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Safety and Efficacy of Intratumoral Injections of Chimeric Antigen Receptor (CAR) T Cells in Metastatic Breast Cancer
- Source :
- Cancer Immunology Research. 5:1152-1161
- Publication Year :
- 2017
- Publisher :
- American Association for Cancer Research (AACR), 2017.
-
Abstract
- Chimeric antigen receptors (CAR) are synthetic molecules that provide new specificities to T cells. Although successful in treatment of hematologic malignancies, CAR T cells are ineffective for solid tumors to date. We found that the cell-surface molecule c-Met was expressed in ∼50% of breast tumors, prompting the construction of a CAR T cell specific for c-Met, which halted tumor growth in immune-incompetent mice with tumor xenografts. We then evaluated the safety and feasibility of treating metastatic breast cancer with intratumoral administration of mRNA-transfected c-Met-CAR T cells in a phase 0 clinical trial (NCT01837602). Introducing the CAR construct via mRNA ensured safety by limiting the nontumor cell effects (on-target/off-tumor) of targeting c-Met. Patients with metastatic breast cancer with accessible cutaneous or lymph node metastases received a single intratumoral injection of 3 × 107 or 3 × 108 cells. CAR T mRNA was detectable in peripheral blood and in the injected tumor tissues after intratumoral injection in 2 and 4 patients, respectively. mRNA c-Met-CAR T cell injections were well tolerated, as none of the patients had study drug–related adverse effects greater than grade 1. Tumors treated with intratumoral injected mRNA c-Met-CAR T cells were excised and analyzed by immunohistochemistry, revealing extensive tumor necrosis at the injection site, cellular debris, loss of c-Met immunoreactivity, all surrounded by macrophages at the leading edges and within necrotic zones. We conclude that intratumoral injections of mRNA c-Met-CAR T cells are well tolerated and evoke an inflammatory response within tumors. Cancer Immunol Res; 5(12); 1152–61. ©2017 AACR.
- Subjects :
- Adult
Cytotoxicity, Immunologic
0301 basic medicine
Cancer Research
Pathology
medicine.medical_specialty
Recombinant Fusion Proteins
T-Lymphocytes
T cell
medicine.medical_treatment
Immunology
Receptors, Antigen, T-Cell
Gene Expression
Breast Neoplasms
Article
Mice
03 medical and health sciences
0302 clinical medicine
Antigen
Antigens, Neoplasm
Cell Line, Tumor
Biomarkers, Tumor
medicine
Animals
Humans
RNA, Messenger
Lymph node
Aged
business.industry
Cancer
Immunotherapy
Middle Aged
Proto-Oncogene Proteins c-met
medicine.disease
Xenograft Model Antitumor Assays
Metastatic breast cancer
Chimeric antigen receptor
Disease Models, Animal
Treatment Outcome
030104 developmental biology
medicine.anatomical_structure
030220 oncology & carcinogenesis
Female
Tumor necrosis factor alpha
business
Subjects
Details
- ISSN :
- 23266074 and 23266066
- Volume :
- 5
- Database :
- OpenAIRE
- Journal :
- Cancer Immunology Research
- Accession number :
- edsair.doi.dedup.....c5260cdac047ce7957d408085b6fe8ee