Deep dive into the immune response against murine mesothelioma permits design of novel anti-mesothelioma therapeutics

Our plain-English summary of Deep dive into the immune response against murine mesothelioma permits design of novel anti-mesothelioma therapeutics, by E. Stern, S. Caruso, C. Meiller, et al (Frontiers in Immunology, 2022).

The study

• Authors: E. Stern, S. Caruso, C. Meiller, I. Mishalian, T.Z. Hirsch, Q. Bayard, C.T. Tadmor, H. Wald, D. Jean, O. Wald
• Journal: Frontiers in Immunology
• Published: 2022;13:1026185
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Given the need to improve the efficacy of standard-of-care immunotherapy (anti-CTLA-4 + anti-PD-1) in human malignant pleural mesothelioma (hMPM), we thoroughly characterized the immunobiology of the AB12 murine mesothelioma (MM) model, aiming to increase its accuracy in predicting the response of hMPM to immunotherapy and in designing novel anti-hMPM treatments. Specifically, we used immunologic, transcriptomic and survival analyses, to synchronize the MM tumor growth phases and immune evolution with the histo-molecular and immunological characteristics of hMPM while also determining the anti-MM efficacy of standard-of-care anti-hMPM immunotherapy as a benchmark that novel therapeutics should meet. We report that early-, intermediate- and advanced- AB12 tumors are characterized by a bell-shaped anti-tumor response that peaks in intermediate tumors and decays in advanced tumors. We further show that intermediate- and advanced- tumors match with immune active ("hot") and immune inactive ("cold") hMPM respectively, and that they respond to immunotherapy in a manner that corresponds well with its performance in real-life settings. Finally, we show that in advanced tumors, addition of cisplatin to anti CTLA-4 + anti PD-1 can extend mice survival and invigorate the decaying anti-tumor response. Therefore, we highlight this triple combination as a worthy candidate to improve clinical outcomes in hMPM.

Copyright © 2023 Stern, Caruso, Meiller, Mishalian, Hirsch, Bayard, Tadmor, Wald, Jean and Wald.

In plain English

This was a laboratory study in mice, not people. The authors injected AB12 murine mesothelioma cells into the peritoneum (abdominal cavity) of 8-week-old female BALB/c mice. Untreated mice survived 20 to 30 days. The authors defined early, intermediate and advanced tumor phases. They compared the mouse tumors' gene activity with 295 human malignant pleural mesothelioma samples. The mouse tumors grouped with the human cluster judged biphasic, which made up 52% of the human samples. The immune response against the tumor peaked in intermediate-phase tumors. Intermediate tumors resembled immune-active ('hot') human tumors, and advanced tumors resembled immune-inactive ('cold') ones. When started on day 9, the standard combination of anti-CTLA-4 plus anti-PD-1 raised cure rates (survival beyond 80 days) to 78.6%. Each drug alone gave 28.6% and 35.7%. The combination kept its efficacy when started on day 12, but its efficacy declined when started on day 14. In advanced tumors, adding the chemotherapy drug cisplatin improved on the standard combination; adding anti-LAG-3 did not. The authors concluded that this triple combination is a promising candidate.

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: Animal experiment (mouse tumor model) combined with comparison of gene-expression data to human tumor datasets
• Who was studied: 8-week-old female BALB/c mice injected in the peritoneum with 1 × 10^5 AB12 murine mesothelioma cells (at least 7 mice per group). Mouse tumors were compared with 295 human malignant pleural mesothelioma samples from the Bueno (209) and TCGA (86) datasets.
• Exposure: No asbestos exposure was studied. The exposures were treatments given to tumor-bearing mice at different tumor phases: blocking antibodies against CTLA-4, PD-1, LAG-3 or TIM-3 (200 µg injected into the peritoneum), and cisplatin (5 mg/kg intravenously), alone or in combinations.
• Main results:
  • Untreated mice with AB12 tumors survived 20 to 30 days after tumor implantation.
  • In combined clustering, AB12 tumors at all growth phases fell in cluster C3. The authors identified C3 as the biphasic cluster, which held 52% of the human samples; C1 (sarcomatoid) held 23% and C2 (epithelioid) 24%.
  • TIS.2 (IFN-gamma predominant) was the most common immune subtype among the human tumors (32%). All AB12 tumors were TIS.2.
  • Early- and advanced-phase mouse tumors clustered with immune-inactive ('cold') human tumors. Intermediate-phase tumors, and advanced tumors from mice given early anti-CTLA-4, clustered with immune-active ('hot') human tumors.
  • Spleen cells from mice with intermediate-phase tumors produced the most IFN-gamma against AB12 cells in the lab dish. Spleen cells from mice with early- or advanced-phase tumors produced minimal amounts.
  • Early anti-CTLA-4 treatment increased the IFN-gamma production of spleen cells (p less than 0.0001); late treatment did not.
  • Used alone, anti-CTLA-4 gave high cure rates only when started on day 3 or day 6. Anti-PD-1 gave moderate cure rates and was most potent when started on day 9.
  • Cure was defined as surviving more than 80 days.
  • In intermediate-phase (day 9) tumors, anti-CTLA-4 plus anti-PD-1 raised cure rates to 78.6%, compared with 28.6% for anti-CTLA-4 alone and 35.7% for anti-PD-1 alone. Median survival rose from 17 and 29 days, respectively, to more than 57 days with the combination.
  • The anti-CTLA-4 plus anti-PD-1 combination maintained its efficacy when started on day 12 (late-intermediate tumors). It did not maintain that efficacy when started on day 14 (advanced tumors).
  • In their discussion, the authors described the combination's efficacy as declining in advanced-phase tumors, not as disappearing.
  • In intermediate-phase tumors, anti-CTLA-4 combined with cisplatin showed a marginally significant (p = 0.057) synergistic effect compared with either drug alone.
  • In advanced-phase tumors, adding cisplatin to anti-CTLA-4 plus anti-PD-1 improved efficacy. The article text gives no survival figures for this result.
  • Adding anti-LAG-3 to anti-CTLA-4 plus anti-PD-1 did not improve efficacy over the standard combination.
• The authors' conclusion: The authors concluded that treatments should be tested against the standard of care in intermediate- and advanced-phase tumors. In their view, those effective in advanced-phase tumors should move toward the clinic, and the anti-CTLA-4 plus anti-PD-1 plus cisplatin triple therapy is one such promising combination.
• Limitations the authors state:
  • The authors used young female mice, although human malignant pleural mesothelioma is mainly diagnosed in elderly males and immunotherapy efficacy is partly age dependent.
  • The model represented only biphasic mesothelioma, using the AB12 cell line. Other mouse cell lines mimic other histological subtypes.

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, Immunotherapy, CTLA-4, Pleural Mesothelioma, Cisplatin.

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