Recent advances in immuno-oncology are transforming the practice of medical oncology. Currently, antibodies directed against negative regulators of T-cell function, the so-called checkpoint inhibitors, oncolytic virus, and engineered cell therapies such as chimeric antigen receptor (CAR)-T products have received market approval in treating more than 16 types of haematological and solid malignancies and two tissue-agnostic cancer indications including tumours with microsatellite instability (dMMR/MSI-H) and high tumour mutation burden (TMB).
In 2022, the first randomised phase III trial of adoptive cell therapy with tumour-infiltrating lymphocyte (TIL) treatment was presented. This trial was led by The Netherlands Cancer Institute in collaboration with the National Center for Cancer Immune Therapy in Copenhagen, Denmark and compared the ex vivo modified patient’s own immune cells versus ipilimumab alone in patients with stage IV melanoma. TIL treatment led to a significant progression-free survival benefit of four months (seven versus three months) and in 20% of patients, the metastases disappeared completely (vs. 7% in the ipilimumab arm). Although the comparator arm is not the current standard of care (ipilimumab plus nivolumab) and the data are immature for evaluating overall survival benefit, authors reported a difference in two-year survival of 10% (54.4% vs. 44.1%).
Reprogramming patient or donor T-cells that are designed to express chimeric antigen receptors on their surface (the so-called CAR-T cell) to recognise and target specific tumour-associated antigens has revolutionised haematologic malignancies such as leukaemia and lymphoma, leading to six approved CAR-T cell treatments since 2017. Several clinical trials are underway focusing on this type of therapy option for solid tumours. A recent phase I trial of CAR-T cell and mRNA vaccine targeting carcinoembryonic antigen claudin 6 (CLDN6) in solid tumours that expressing this protein showed a highly impressive objective response rate of 57% and a disease control rate up to 85% in patients with testicular cancer.
Since 2021, two bispecific antibodies, a new form of immunotherapy, have been approved for the treatment of advanced uveal melanoma (Kimmtrak) and metastatic non–small cell lung cancer with certain EGFR mutations (Rybrevant). These antibodies bind onto two specific proteins—one on the surface of the cancer cell and one on the T-cell. Thus, they bring the two cells closer together, allowing the T-cell to better recognise and kill the cancer cell.
Although personalised immunotherapy is an obvious strategy to pursue, its high cost as well as frequent serious toxicities, including cytokine-release syndrome, make them not applicable to all cancer patients. Combining immune therapies with other types of treatment—such as chemotherapy, targeted therapy, radiotherapy, and interventional radiology—many of which are standard of care, can provide additional benefit, as has been shown in several trials. Finally, it is increasingly obvious that other characteristics of the host including sex, microbiome, obesity, and smoking play a role in inducing different responses in immunotherapies.
For the future, the challenge remains—learn how we can identify the patients who will respond to current immune-based cancer therapies and increase the rate of durable clinical responses.
Antonia Digklia is a specialist in medical and interventional oncology at the Centre hospitalier universitaire de Lausanne (Lausanne, Switzerland).
The author declared no relevant disclosures.
