Novel approaches to improve immunotherapy and more news on synthetic lethality

  • Markus Joerger
Immunotherapy ESMO Congress 2021

The ESMO Congress 2021 has started today with three sessions on developmental therapeutics, including immunotherapy. The overarching theme in these sessions is the improvement of checkpoint inhibitor-based immunotherapy and a new flavour of synthetic lethality in molecularly pre-defined solid tumours.

Markus Joerger

The ESMO Congress 2021 has started today with three sessions on developmental therapeutics, including immunotherapy. The overarching theme in these sessions is the improvement of checkpoint inhibitor-based immunotherapy and a new flavour of synthetic lethality in molecularly pre-defined solid tumours.  

We have been awaiting the therapeutic targeting of the inhibitory checkpoint molecule B7-H3 for some time, and the new B7-H3 antibody–drug conjugate, DS-7300, represents high hopes for this approach, with a response rate of 23% and good tolerability in unselected patients with advanced cancer. Switching macrophages toward an anti-inflammatory M1 phenotype is another promising strategy that has finally brought some success with the novel anti-Clever-1 antibody, bexmarilimab. Investigators found intriguing single-agent activity with disease control rates of 30% in patients with advanced melanoma, gastric cancer, cholangiocarcinoma and hepatocellular cancer. HPV-associated malignancies are known to show limited responses to checkpoint inhibitors, but the bifunctional fusion protein bintrafusp-alfa that co-targets PD-L1 and TGF-β, is suggested to bring substantial progress, with a median duration of response of more than 17 months in 75 pre-treated patients with HPV-associated tumours. Mesothelin-expressing solid tumours, such as mesothelioma, ovarian and cholangiocellular cancer in turn showed encouraging responses to the anti-mesothelin T-cell receptor fusion construct gavo-cel (gavocabtagene autoleucel), with a disease control rate of 92%. Finally, a success story for difficult-to-treat, relapsed high-grade neuroblastoma – a tumour entity expressing surface GD2 that offers a specific target for cancer therapy. The anti-GD2 antibody naxitamab showed a high response rate of 58% with a manageable toxicity profile in patients with relapsed high-risk neuroblastoma. 

Finally, there was also potential ground-breaking progress for patients with ARID1A-deficient solid tumours with the oral ataxia telangiectasia and rad3 related (ATR) kinase inhibitor ceralasertib showing intriguing single-agent activity with radiological responses in 20% of patients, including ongoing complete responses. This is an emerging case of synthetic lethality, and deficiency in ARID1A is a pretty common genetic alteration in gynaecological, gastric, squamous-cell lung and colon cancers. We are experiencing exciting times to bring all these new treatments to cancer patients with the highest medical need.  

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