Next generation immunotherapy in non-small-cell lung cancer

Immunotherapy is a game-changer in cancer research and treatment. For the first time in decades, its use has led to new standards of care in at least three refractory lung cancers: stage 3 unresectable non-small-cell lung cancer (NSCLC; PACIFIC), extensive-stage small-cell lung cancer (IMpower133), and squamous NSCLC (KEYNOTE-407). Research is rapidly expanding our knowledge of the immune system and how it interacts with cancer cells. While much work remains to be done, progress is accelerating. Future advances will feature new biomarkers and agents as well as new strategic directions, such as "immune normalisation” [1].

Prof. Solange Peters (Lausanne University Hospital and Ludwig Institute, Switzerland) described immunotherapy as a revolution in cancer care. “Over 2000 immunotherapy agents are in development,” she said at the Future of IO, a mini-symposium on immuno-oncology. She showed how phenotypes in the immune cycle are affected by inflamed tumours, lack of T-cells, and immune exclusion—factors that affect the success or failure of immunotherapy.

According to Prof. Peters, it is time to redefine these phenotypes according to immune status, therapeutic aim, and clinical pipeline (see Figure). This approach calls for priming a new response in cold tumours with no effective anti-tumour immunity; potentiating existing responses in cells with suboptimal or exhausted anti-tumour immunity (e.g. PD-L+ tumour); and reversing tumour suppression if immunity is diminished by the tumour microenvironment (e.g. CD73+ tumour). The clinical pipeline offers a wide choice of treatment options for patients in each category, but many are not routinely used in practice.

Figure: Redefined immune cycle, broken out by immune status, therapeutic aim, and clinical pipeline



“The goal is to achieve highly active anti-tumour activity,” said Prof. Peters, who then focused on a self-described list of subjective strategies to focus on. These included TGF-β, a multifunctional cytokine that attenuates tumour response to PD-L1 blockade by contributing to the exclusion of T-cells [2]; ALT-803, an IL-15 superagonist with nivolumab [3]; and NTRK-214, which increases proliferation of tumour-infiltrating lymphocytes and PD-1 expression on the surface of CD8+ T-cells.

She also discussed the targeting of carcinoembryonic antigens in NSCLC and new strategies that specifically exploit the adenosine pathway in NSCLC. “There is incredible room for progress, with some interesting activities of immuno-oncology beyond PD-L1/CTLA-4,” Prof. Peters said. She noted that academic decisions on strategies to prioritise research are critical and warned that drug development is outpacing biological insight. She also lauded participation in clinical trials, noting that it is key to advances in immunotherapy. At the same time, she stressed the importance of patient access to sufficiently established innovation. “That has to be the priority,” she said.