Construction and evaluation of a novel humanized HER2-specific chimeric receptor.

[severe combined immunodeficiency]

The human epidermal growth factor receptor 2 (HER 2 ) represents one of the most studied tumor -associated antigens (TAAs ) for cancer immunotherapy . The monoclonal antibody (mAb ) trastuzumab has improved the outcomes of patients with HER 2 + breast cancer . However , a large number of HER 2 + tumors are not responsive to , or become resistant to , trastuzumab-based therapy , and thus more effective therapies targeting HER 2 are needed .H ER 2 -specific T cells were generated by the transfer of genes that encode chimeric antigen receptor (CAR ). Using a multistep overlap extension PCR method , we constructed a novel , humanized HER 2 CAR-containing , chA 21 single -chain variable fragment (scFv ) region of antigen-specific mAb and T -cell intracellular signaling chains made up of CD 28 and CD 3 ζ . An interferon γ and interleukin 2 enzyme-linked immunosorbent assay and a chromium-51 release assay were used to evaluate the antitumor immune response of CAR T cells in coculture with tumor cells . Furthermore , SKBR 3 tumor -bearing nonobese diabetic /severe combined immunodeficiency (NOD /SCID ) mice were treated with HER 2 CAR T cells to evaluate antitumor activity . Human CD 3 + T cell accumulation in tumor xenograft was detected by immunohistochemistry .chA 21 -28 z CAR was successfully constructed , and both CD 4 + and CD 8 + T cells were transduced . The expanded HER 2 CAR T cells expressed a central memory phenotype and specifically reacted against HER 2 + tumor cell lines . Furthermore , the SKBR 3 tumor xenograft model revealed that HER 2 CAR T cells significantly inhibited tumor growth in vivo . Immunohistochemical analysis showed robust accumulation of human CD 3 + T cells in regressing SKBR 3 lesions .The results of this study show that novel chA 21 scFv-based , HER 2 -specific CAR T cells not only recognized and killed HER 2 + breast and ovarian cancer cells ex vivo but also induced regression of experimental breast cancer in vivo . Our data support further exploration of the HER 2 CAR T -cell therapy for HER 2 -expressing cancers .

Diseases
Validation

Diseases presenting "large number" symptom

acute rheumatic fever

adrenal incidentaloma

allergic bronchopulmonary aspergillosis

canavan disease

coats disease

cowden syndrome

dedifferentiated liposarcoma

dracunculiasis

epidermolysis bullosa simplex

fabry disease

familial mediterranean fever

gm1 gangliosidosis

heparin-induced thrombocytopenia

hereditary cerebral hemorrhage with amyloidosis

hirschsprung disease

kindler syndrome

legionellosis

malignant atrophic papulosis

neuralgic amyotrophy

phenylketonuria

pleomorphic liposarcoma

primary effusion lymphoma

scrub typhus

severe combined immunodeficiency

triple a syndrome

waldenström macroglobulinemia

well-differentiated liposarcoma

wiskott-aldrich syndrome

wolf-hirschhorn syndrome

x-linked adrenoleukodystrophy

zellweger syndrome

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