After three decades of failures in about 70 randomized trials, in June 2010, participants of the annual meeting of the American Society of Clinical Oncology (ASCO) witnessed a long-awaited breakthrough in cancer research -- clinical trial results for significant survival advantage improvement in metastatic melanoma, when treated with ipilimumab (Yervoy) developed by Bristol-Myers Squibb. Encouraging clinical trial results presented a promising future for the new monoclonal antibody targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), a switch that limits the ability of T cells to attack cancer cells.
The approval of ipilimumab marked the beginning of the "checkpoint revolution", which would lead to a kaleidoscope of approvals in the coming decade, including such breakthroughs as the anti-PD-1 antibody Keytruda, introduced by Merck to treat multiple advanced solid tumors, nivolumab developed by Bristol-Myers Squibb (brand name Opdivo ), the nivolumab/ipilimumab combination for treating BRAF V600 wild-type melanoma, pembrolizumab for the treatment of advanced non-small cell lung cancer (NSCLC) and so on.
Today, there are nine FDA-approved checkpoint immunotherapies available for patients, including those targeting the PD-1/PD-L1 checkpoint, CTLA-4 checkpoint, and in 2022 -- a newly introduced LAG-3 immune checkpoint pathway.
In contrast to the narrow application of adoptive T-cell therapy, immunotherapy using checkpoint blockade antibodies has shown promising results across a wide range of cancer types, not only in traditionally immunogenic tumors such as melanoma and renal cell carcinoma, but also in lung cancer, bladder cancer, and head and neck cancer.
Yet, the approved checkpoint therapies also brought considerable safety and tolerability concerns. For example, the pioneering ipilimumab (Yervoy) can trigger immune-related adverse events in approximately 60% of patients
receiving the drug compared with about 30% of those receiving only gp100. Common autoimmune-related side effects of ipilimumab include fatigue, diarrhea, skin rash, endocrine deficiencies, and colitis. Severe or fatal autoimmune reactions were reported in 12.9% of ipilimumab patients.
The even greater problem is that the clinical benefit of immunotherapy is limited, with only a small percentage of patients experiencing significant improvement (typically around 15-40%, depending on the type of cancer). There is a need to improve immunotherapy to realize its potential fully and potentially provide benefits to patients whose tumors do not respond to current treatments.