Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies

Our plain-English summary of Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies, by G.L. Beatty, A.R. Haas, M.V. Maus, et al (Cancer Immunology Research, 2014).

The study

• Authors: G.L. Beatty, A.R. Haas, M.V. Maus, D.A. Torigian, M.C. Soulen, G. Plesa, A. Chew, Y. Zhao, B.L. Levine, S.M. Albelda, M. Kalos, C.H. June
• Journal: Cancer Immunology Research
• Published: 2014;2(2):112-20
• Cited by: 741 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This article presented two case reports from first-in-human University of Pennsylvania studies of CARTmeso cells. These are T cells engineered with mRNA to carry, briefly, a receptor targeting mesothelin, a protein found on many mesothelioma and pancreatic cancer cells. The article did not discuss asbestos exposure. One elderly patient had malignant pleural mesothelioma and received three infusions in a phase I trial. The other had metastatic pancreatic cancer and received eight intravenous doses and two injections into the tumor. The mesothelioma patient had a confirmed partial response, with disease progression 6 months later, and the blood marker SMRP fell from 17 to 12 nmol/L. The pancreatic cancer patient had stable disease after 3 weeks of intravenous treatment, a 40% decrease in the concentration of mesothelin- and c-met-positive tumor cells in abdominal fluid between days 3 and 15, and a rising CA19-9 marker. The engineered cells reached tumor sites, and both patients developed new antibodies. The mesothelioma patient had a transient cytokine release syndrome and an anaphylactic event. The authors concluded that the findings support developing mRNA CAR-based strategies for solid tumors.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Two case reports from first-in-human studies (one patient in a phase I trial, one under a compassionate use study)
• Who was studied: Two elderly patients with advanced, chemotherapy-refractory cancer treated at the Abramson Cancer Center, University of Pennsylvania. Patient 17510-105 had advanced malignant pleural mesothelioma (MPM) and was enrolled in phase I trial NCT01355965. Patient 21211-101 had metastatic pancreatic cancer (PDA) and was treated under a compassionate use study.
• Exposure: Not an asbestos exposure study. The intervention was T cells engineered by mRNA electroporation to transiently express a mesothelin-targeting chimeric antigen receptor (CARTmeso cells). The MPM patient received three infusions under schedules 1 and 2. The PDA patient received eight intravenous doses and two intratumoral injections under schedule 3. This patient's T cells were obtained from the patient's monozygotic twin brother.
• Main results:
  • MPM patient 17510-105 had stable disease after schedule 1, then a confirmed partial response by modified RECIST after one infusion on schedule 2. Disease progression was observed 6 months later.
  • In the MPM patient, serum mesothelin-related peptide (SMRP) declined from 17 to 12 nmol/L after the first infusion on schedule 2.
  • PDA patient 21211-101 had stable disease by RECIST 1.1 after 3 weeks of intravenous therapy. PET/CT showed a decrease in maximum standardized uptake value at all disease sites. The decrease in metabolic volume was seen only in peritoneal lesions, was transient, and was not sustained on repeat imaging.
  • In the PDA patient's ascites, the concentration of tumor cells coexpressing mesothelin and c-met fell by 40% between day 3 and day 15 after therapy began.
  • In the PDA patient, CA19-9 rose from 449 units/mL at baseline to 1,429 units/mL after intravenous therapy. After the intratumoral injections, it rose to 1,865 units/mL on day 59 and 2,271 units/mL by day 71, consistent with disease progression.
  • CARTmeso transgene was detected in the blood of both patients after each infusion, with levels falling on successive days. In the PDA patient, it was detected in every ascites and tumor biopsy sample tested.
  • In the PDA patient, new antibody responses to more than 100 proteins were detected at day 44. Responses elevated at least 10-fold over baseline were detected for 18 proteins. Elevated antibody responses to a subset of proteins were also seen in the MPM patient.
  • The MPM patient had a transient cytokine release syndrome after the third infusion. Both patients developed antibodies against the CARTmeso cells. In the MPM patient, this antibody response caused an anaphylactic event when infusions were restarted after a 4-week break.
  • The authors did not observe overt evidence of off-tumor toxicities such as pleuritis, pericarditis or peritonitis.
• The authors' conclusion: The authors concluded that short-lived mRNA CAR T cells can induce epitope spreading and mediate antitumor activity in patients with advanced cancer, and that these findings support developing mRNA CAR-based strategies for carcinoma and other solid tumors.
• Limitations the authors state:
  • The authors stated that their hypothesis about why normal mesothelin-expressing tissues were not targeted needs formal testing with frequent, repeated dosing in more patients.
  • The authors noted that the cells persisted less with repeated infusions, and stated that humanized or fully human versions will be required.
  • The authors noted that most antibodies detected by protoarray recognized proteins not linked to cancer.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelin, Carcinoma.

Related studies

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• T cells expressing chimeric antigen receptors can cause anaphylaxis in humans — M.V. Maus, A.R. Haas, et al. (2013)
• Chimeric Antigen Receptor (CAR) T-Cell Therapy for Thoracic Malignancies — S. Kiesgen, L. Chicaybam, et al. (2018)
• A regional approach for CAR T-cell therapy for mesothelioma: from mouse models to clinical trial — M. Mayor, M. Zeltsman, et al. (2016)
• Mesothelin-Targeted CARs: Driving T Cells to Solid Tumors — A. Morello, M. Sadelain, et al. (2016)
• Mesothelin-targeted CAR-T cell therapy for solid tumors — A. Klampatsa, V. Dimou, et al. (2021)

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