Mesothelin-specific Chimeric Antigen Receptor mRNA-Engineered T cells Induce Anti-Tumor Activity in Solid Malignancies

By G. Beatty, A. Haas, M. Maus, D. Torigian, Michael C. Soulen, G. Plesa, A. Chew, Yangbing Zhao, B. Levine, S. Albelda and 2 more. Cancer immunology research, 2013

804 citations recorded by the source corpus.

Beatty, Haas, and colleagues report antitumor activity in two patients treated with autologous T cells transfected with mRNA encoding a chimeric antigen receptor that recognizes mesothelin and contains the CD3-ζ and 4-1BB costimulatory domains (CARTmeso). The short-lived CARTmeso cells induced novel antiself antibodies and a broadly directed epitope spreading. Off-target toxicity due to the expression of target antigens in normal tissue represents a major obstacle to the use of chimeric antigen receptor (CAR)-engineered T cells for treatment of solid malignancies. To circumvent this issue, we established a clinical platform for engineering T cells with transient CAR expression by using in vitro transcribed mRNA encoding a CAR that includes both the CD3-ζ and 4-1BB costimulatory domains. We present two case reports from ongoing trials indicating that adoptive transfer of mRNA CAR T cells that target mesothelin (CARTmeso cells) is feasible and safe without overt evidence of off-tumor on-target toxicity against normal tissues. CARTmeso cells persisted transiently within the peripheral blood after intravenous administration and migrated to primary and metastatic tumor sites. Clinical and laboratory evidence of antitumor activity was shown in both patients, and the CARTmeso cells elicited an antitumor immune response revealed by the development of novel antiself antibodies. These data show the potential of using mRNA-engineered T cells to evaluate, in a controlled manner, potential off-tumor on-target toxicities and show that short-lived CAR T cells can induce epitope spreading and mediate antitumor activity in patients with advanced cancer. Thus, these findings support the development of mRNA CAR-based strategies for carcinoma and other solid tumors. Cancer Immunol Res; 2(2); 112–20. ©2013 AACR.

Subfields: Electrical and Electronic Engineering, Genetics, Oncology

View Paper: https://www.semanticscholar.org/paper/8e3ef407c842e6219eaa0190a442d4ed2db8ca8a

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Genetics

1. C. June
2. B. Levine
3. B. Keith
4. J. Kochenderfer
5. Jennifer N. Brudno

In Oncology

1. C. June
2. B. Levine
3. M. Milone
4. J. Kochenderfer
5. Jennifer N. Brudno
6. Michel Sadelain

Citations in the corpus

• Multiplex genome editing to generate universal CAR T cells resistant to PD1 inhibition (2016, methodology): “We are currently conducting trials to test non-gene–edited CAR T cells that have beenmanufacturedwith RNA electroporation (34).”
• Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells. (2016, methodology): “These CARs were chosen because they have been tested extensively in clinical trials (Beatty et al., 2014; Kochenderfer et al., 2012; Lee et al., 2015; Maude et al., 2014; Maus et al., 2013; Porter et al., 2015).”
• Hitting the Bull’s-Eye: Mesothelin’s Role as a Biomarker and Therapeutic Target for Malignant Pleural Mesothelioma (2021, background): “The first achieved a satisfactory safety profile with transient tumor responses noted in 2 of 18 patients [137].”
• Global Manufacturing of CAR T Cell Therapy (2016, methodology): “CAR T cells generated using transient mRNA transfection have been used in the clinic; however, this approach requires several rounds of CAR T cell infusion.(28) Furthermore, while the Sleeping Beauty transposon system is considered to be inexpensive and has been tested in early-phase clinical trials”