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 "cancer" symptom

achondroplasia

acute rheumatic fever

adrenal incidentaloma

alpha-thalassemia

benign recurrent intrahepatic cholestasis

cadasil

canavan disease

carcinoma of the gallbladder

cholangiocarcinoma

coats disease

congenital adrenal hyperplasia

congenital diaphragmatic hernia

cowden syndrome

cushing syndrome

cutaneous mastocytosis

dedifferentiated liposarcoma

dystrophic epidermolysis bullosa

epidermolysis bullosa simplex

erdheim-chester disease

erythropoietic protoporphyria

esophageal adenocarcinoma

esophageal carcinoma

esophageal squamous cell carcinoma

familial hypocalciuric hypercalcemia

familial mediterranean fever

gm1 gangliosidosis

heparin-induced thrombocytopenia

hereditary cerebral hemorrhage with amyloidosis

hirschsprung disease

hodgkin lymphoma, classical

inclusion body myositis

junctional epidermolysis bullosa

kabuki syndrome

kallmann syndrome

kindler syndrome

lamellar ichthyosis

liposarcoma

locked-in syndrome

lymphangioleiomyomatosis

monosomy 21

neuralgic amyotrophy

oculocutaneous albinism

oligodontia

oral submucous fibrosis

papillon-lefèvre syndrome

pendred syndrome

pleomorphic liposarcoma

primary effusion lymphoma

proteus syndrome

pyomyositis

pyruvate dehydrogenase deficiency

severe combined immunodeficiency

sneddon syndrome

systemic capillary leak syndrome

triple a syndrome

von hippel-lindau disease

waldenström macroglobulinemia

well-differentiated liposarcoma

werner syndrome

wiskott-aldrich syndrome

wolf-hirschhorn syndrome

x-linked adrenoleukodystrophy

This symptom has already been validated