CTLA4 blockade in mesothelioma: finally a competing strategy over cytotoxic/target therapy?

Our plain-English summary of CTLA4 blockade in mesothelioma: finally a competing strategy over cytotoxic/target therapy?, by L. Calabrò, G.L. Ceresoli, A. di Pietro, et al (Cancer Immunology, Immunotherapy, 2015).

The study

• Authors: L. Calabrò, G.L. Ceresoli, A. di Pietro, O. Cutaia, A. Morra, R. Ibrahim, M. Maio
• Journal: Cancer Immunology, Immunotherapy
• Published: 2015;64(1):105-12
• Type of article: Review
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

No second-line treatment significantly prolongs the survival of malignant mesothelioma patients who have a high unmet medical need. Here, we comment on the therapeutic potential of cytotoxic T-lymphocyte-associated protein (CTLA)4-blockade by the anti-CTLA4 monoclonal antibody (mAb) tremelimumab of refractory malignant mesothelioma patients. We also focus on the critical role of an accurate tumor assessment in the course of treatment with immunomodulating mAb. Finally, treatment with potentially effective, second-generation checkpoint(s) inhibiting mAb, as well future combination strategies in this deadly disease, will be discussed.

In plain English

This article was a short review, based on a 2013 meeting presentation, of treating malignant mesothelioma with tremelimumab, an antibody that blocks CTLA4, a brake on the immune system. It did not study asbestos exposure. The authors described their earlier MESOT-TREM-2008 trial in patients whose disease had progressed after platinum chemotherapy. Of 29 treated patients, 2 had a long-lasting partial response and 7 had prolonged disease stabilization. The disease control rate was 31 percent, and survival at 1 and 2 years was 48.3 and 36.7 percent. An early rise in certain blood T cells (CD4+ICOS+) was associated with improved survival. A second trial using more frequent dosing had enrolled its planned 29 patients. A placebo-controlled trial was recruiting. The authors noted that tumors may grow at first and later shrink on this treatment. In new laboratory work, they reported that 60 percent of the mesothelioma cell lines tested expressed PD-L1, another immune target, and called this preliminary. The authors concluded that CTLA4 blockade was a novel and highly promising strategy.

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: Focussed research review based on a meeting presentation, with a small set of new laboratory data (PD-L1 expression in mesothelioma cell lines)
• Who was studied: Reviewed clinical trials of tremelimumab in malignant mesothelioma patients, mainly the authors' earlier MESOT-TREM-2008 trial (29 treated patients whose disease progressed after first-line platinum-based treatment). It also reported laboratory testing of human mesothelioma cell lines; the table lists nine lines.
• Exposure: No asbestos exposure was studied. The article concerns treatment with the anti-CTLA4 antibody tremelimumab. Asbestos is mentioned only as the cause of rising mesothelioma incidence and of immune suppression.
• Main results:
  • In the earlier MESOT-TREM-2008 trial, 2 of 29 treated patients had a long-lasting partial response and 7 had prolonged stable disease (median duration 12.4 months). The disease control rate was 31 %.
  • In MESOT-TREM-2008, survival rates at 1 and 2 years were 48.3 % and 36.7 %.
  • In mesothelioma patients treated with tremelimumab, an early increase in circulating CD4+ICOS+ T lymphocytes was significantly associated with improved survival.
  • The second trial, MESOT-TREM-2012, tested 10 mg/kg every 4 weeks for 6 doses followed by dosing every 12 weeks. It had enrolled its planned 29 patients, with preliminary data presented in 2014.
  • A randomized, double-blind, placebo-controlled trial in unresectable pleural or peritoneal mesothelioma was recruiting. Patients were to be assigned 2:1 to tremelimumab or placebo, with about 564 subjects planned.
  • One pleural mesothelioma patient treated with tremelimumab showed disease progression on the week-12 scan and later achieved a partial response. The authors used this case to illustrate that initial growth does not necessarily mean treatment failure.
  • In the authors' laboratory testing, 60 % of the investigated mesothelioma cell lines expressed PD-L1.
• The authors' conclusion: The authors concluded that CTLA4 blockade is a novel and highly promising strategy for mesothelioma. They added that the PD-L1 findings support designing a clinical study of PD-1/PD-L1 blockade in mesothelioma patients.
• Limitations the authors state:
  • The authors described their PD-L1 cell-line results as preliminary.

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: Mesothelioma, Malignant Mesothelioma, Monoclonal Antibody, Tremelimumab.

Related studies

• Anti-CTLA-4 therapy for malignant mesothelioma — A. Guazzelli, E. Bakker, et al. (2017)
• Clinical studies with anti-CTLA-4 antibodies in non-melanoma indications — L. Calabrò, R. Danielli, et al. (2010)
• Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial — L. Calabrò, A. Morra, et al. (2013)
• CTLA-4 blockade in mesothelioma: ineffective or reason for optimism? — A. Thomas, R. Hassan (2017)
• CTLA4 blockade in patients with malignant mesothelioma — B.M. Burt (2015)
• Efficacy and safety of an intensified schedule of tremelimumab for chemotherapy-resistant malignant mesothelioma: an open-label, single-arm, phase 2 study — L. Calabrò, A. Morra, et al. (2015)

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