Checkpoint blockade in tumour immunotherapy: new insights and opportunities
James Allison
Memorial Sloan-Kettering Cancer Center, New York, USA
It has become apparent that the effectiveness of active immunologic strategies for cancer therapy can be limited by cell intrinsic and extrinsic checkpoints that limit immune responses in order to maximise target destruction and minimise harm to normal tissues. The prototype of cell intrinsic “checkpoints” whose blockade enhances anti-tumor responses is CTLA-4, which has been extensively studied in animal models and shown to be quite effective in achieving complete tumour eradication and long lasting tumor immunity. Over 4,000 patients have been treated with an antibody to human CTLA-4 (Ipilimumab, Medarex and Bristol-Meyers Squibb). Significant responses, including complete remissions, have been observed in about 15% of metastatic melanoma patients, with effects on survival in about 40%. This has led to considerable effort to identify biomarkers that would be useful in determining the impact of CTLA-4 blockade on immune responses in order to identify changes that correlate with clinical responses, as well as to inform combinatorial strategies that might enhance the effectiveness of Ipilimumab.
We have shown in melanoma and prostate cancer models in mice that tumour rejection is closely correlated with an increase in the ratio of both CD4 and CD8 effector cells to FoxP3+ regulatory cells. In both metastatic melanoma and prostate cancer patients, we have shown that existence of pre-existing immune responses to tumour, as indicated by high titer of serum antibodies to the cancer testis antigen NY-ESO-1, is predictive of clinical benefit of Ipilimumab treatment. In a presurgical bladder cancer trial it was shown that Ipilimumab treatment results in an increase in the frequency of CD4 T cells that express high levels of the CD28/CTLA-4 homolog ICOS. We have shown that this is also true in metastatic melanoma and prostate cancer. In melanoma, sustained elevation of ICOS expression by CD4 T cells appears to correlate with clinical benefit.
Declaration of competing interest for James Allison: Inventor of intellectual property held by the University of California, Berkley and licensed to Medarex, Bristol Myers Squibb & Pfizer; Consultant to Medarex & Bristol-Myers Squibb
