

    0.73

    PD

    DOD 2 months

    6

    50

    F

    Adeno-

    carcinoma

    Pemetrexed/DDP, SD

    Gefitinib, PR (5 months)

    Right lung, Bones

    Mediastinal lymph nodes

    Refractory

    Docetaxel

    /DDP/CTX

    1.09

    SD 2.4

    AWD 7 months

    7

    59

    M

    Squamous

    cell

    carcinoma

    ⅡB

    Surgery

    Doxetaxel/DDP, SD

    Radiotherapy

    S-1, SD

    Mediastinal lymph nodes

    Refractory

    None

    0.45

    SD 8+

    AWD 8 months

    8

    40

    M

    Adeno-

    carcinoma

    Pemetrexed/DDP, SD

    Lung, Bones

    Mediastinal lymph nodes

    Pleural effusion

    Refractory

    Pemetrexed/DDP/CTX

    1.26

    PR 3.5

    AWD 8 months

    9**

    61

    F

    Adeno-

    carcinoma

    &MCL

    Radiotherapy

    Gemcitabine/COP, PD

    Lung

    Mediastinal lymph nodes

    Pleural effusion

    Refractory

    Docetaxel

    /DDP/CTX

    1.87

    PR 2

    AWD 7 months

    10

    46

    M

    Adeno-

    carcinoma

    ⅢA

    Surgery

    Gemcitabine/DDP, PD

    Pemetrexed/DDP, SD

    Pleura

    Refractory

    None

    0.97

    SD 5.5+

    AWD 5.5 months

    11

    58

    M

    Adeno-

    carcinoma

    Pemetrexed/DDP, SD

    Doxetaxel/DDP, SD

    Lung

    Mediastinal lymph nodes

    Pleural effusion

    Refractory

    Docetaxel

    /DDP/CTX

    0.04

    SD 2

    AWD 6 months

    PR, partial response. SD, stable disease. PD, progressive disease. DDP, cisplatin. CBP, carboplatin. CTX, cyclophosphamide. AWD, alive with disease. DOD, died of disease. *, Response duration is time from first documentation of response post CAR-EGFR T cells infusion until progression. **, Patient 9, having a history of mantle cell lymphoma (MCL), was diagnosed as right lung adenocarcinoma one year ago and PET/CT identified the relapse of MCL meanwhile. Considering the co-existence of lung cancer and MCL, she was administrated with chemotherapy regimens consisted of gemcitabine, cyclophosphamide, vindesine and prednisone (COP), which could be effective to both malignancies.

  • Table 2   Adverse events graded according to national cancer institute common terminology criteria for adverse events version 4.0

    Adverse events

    Grade 1–2

    Grade 3–4

    No. of patients

    %

    No. of patients

    %

    Rash/Acne/Dry Skin

    2

    18.2

    0

    0

    Nausea

    1

    9.1

    0

    0

    Vomiting

    1

    9.1

    0

    0

    Dyspnea

    4

    36.4

    0

    0

    Hypotension

    1

    9.1

    0

    0

    Serum amylase elevation

    1

    9.1

    0

    0

    Serum lipase elevation 0 0 1 9.1
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