How Our Continuing Studies of the Pre-clinical Inbred Mouse Models of Mesothelioma Have Influenced the Development of New Therapies

Our plain-English summary of How Our Continuing Studies of the Pre-clinical Inbred Mouse Models of Mesothelioma Have Influenced the Development of New Therapies, by B.W.S. Robinson, A.J. Redwood, J. Creaney (Frontiers in Pharmacology, 2022).

The study

• Authors: B.W.S. Robinson, A.J. Redwood, J. Creaney
• Journal: Frontiers in Pharmacology
• Published: 2022;13:858557
• Type of article: Review
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Asbestos-induced preclinical mouse models of mesothelioma produce tumors that are very similar to those that develop in humans and thus represent an ideal platform to study this rare, universally fatal tumor type. Our team and a number of other research groups have established such models as a stepping stone to new treatments, including chemotherapy, immunotherapy and other approaches that have been/are being translated into clinical trials. In some cases this work has led to changes in mesothelioma treatment practice and over the last 30 years these models and studies have led to trials which have improved the response rate in mesothelioma from less than 10% to over 50%. Mouse models have had a vital role in that improvement and will continue to play a key role in the future success of mesothelioma immunotherapy. In this review we focus only on these original inbred mouse models, the large number of preclinical studies conducted using them and their contribution to current and future clinical therapy for mesothelioma.

Copyright © 2022 Robinson, Redwood and Creaney.

In plain English

This article was a review in which the authors described their own research program using inbred mouse models of mesothelioma and how that work led to clinical trials. The models were made by injecting crocidolite asbestos into the abdominal cavity (intraperitoneal injection) of mice, then growing cell lines from tumors in three strains: BALB/c, CBA and C57Bl/6. The review described earlier mouse studies in which gemcitabine-cisplatin chemotherapy reduced the growth of small and large tumors, and in which chemotherapy combined with anti-CD40 immunotherapy cured mesothelioma in the majority of mice. It also summarized human trials that followed. In a single-centre study of 21 patients given cisplatin and gemcitabine, 48% had a partial response. A multicenter phase II study reported a 33% partial response rate and a median survival of 17.3 months. Interferon alpha given under the skin produced responses in only 12% of patients. When anti-CD40 was added to cisplatin-pemetrexed, response rates were similar to chemotherapy alone, but 20% of patients achieved long-term survival. The authors concluded that the models had been a useful platform for moving research findings into clinical trials.

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: Narrative review of the authors' own preclinical mouse studies and the clinical trials that followed from them
• Who was studied: Inbred mice of three strains (BALB/c, CBA and C57Bl/6) and mesothelioma cell lines derived from their tumors. The review also covered human mesothelioma patients in the clinical trials it describes, for example a single-centre study of 21 patients.
• Exposure: Crocidolite asbestos injected intraperitoneally into mice to produce mesothelioma. The treatments then tested in the models included chemotherapy (gemcitabine-cisplatin, cyclophosphamide), immunotherapy (interferon alpha, anti-CD40, checkpoint inhibitors), gene therapy, intratumoral agents and surgery.
• Main results:
  • In an earlier mouse study described in the review, gemcitabine-cisplatin reduced the growth of both small and large mesothelioma tumors in mice.
  • In the original single-centre study of 21 patients given intravenous cisplatin and gemcitabine, the objective partial response rate was 48% and 57% of patients had symptom improvement.
  • A later multicenter phase II study of the same combination reported a partial response rate of 33%, stable disease in 60%, and a median survival of 17.3 months.
  • Subcutaneous recombinant interferon alpha produced tumor regressions in only a minority of patients (12%). The remaining patients had a disabling flu-like illness.
  • In mice, combining chemotherapy with anti-CD40 therapy led to mesothelioma cure in the majority of mice, including mice with well-established tumors.
  • In a pilot study of intratumoral interferon alpha infusion, two of six patients showed responses. In a study of 14 patients given infused GM-CSF, two patients responded, but neutrophil plugging of blood vessels occurred at some doses.
  • In a trial of anti-CD40 with cisplatin-pemetrexed in patients, objective response rates were similar to chemotherapy alone, but 20% of patients achieved long-term survival. Most patients experienced cytokine release syndrome.
  • In mice, partial tumor resection was more beneficial than complete resection in some situations. Tumor-specific immune responses detected post-surgical recurrence before it was visible on PET-CT.
  • The authors stated that, over 30 years, trials arising from these models and studies improved the response rate in mesothelioma from less than 10% to over 50%.
• The authors' conclusion: The authors concluded that their inbred mouse models of mesothelioma had been a useful platform for translating research findings into novel clinical trials, and that current and future success of mesothelioma immunotherapy is partly founded on such models.
• Limitations the authors state:
  • The authors restricted the review to the original inbred mouse models and the studies that used them.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Chemotherapy, Immunotherapy, Clinical Trial.

Related studies

• Inflammation precedes the development of human malignant mesotheliomas in a SCID mouse xenograft model — J.M. Hillegass, A. Shukla, et al. (2010)
• Endogenous retrovirus expression activates type-I interferon signaling in an experimental mouse model of mesothelioma development — S. Sun, F. Frontini, et al. (2021)
• Near-infrared photoimmunotherapy targeting GPR87: Development of a humanised anti-GPR87 mAb and therapeutic efficacy on a lung cancer mouse model — H. Yasui, Y. Nishinaga, et al. (2021)
• Mouse models for mesothelioma drug discovery and development — K.P. Seastedt, N. Pruett, et al. (2021)
• A regional approach for CAR T-cell therapy for mesothelioma: from mouse models to clinical trial — M. Mayor, M. Zeltsman, et al. (2016)
• Keynote lecture in the 13th Japanese Society of Immunotoxicology (JSIT 2006) : -Pathophysiological Development and Immunotoxicology: what we have found from research related to silica and silicate such as asbestos- — T. Otsuki, Y. Miura, et al. (2007)

Browse return to medical research.