Circulating biomarkers in melanoma immunotherapy
Posted 29th June 2021 by Nick Noakes
Genevieve Boland, speaking at the Research & Technology Series, described the translational research conducted at her laboratory. Using tumour and blood samples from patients before treatment, at meaningful clinical changes, progression, and post-mortem she, and her team are trying to understand the biology of Melanoma to treat patients better.
Attempts to harness the body’s immune response to fight cancer started back in the 1890s when William Coley injected heat-inactivated bacteria into tumours with some anecdotal success. In the intervening years, not much had changed. However, since the approval of Ipilimumab & Vemurafenib in 2011, there has been a rapid progression with game-changing advances in cancer treatment, including the Nobel Prize-winning work on immune checkpoint inhibitors by Honju and Allison.
So Why the Excitement?
“This is very exciting for us and cancer. And the reason is under ideal circumstances your tumour produces both neoantigens and other antigens. And these are you, but not you. They are antigens that your body’s immune system can recognize. And the T cells can recognize these, become activated and then go back and kill the tumour cells.”Genevieve Boland, Director, Surgical Oncology Research Laboratories , Harvard University
The graphs show the response of patients that have high burden disease. One set treated with a molecular-targeted therapy, specifically targeting a mutation in the tumour and the other with immunotherapies.
Patients treated with targeted therapies improve their progression-free survival, but at some point, cancer recurs, and most still die of their disease. Patients treated with Immunotherapy did not produce as high an initial response, but a subset secured long-term durable control of the disease.
So, what are the questions clinicians want answered?
- Can we predict who will respond right now?
- Can we monitor these responses and differentiate between patients progressing or pseudo-progressing where the tumours grow and then shrink?
- Can we determine when to stop right when patients have a stable disease that is not biologically active?
To answer these questions Genevieve says that “there is a lot of information that can be gleaned from the circulation. Plasma proteomics can give us both tumour intrinsic and immune derived signals.” She adds that Extracellular vesicles (EVs) are interesting, with evidence of cytokines and chemokines at a protein level and EV transcripts arise from a variety of cell types which may assist in predicting or monitoring ICI response. This research will be refined as the team learn, which, cell populations are responsible for differentially expressed genes, and as the cohort size increases over time.
Looking to the future Genevieve expects that these same applications, particularly those that monitor the tumour and immune changes, will help to understand immune checkpoint inhibitor toxicity and auto-immune toxicity. She says that “the signals will be different, but potentially the same applications can be used.”
Genevieve Boland, Section Head, Melanoma/Sarcoma Surgery, Surgical Director, Termeer Center for Targeted Therapies, Director, Surgical Oncology Research Laboratories, Harvard University, USA.
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