University of Malaya, Malaysia
Assoc. Prof. Dr Ho Gwo Fuang is an Associate Professor and clinical oncologist/radiotherapist at University Malaya Medical Centre and University Malaya Specialist Centre, Kuala Lumpur, Malaysia.
He was trained at Barts and The London National Health Service (NHS) Trust and The Royal Marsden NHS Trust in London. He attained his Certificate for Completion of Specialist Training (CCST) in 2007 and joined the Faculty of Medicine at University Malaya. He was the recipient of the Joint Commission International (JCI) Outstanding Young Malaysian Award in 2009 for medical innovation. He is the oncology lead for Centre for Image Guided & Minimally Therapy (CIGMIT) stereotactic radiosurgery project at the University, as well as sub-investigators for University Malaya’s High Impact Research (HIR) Grant projects.
His research interests involve breast, gastrointestinal and gynaecological cancers. He is involved in many national and international collaborative research work. Being a council member of Together Against Cancer (TAC), he champions cancer patients’ rights in Malaysia.
Immunotherapy for Solid Cancers: An Update
Harnessing the body’s ability to mount an immune response against cancer cells is now a well-established strategy to treat cancers. It has been known for many years that the immune system can help to treat cancer; however, initial attempts to utilize its potential had not gain widespread use.
Recently, interest in this strategy has increased, as a result of two main areas of breakthrough:
1. Checkpoint inhibitors using antibody against programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1)
2. Chimeric antigen receptor (CAR) T-cell therapy
Remarkable success has been achieved with many tumour types: pembrolizumab, an anti-PD1 antibody, is approved for treatment of melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), head and neck squamous cell carcinoma, classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, urothelial carcinoma, microsatellite instability-high (MSI-H) cancer, gastric cancer, oesophageal cancer, cervical cancer, hepatocellular carcinoma, Merkel cell carcinoma, renal cell carcinoma, and endometrial carcinoma.
An anti-PD-L1 antibody, atezolizumab, is indicated for the treatment of advanced urothelial carcinoma, NSCLC, SCLC, and for use in combination with abraxane for the treatment of metastatic triple-negative breast cancer.
Despite its impressive result in some patients, checkpoint inhibitors do not work for most patients, with single agent response rate ranging between 10-40%. The search is on for better predictor of response apart from the known PDL-1 and MSI-H, as well as to improve response rate using combined approaches. Tumour mutational burden (TMB) load, gut microbiome, tumour-infiltrating CD8+ lymphocytes and specific gene signatures are some of the candidate biomarkers.
Combining anti-CTLA-4 and anti–PD-1 therapies has been shown to be associated with meaningful survival improvements, and inhibition of CTLA-4 activates T-cell immune responses, leading to a potentially synergistic effect with PD-1/PD-L1 inhibitors. This strategy has been shown to be effective in treating melanoma and NSCLC.
Combining immunotherapy and chemotherapy is now a proven strategy for NSCLC and breast cancer.
Combining immunotherapy and targeted therapy is effective for renal cell carcinoma (axitinib and pembrolizumab), endometrial and hepatocellular carcinoma (lenvatinib and pembrolizumab). This approach is currently investigated for multiple tumour sites.
Despite achieving great success in leukaemia, CAR-T cell therapy has so far made limited impact in solid tumours, with the main limiting factor being tumour heterogeneity. Other T cell approaches: tumour-infiltrating lymphocytes and adoptive T cell transfer, have reported success in small studies in ovarian cancers and nasopharyngeal and head and neck cancers.
Approaches using cancer vaccine: single tumour antigen (peptide, nucleic acid or protein) or multiple antigens (pulsed dendritic cells, whole tumour cell) are still under investigation, with many failed attempts encountered despite initial phase 2 successes. Approaches that utilise tailor-made vaccine, using patient’s own tumour are more likely to be successful, but are much more labour intensive.Next generation immunotherapy is now subject of intense research, with immune agonist and Bi-specific T-cell (BiTEs) the two main approaches. BiTEs form a link between T cells and tumour cells, causing T cells to exert cytotoxic activity on tumour cells, independent of MHC I or co-stimulatory molecules.