Key takeaways: Besides chemotherapy and surgery, there are numerous diagnostic and treatment
options for mesothelioma that originate in the immune system. Mesothelioma has certain
immune checkpoints, like ramped up or dampened immune functions, that provide a means to
intercept the cancer and improve prognosis outcomes. Contextual and patient-unique
combinations of immune checkpoints and chemotherapy are currently being researched.
What is the Immune Milieu of Mesothelioma?
Mesothelioma tumors suppress certain immune responses and amplify others. Some immune
cells that are frequently upregulated (found in higher numbers because of the cancer) include T
lymphocytes, macrophages, and natural killer cells. The function of these cells is to detect, alert,
and kill pathogens (or cancerous cells), so their upregulation makes sense: the body is attempting
to mitigate the growth of the tumor(s). However, despite their function to protect the body
against cancerous cells, it is believed that other immunosuppressant functions are upregulated,
too. Immunosuppressant cells–naturally produced by the body or excessively produced by the
tumor(s)–are responsible for hampering the traditional effects of immune cells. This means that
the two responses–immune and immunosuppressant–essentially negate each other when they’re
both present. In the case of a mesothelioma diagnosis, both are present.
Immune Checkpoints and Possible Interventions
Upregulation of PD-1 (programmed cell death protein 1) is associated with immunosuppression,
and is present in approximately 20-40% of mesothelioma cases. The anti-PD-1 drug (meaning
that the drug blocks the body’s natural immunosuppression, thus enhancing the body’s immune
response) nivolumab has quantifiable effects: “24% [of patients treated with nivolumab]
achieved a partial response at 12 weeks and another 25% achieved stable disease.”
Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is another immune checkpoint that can be
successfully manipulated to fight against mesothelioma. CTLA-4 prevents T cell binding to
antigens, meaning that it also hampers the body’s immune response. Anti-CTLA-4, which by
blocking the immunosuppressant response ultimately bolsters natural immunity, is another drug
that has been used in mesothelioma patients: “The phase 2 MESOT-TREM-2008 study
investigated second line treatment of mesothelioma using the anti-CTLA-4 mAb, tremelimumab.
The study yielded positive signals with prolonged duration of response and a 2 year survival rate
of 36% [50].”
A combination of CTLA-4 and PD-1 inhibitors has proven more successful than administration
of the drugs separately, as they work to dismantle distinct immune responses that separately
contribute to the cancer’s growth.
There are currently 28 ongoing clinical trials attempting to utilize immune checkpoints to a.)
diagnose mesothelioma quicker, and b.) intercept the body’s “immune sabotaging” by altering
immune functions.
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Source:
Ye, L., Ma, S., Robinson, B. W., & Creaney, J. (2019). Immunotherapy strategies for
mesothelioma – the role of tumor specific neoantigens in a new era of precision medicine. Expert
Review of Respiratory Medicine, 13(2), 181–192.
https://doi.org/10.1080/17476348.2019.1563488
