T cells expressing chimeric antigen receptors can cause anaphylaxis in humans

Our plain-English summary of T cells expressing chimeric antigen receptors can cause anaphylaxis in humans, by M.V. Maus, A.R. Haas, G.L. Beatty, et al (Cancer Immunology Research, 2013).

The study

• Authors: M.V. Maus, A.R. Haas, G.L. Beatty, S.M. Albelda, B.L. Levine, X. Liu, Y. Zhao, M. Kalos, C.H. June
• Journal: Cancer Immunology Research
• Published: 2013;1(1):26-31
• Type of article: Case report
• Cited by: 502 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

T cells can be redirected to overcome tolerance to cancer by engineering with integrating vectors to express a chimeric antigen receptor (CAR). In preclinical models, we have previously shown that transfection of T cells with mRNA coding for a CAR is an alternative strategy that has antitumor efficacy and the potential to evaluate the on-target off-tumor toxicity of new CAR targets safely due to transient mRNA CAR expression. Here, we report the safety observed in four patients treated with autologous T cells that had been electroporated with mRNA coding for a CAR derived from a murine antibody to human mesothelin. Because of the transient nature of CAR expression on the T cells, subjects in the clinical study were given repeated infusions of the CAR-T cells to assess their safety. One subject developed anaphylaxis and cardiac arrest within minutes of completing the third infusion. Although human anti-mouse immunoglobulin (Ig)G antibodies have been known to develop with CAR-transduced T cells, they have been thought to have no adverse clinical consequences. This is the first description of clinical anaphylaxis resulting from CAR-modified T cells, most likely through IgE antibodies specific to the CAR. These results indicate that the potential immunogenicity of CARs derived from murine antibodies may be a safety issue for mRNA CARs, especially when administered using an intermittent dosing schedule.

©2013 AACR.

In plain English

This article reported safety findings from a first-in-human study. Patients' own T cells were modified with mRNA to carry a receptor (a CAR) built partly from a mouse antibody against mesothelin, a protein found on several cancers including mesothelioma. Twenty-one infusions had been given to 4 patients, one with pancreatic adenocarcinoma and three with malignant pleural mesothelioma. All but one infusion were well tolerated. The exception was an 81-year-old man with stage IV mesothelioma and a history of asthma and asbestos exposure. Within 1 minute of finishing his third infusion he developed shortness of breath and went into cardiac arrest. He was resuscitated and went home 10 days later. His blood tryptase was markedly raised, which the authors said confirmed anaphylaxis, a severe allergic reaction. His IgG antibodies against mouse proteins rose after his earlier infusions, but tests for IgE antibodies against mouse serum proteins were negative. The authors concluded that the cells most likely caused anaphylaxis by inducing IgE antibodies against the mouse-derived part of the receptor. They shortened the allowed infusion schedule.

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: Report of safety findings from a first-in-human clinical study of mRNA CAR-T cells, centred on a case report of one serious adverse event
• Who was studied: 4 patients at the University of Pennsylvania: 1 with pancreatic adenocarcinoma and 3 with malignant pleural mesothelioma. The case report concerns subject 105, an 81-year-old lifelong nonsmoking man with asthma and asbestos exposure in his history, diagnosed with stage IV mesothelioma with bilateral pleural disease and mediastinal and peritoneal nodal involvement 3 years before enrollment.
• Exposure: Infusions of the patients' own T cells electroporated with mRNA coding for a chimeric antigen receptor against mesothelin. The receptor's binding part came from the mouse monoclonal antibody SS1. Asbestos exposure appears only as part of subject 105's medical history and was not studied.
• Main results:
  • Of 21 infusions in 4 patients, only one was poorly tolerated.
  • Subject 105 had the serious adverse event within minutes of his first infusion in the extended cohort, which was his third infusion overall.
  • Within 1 minute of completing that infusion, subject 105 developed plethora, tingling hands, shortness of breath and hypoxia, then cardiac arrest. He was resuscitated and discharged home 10 days after the event.
  • Subject 105 was discharged home 10 days after the event.
  • Subject 105's serum tryptase was markedly elevated in the first few hours after the event, which the authors said confirmed anaphylaxis.
  • In subject 105, several serum cytokines (IL-6, G-CSF, MIP-1b, MCP-1, IP-10, MIG, IL-8) rose up to 1,000-fold within 24 hours of the event. They returned to baseline by day 4.
  • Subject 105's IgG antibodies against mouse proteins (HAMA) were minimally positive before enrollment and rose after the first cohort of infusions. The table shows 80, 87 and 119 ng/mL against a Quest reference range below 75 ng/mL. A LabCorp test at day 141 was above 600 ng/mL.
  • Subject 105's serum tested negative for IgE against mouse serum proteins at all time points.
  • Subject 105's immunoglobulin levels were normal, which the authors said excluded IgA deficiency as the cause.
  • Subject 102 also developed a positive IgG HAMA at day 21 (88 ng/mL in the table) but received no further infusions.
  • Subject 101 tolerated 6 additional infusions with minimal arthralgias and fatigue.
• The authors' conclusion: The authors concluded that the meso-RNA-CAR-T cells most likely triggered anaphylaxis by inducing an IgE antibody specific for the mouse-based antibody sequences in the CAR. They changed the schedule so that infusions are no more than 10 days apart and are completed within 21 days.
• Limitations the authors state:
  • Both the infused CAR-T cells and the mast cells could have produced cytokines, so the source of the cytokines seen in the first 24 hours could not be determined.
  • The immune response may have been directed at the activated T cells themselves, in addition to or instead of the CAR.

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelin, CAR-T Cell.

Related studies

• Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies — G.L. Beatty, A.R. Haas, et al. (2014)
• Mesothelin as a target for chimeric antigen receptor-modified T cells as anticancer therapy — M. O'Hara, C. Stashwick, et al. (2016)
• 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)
• Clinical Evaluation of ErbB-Targeted CAR T-Cells, Following Intracavity Delivery in Patients with ErbB-Expressing Solid Tumors — S. Papa, M. van Schalkwyk, et al. (2015)
• Generation of Potent T-cell Immunotherapy for Cancer Using DAP12-Based, Multichain, Chimeric Immunoreceptors — E. Wang, L.C. Wang, et al. (2015)

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