A regional approach for CAR T-cell therapy for mesothelioma: from mouse models to clinical trial

Our plain-English summary of A regional approach for CAR T-cell therapy for mesothelioma: from mouse models to clinical trial, by M. Mayor, M. Zeltsman, E. McGee, et al (Immunotherapy, 2016).

The study

• Authors: M. Mayor, M. Zeltsman, E. McGee, P.S. Adusumilli
• Journal: Immunotherapy
• Published: 2016;8(5):491-4
• Type of article: Editorial
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Summary of the article

In this editorial, researchers from Memorial Sloan Kettering Cancer Center discussed regional (intrapleural) delivery of chimeric antigen receptor (CAR) T-cell therapy for malignant pleural mesothelioma (MPM). They described MPM as a rare, highly aggressive pleural tumor with a median survival of 9–20 months, whose harm results mainly from local invasion rather than distant spread. Earlier intrapleural treatments, including chemotherapy, photodynamic therapy, brachytherapy, oncolytic viruses, IFN-β gene transfer and IL-2, had limited success. The authors summarized their earlier studies of 175 and 230 patients with epithelioid MPM, which linked immune features of the tumor to survival. They presented mesothelin as a target antigen and noted that a Phase II trial of amatuximab with pemetrexed and cisplatin reported a 40% partial response rate and a 51% stable disease rate. In their orthotopic mouse model, mesothelin-targeted CAR T cells given intrapleurally eradicated established pleural tumors at a 30-fold lower dose than cells given intravenously. CD4+ CAR T cells were important to this effect and gave protection against tumor challenge at 196 days. In an earlier intravenous Phase I trial that included three MPM patients, all three developed antibodies and one had an anaphylactic reaction. The authors described their ongoing Phase I trial (NCT02414269), which gives the cells through an indwelling intrapleural catheter. They concluded that regional CAR T-cell delivery deserves investigation for locoregionally aggressive solid tumors.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.

In plain English

This article is an editorial and reports no new data. The authors, from Memorial Sloan Kettering Cancer Center, gave an overview of CAR T-cell therapy for malignant pleural mesothelioma. In this treatment, a patient's own T cells are genetically engineered to attack a tumor target and are then returned to the patient. The editorial does not discuss asbestos exposure. It described the authors' laboratory mouse model and summarized their earlier published mouse experiments. In those experiments, CAR T cells aimed at a protein called mesothelin were given into the chest cavity (intrapleural delivery). Given this way, they eradicated established pleural tumors at a 30-fold lower dose than T cells given into a vein. T cells given into a vein were held up in the lung. The editorial also described another group's Phase I trial of intravenous mesothelin-targeted CAR T cells that included three mesothelioma patients. All three developed an antibody response to the mouse-derived part of the CAR, and one had an anaphylactic reaction. The authors reported running a Phase I safety trial (NCT02414269) of CAR T cells given into the chest cavity. The authors concluded that this regional approach provides an opportunity to investigate regional immune interventions.

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: Editorial (narrative overview of earlier research, including the authors' own published work); no new data reported
• Who was studied: No new patients or animals were studied. The editorial describes the authors' laboratory mouse model of malignant pleural mesothelioma (MPM) and earlier published studies.
• Exposure: Not an asbestos exposure study. The treatment discussed is mesothelin-targeted CAR T-cell therapy, particularly a CD28 co-stimulated construct (M28z), given into the pleural space.
• Main results:
  • As described from the authors' earlier published mouse study (not new data): in mice, CAR T cells given systemically were held up (sequestered) in the lung and entered the pleural tumor late.
  • As described from the authors' earlier published mouse study: M28z CAR T cells given intrapleurally eradicated established pleural tumors, even at a 30-fold lower dose than CAR T cells given intravenously.
  • As described from the authors' earlier mouse work: CD4+ CAR T cells prevented tumor growth after an intraperitoneal tumor challenge given 196 days after a single intrapleural dose.
  • As described from another group's Phase I clinical trial of intravenous mesothelin-targeted CAR T cells that included three MPM patients: all three developed an antibody response to the murine (mouse-derived) part of the CAR, and one had an anaphylactic reaction.
  • The authors reported that they were conducting a Phase I trial (NCT02414269) to evaluate the safety of regionally administered mesothelin-targeted CAR T cells in patients with pleural mesothelioma or with secondary pleural cancers (lung and breast) that express mesothelin. No results of this trial are reported.
• The authors' conclusion: The authors concluded that regional administration of CAR T cells for locoregionally aggressive solid tumors such as MPM provides an opportunity to investigate regional immune interventions, alone or in combination with systemic immune interventions.

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, Clinical Trial, Memorial Sloan Kettering, Pleural Mesothelioma, Median Survival, Chemotherapy, Brachytherapy, Epithelioid.

Related studies

• Mesothelin as a target for chimeric antigen receptor-modified T cells as anticancer therapy — M. O'Hara, C. Stashwick, et al. (2016)
• T cells expressing chimeric antigen receptors can cause anaphylaxis in humans — M.V. Maus, A.R. Haas, et al. (2013)
• CAR T-cell therapy for lung cancer and malignant pleural mesothelioma — M. Zeltsman, J. Dozier, et al. (2017)
• 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-Targeted CARs: Driving T Cells to Solid Tumors — A. Morello, M. Sadelain, et al. (2016)
• Mesothelin as a target for cervical cancer therapy — K. Jöhrens, L. Lazzerini, et al. (2019)

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