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Safety and Efficacy of Intratumoral Injections of Chimeric Antigen Receptor (CAR) T Cells in Metastatic Breast Cancer.

Publication ,  Journal Article
Tchou, J; Zhao, Y; Levine, BL; Zhang, PJ; Davis, MM; Melenhorst, JJ; Kulikovskaya, I; Brennan, AL; Liu, X; Lacey, SF; Posey, AD; Williams, AD ...
Published in: Cancer Immunol Res
December 2017

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.

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Published In

Cancer Immunol Res

DOI

EISSN

2326-6074

Publication Date

December 2017

Volume

5

Issue

12

Start / End Page

1152 / 1161

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Treatment Outcome
  • T-Lymphocytes
  • Recombinant Fusion Proteins
  • Receptors, Antigen, T-Cell
  • RNA, Messenger
  • Proto-Oncogene Proteins c-met
  • Middle Aged
  • Mice
  • Immunotherapy
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Tchou, J., Zhao, Y., Levine, B. L., Zhang, P. J., Davis, M. M., Melenhorst, J. J., … June, C. H. (2017). Safety and Efficacy of Intratumoral Injections of Chimeric Antigen Receptor (CAR) T Cells in Metastatic Breast Cancer. Cancer Immunol Res, 5(12), 1152–1161. https://doi.org/10.1158/2326-6066.CIR-17-0189
Tchou, Julia, Yangbing Zhao, Bruce L. Levine, Paul J. Zhang, Megan M. Davis, Jan Joseph Melenhorst, Irina Kulikovskaya, et al. “Safety and Efficacy of Intratumoral Injections of Chimeric Antigen Receptor (CAR) T Cells in Metastatic Breast Cancer.Cancer Immunol Res 5, no. 12 (December 2017): 1152–61. https://doi.org/10.1158/2326-6066.CIR-17-0189.
Tchou J, Zhao Y, Levine BL, Zhang PJ, Davis MM, Melenhorst JJ, et al. Safety and Efficacy of Intratumoral Injections of Chimeric Antigen Receptor (CAR) T Cells in Metastatic Breast Cancer. Cancer Immunol Res. 2017 Dec;5(12):1152–61.
Tchou, Julia, et al. “Safety and Efficacy of Intratumoral Injections of Chimeric Antigen Receptor (CAR) T Cells in Metastatic Breast Cancer.Cancer Immunol Res, vol. 5, no. 12, Dec. 2017, pp. 1152–61. Pubmed, doi:10.1158/2326-6066.CIR-17-0189.
Tchou J, Zhao Y, Levine BL, Zhang PJ, Davis MM, Melenhorst JJ, Kulikovskaya I, Brennan AL, Liu X, Lacey SF, Posey AD, Williams AD, So A, Conejo-Garcia JR, Plesa G, Young RM, McGettigan S, Campbell J, Pierce RH, Matro JM, DeMichele AM, Clark AS, Cooper LJ, Schuchter LM, Vonderheide RH, June CH. Safety and Efficacy of Intratumoral Injections of Chimeric Antigen Receptor (CAR) T Cells in Metastatic Breast Cancer. Cancer Immunol Res. 2017 Dec;5(12):1152–1161.

Published In

Cancer Immunol Res

DOI

EISSN

2326-6074

Publication Date

December 2017

Volume

5

Issue

12

Start / End Page

1152 / 1161

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Treatment Outcome
  • T-Lymphocytes
  • Recombinant Fusion Proteins
  • Receptors, Antigen, T-Cell
  • RNA, Messenger
  • Proto-Oncogene Proteins c-met
  • Middle Aged
  • Mice
  • Immunotherapy