Combination immune checkpoint blockade as an effective therapy for mesothelioma

Our plain-English summary of Combination immune checkpoint blockade as an effective therapy for mesothelioma, by V.S. Fear, C. Tilsed, J. Chee, et al (Oncoimmunology, 2018).

The study

• Authors: V.S. Fear, C. Tilsed, J. Chee, C.A. Forbes, T. Casey, J.N. Solin, S.M. Lansley, W.J. Lesterhuis, I.M. Dick, A.K. Nowak, B.W. Robinson, R.A. Lake, S.A. Fisher
• Journal: Oncoimmunology
• Published: 2018;7(10):e1494111
• Cited by: 35 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Mesothelioma is an aggressive asbestos induced cancer with extremely poor prognosis and limited treatment options. Immune checkpoint blockade (ICPB) has demonstrated effective therapy in melanoma and is now being applied to other cancers, including mesothelioma. However, the efficacy of ICPB and which immune checkpoint combinations constitute the best therapeutic option for mesothelioma have yet to be fully elucidated. Here, we used our well characterised mesothelioma tumour model to investigate the efficacy of different ICBP treatments to generate effective therapy for mesothelioma. We show that tumour resident regulatory T cell co-express high levels of CTLA-4, OX40 and GITR relative to T effector subsets and that these receptors are co-expressed on a large proportion of cells. Targeting any of CTLA-4, OX40 or GITR individually generated effective responses against mesothelioma. Furthermore, the combination of αCTLA-4 and αOX40 was synergistic, with an increase in complete tumour regressions from 20% to 80%. Other combinations did not synergise to enhance treatment outcomes. Finally, an early pattern in T cell response was predictive of response, with activation status and ICP receptor expression profile of T effector cells harvested from tumour and dLN correlating with response to immunotherapy. Taken together, these data demonstrate that combination ICPB can work synergistically to induce strong, durable immunity against mesothelioma in an animal model.

In plain English

This was a laboratory study in mice, not people. The authors grew mesothelioma tumours in BALB/c mice using cell lines originally made by injecting crocidolite asbestos into mice. They also tested a mouse lung adenocarcinoma line. Mice received antibody drugs called immune checkpoint blockers, alone or in pairs. In the main AB1-HA mesothelioma model, antibodies against CTLA-4, OX40 or GITR each improved survival compared with untreated mice. Antibodies against PD-1 or TIM-3 alone did not. Long-term survival was 12.5% (1 of 8 mice) with anti-CTLA-4 alone and 80% (8 of 10) with anti-CTLA-4 plus anti-OX40. When tumour cells were injected into the pleural cavity, 9 of 10 mice given this pair remained healthy, while all untreated mice had succumbed by day 28. Adding anti-GITR to anti-CTLA-4 cancelled out the effect that anti-CTLA-4 alone had on survival and tumour growth. In a second mesothelioma line, AB12, no treatment group differed from untreated mice in survival or tumour growth. One AB12 mouse given anti-CTLA-4 had a partial response. The authors concluded that combination checkpoint blockade can work synergistically to induce strong, durable immunity against mesothelioma in animal models.

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 (preclinical study of immune checkpoint antibody treatments in mouse tumour models)
• Who was studied: BALB/c mice carrying tumours from the mouse mesothelioma cell lines AB1-HA and AB12, which were derived from mice injected with crocidolite asbestos, and from the Line-1M lung alveolar adenocarcinoma line. Groups were mostly 8 to 10 mice.
• Exposure: Antibodies against the immune checkpoint molecules CTLA-4, OX40, GITR, PD-1 and TIM-3, given alone or in pairs by injection into the abdomen, mainly on days 10, 13 and 16 after tumour inoculation. Untreated control mice received saline (PBS).
• Main results:
  • In AB1-HA mesothelioma, survival improved compared with untreated (PBS) mice in mice given anti-CTLA-4 (p less than 0.01), anti-GITR or anti-OX40 (p less than 0.05) alone.
  • Anti-PD-1 or anti-TIM-3 given alone did not change survival or tumour growth compared with untreated AB1-HA mice.
  • In AB1-HA mice, long-term survival was 12.5% (1/8) with anti-CTLA-4 alone and 80% (8/10) with anti-CTLA-4 plus anti-OX40 (p less than 0.0001).
  • In the model where AB1-HA cells were injected into the pleural cavity, 90% (9/10) of mice treated with anti-CTLA-4 plus anti-OX40 remained healthy with minimal signs of disease. All untreated (PBS) mice had succumbed by day 28.
  • In AB1-HA mice, anti-CTLA-4 plus anti-GITR negated the effect of anti-CTLA-4 alone on both overall survival and tumour growth.
  • Anti-CTLA-4 plus anti-GITR gave complete tumour regression in only 10% (1/10) of AB1-HA mice, with no partial responses.
  • In AB12 mesothelioma, no treatment group differed from untreated (PBS) controls in overall survival or tumour growth.
  • Looking at individual AB12 mice, only one mouse responded: it showed a partial response to anti-CTLA-4 alone.
  • In the Line-1M lung adenocarcinoma model, survival improved compared with PBS controls with anti-CTLA-4 (p less than 0.001), anti-OX40 (p less than 0.01), anti-GITR (p less than 0.05) and anti-CTLA-4 plus anti-OX40 (p less than 0.001).
  • In AB1-HA mice carrying a tumour on each flank, complete regression occurred in 70% (7/10) given anti-CTLA-4 and 90% (9/10) given anti-CTLA-4 plus anti-OX40. Later relapse occurred in 30% (3/10) and 10% (1/10) of these groups respectively.
  • Effective treatment was associated with fewer regulatory T cells in the tumour and increased activation of CD8 effector T cells.
• The authors' conclusion: The authors concluded that combination immune checkpoint blockade can work synergistically to induce strong, durable immunity against mesothelioma in animal models.
• Limitations the authors state:
  • The authors could not rule out other immunosuppressive mechanisms to explain why AB12 tumours did not respond.
  • The authors noted that differences between models and treatment protocols make direct comparison with other studies of anti-CTLA-4 plus anti-GITR difficult.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Prognosis, CTLA-4, Immunotherapy.

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