Mesothelin-Specific Chimeric Antigen Receptor mRNA-Engineered T Cells Induce Antitumor Activity in Solid Malignancies

Abstract

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 co-stimulatory 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 demonstrated in both patients and the CARTmeso cells elicited an antitumor immune response revealed by the development of novel anti-self antibodies. These data demonstrate the potential of utilizing 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.

Is autoimmunity the Achilles' heel of cancer immunotherapy?

“…3) shared by normal tissue, which thereby leads to loss of tolerance and autoimmunity. ES has been documented in patients receiving tumor vaccines 41 and in patients who have undergone adoptive transfer (Box 1) of CTLs and CAR T cells 42,43 . Checkpoint therapy with ipilimumab can induce ES 44 , and it is likely that neoantigen-directed immune responses against tumors, when followed by ES, can trigger autoimmunity against nonmalignant tissues in which the neoantigens are absent.…”

Improving Chimeric Antigen Receptor-Modified T Cell Function by Reversing the Immunosuppressive Tumor Microenvironment of Pancreatic Cancer

“…Though several pancreatic cancer-targeted CARs have been developed (carcinoembryonic antigen [CEA], 33 mesothelin, 34 Her2/ neu, 35 and PSCA 9,12 ), the immunosuppressive tumor microenvironment, which can impair the proliferative capacity and in vivo persistence of the infused T cells poses a major challenge to successful immunotherapy. 19,21,22 To overcome this barrier, a number of groups have combined CAR T cells with other therapies designed to modulate the tumor microenvironment including checkpoint inhibitors and oncolytic viruses.…”

The Flipside of the Power of Engineered T Cells: Observed and Potential Toxicities of Genetically Modified T Cells as Therapy

“…[17][18][19] Some antigens that are expressed on normal tissues may still be targetable by CARs without causing dose-limiting toxicity, such as mesothelin and prostate-specific membrane antigen (PSMA) (S.F. Slovin et al, 2013, J Clin Oncol., abstract); 20 however, neither of these targets has brought about dramatic clinical efficacy, and it is possible that these two outcomes are inexorably linked. Other examples of on-target, off-tumor toxicities associated with the most commonly targeted antigens used in CAR pre-clinical studies and clinical trials are shown in Table 1.…”