Editorial
In this issue of The Lancet Oncology, a Review by Eliza Hawkes and colleagues provides a timely overview of PD-1 inhibition in lymphoma. This article is a useful reminder of the enduringly attractive possibilities of engaging the immune system in the fight against cancer. Moreover, since the approval of ipilimumab for use in treatment of metastatic melanoma in 2011, there has been increased interest, and success, in use of immunotherapies for the treatment of cancer. Ironically, after several decades without any truly viable treatment options, melanoma has become a proving ground for immunotherapy, revolutionising the standard of care for these patients and paving the way for immunotherapies in other advanced cancers. But, we must take care not to allow our enthusiasm for these new treatments to outpace the data. Ipilimumab, which targets the CTLA-4 antigen, was the first immune-modulating antibody to show activity and be approved for cancer treatment—first in metastatic melanoma, and more recently in non-smallcell lung cancer. Nivolumab and pembrolizumab, which inhibit the interaction between PD-1 and its ligand, have also been approved for metastatic melanoma, and have activity in bladder cancer, non-small-cell lung cancer, and renal-cell cancer. These immunotherapies act by removing a block or checkpoint on T-cell activation, by contrast with earlier drugs like interleukin 2, which simply stimulated the immune system. Other immunemodulating therapies are being investigated, including antichemokine receptor antibodies, such as mogamulizumab; therapeutic cancer vaccines, including dendritic cell-based vaccines; and oncolytic viruses. In many immunotherapy trials, durable responses and extended long-term survival are seen only in a subset of patients, highlighting the importance of identification of distinguishing clinical and molecular characteristics. This will not only provide clues about what factors might predict response, but also presents an opportunity to develop immunological or other methods to promote response in refractory patients. Although biomarkers are crucial for these purposes, the complexity of the immune system creates an obstacle for easy development. Moreover, tumour response itself must be assessed in a way that takes into account the unique effects of immunotherapy. www.thelancet.com/oncology Vol 16 May 2015
Recently, the RECIST guidelines have been amended to include immune-related progression criteria; however, the adoption of these guidelines is uneven, and the relationship between progression events based on these criteria and overall survival remains unclear. The tendency to report surrogate or intermediate endpoints, sometimes far too enthusiastically, has led to premature or uncritical reporting. This does a disservice to patients and the medical community because it provides false hope and unduly affects future trial design. In view of the complexity in this area, validated endpoints are needed urgently so that the definition of tumour response is a reliable surrogate of harder oncological outcomes, and that treatment successes are clear and genuine. Another way to improve the effectiveness of immunotherapies in a broad array of patients is to investigate the effect of combining modalities: what is the effect of using immunotherapies with chemotherapy, targeted therapy, and even other immunotherapies? There is some evidence, for example, that combining nivolumab and ipilimumab can result in greater responses in a proportion of patients with metastatic melanoma. Caution is recommended, though, for treatment combinations; additive and synergistic responses might be expected from our understanding of biological mechanisms, but the complexity of the immune response could result in unexpected serious adverse events. Critically, immunomodulatory therapies carry distinct risks, including autoimmunity, which requires proper awareness and treatment to avoid fatalities. The fact that autoimmunity might be linked to a greater proportion of patients achieving a response in some studies is all the more reason to determine optimal dose and scheduling for these drugs before approval and widespread use. Immunotherapies hold great promise for patients far beyond what we’ve already seen, but we must remain aware of the risks associated with modification of the immune system, and avoid misinterpretation or overinterpretation of surrogate endpoints when reporting trial results. Harnessing the power of these treatments using rational drug and trial design without succumbing to these missteps could offer the next big step forward in cancer control. ■ The Lancet Oncology
J C Revy, ISM/Science Photo Library
Cancer immunotherapy: enthusiasm and reality aligning at last
See Review page e234
475
In this issue of The Lancet Oncology, a Review by Eliza Hawkes and colleagues provides a timely overview of PD-1 inhibition in lymphoma. This article is a useful reminder of the enduringly attractive possibilities of engaging the immune system in the fight against cancer. Moreover, since the approval of ipilimumab for use in treatment of metastatic melanoma in 2011, there has been increased interest, and success, in use of immunotherapies for the treatment of cancer. Ironically, after several decades without any truly viable treatment options, melanoma has become a proving ground for immunotherapy, revolutionising the standard of care for these patients and paving the way for immunotherapies in other advanced cancers. But, we must take care not to allow our enthusiasm for these new treatments to outpace the data. Ipilimumab, which targets the CTLA-4 antigen, was the first immune-modulating antibody to show activity and be approved for cancer treatment—first in metastatic melanoma, and more recently in non-smallcell lung cancer. Nivolumab and pembrolizumab, which inhibit the interaction between PD-1 and its ligand, have also been approved for metastatic melanoma, and have activity in bladder cancer, non-small-cell lung cancer, and renal-cell cancer. These immunotherapies act by removing a block or checkpoint on T-cell activation, by contrast with earlier drugs like interleukin 2, which simply stimulated the immune system. Other immunemodulating therapies are being investigated, including antichemokine receptor antibodies, such as mogamulizumab; therapeutic cancer vaccines, including dendritic cell-based vaccines; and oncolytic viruses. In many immunotherapy trials, durable responses and extended long-term survival are seen only in a subset of patients, highlighting the importance of identification of distinguishing clinical and molecular characteristics. This will not only provide clues about what factors might predict response, but also presents an opportunity to develop immunological or other methods to promote response in refractory patients. Although biomarkers are crucial for these purposes, the complexity of the immune system creates an obstacle for easy development. Moreover, tumour response itself must be assessed in a way that takes into account the unique effects of immunotherapy. www.thelancet.com/oncology Vol 16 May 2015
Recently, the RECIST guidelines have been amended to include immune-related progression criteria; however, the adoption of these guidelines is uneven, and the relationship between progression events based on these criteria and overall survival remains unclear. The tendency to report surrogate or intermediate endpoints, sometimes far too enthusiastically, has led to premature or uncritical reporting. This does a disservice to patients and the medical community because it provides false hope and unduly affects future trial design. In view of the complexity in this area, validated endpoints are needed urgently so that the definition of tumour response is a reliable surrogate of harder oncological outcomes, and that treatment successes are clear and genuine. Another way to improve the effectiveness of immunotherapies in a broad array of patients is to investigate the effect of combining modalities: what is the effect of using immunotherapies with chemotherapy, targeted therapy, and even other immunotherapies? There is some evidence, for example, that combining nivolumab and ipilimumab can result in greater responses in a proportion of patients with metastatic melanoma. Caution is recommended, though, for treatment combinations; additive and synergistic responses might be expected from our understanding of biological mechanisms, but the complexity of the immune response could result in unexpected serious adverse events. Critically, immunomodulatory therapies carry distinct risks, including autoimmunity, which requires proper awareness and treatment to avoid fatalities. The fact that autoimmunity might be linked to a greater proportion of patients achieving a response in some studies is all the more reason to determine optimal dose and scheduling for these drugs before approval and widespread use. Immunotherapies hold great promise for patients far beyond what we’ve already seen, but we must remain aware of the risks associated with modification of the immune system, and avoid misinterpretation or overinterpretation of surrogate endpoints when reporting trial results. Harnessing the power of these treatments using rational drug and trial design without succumbing to these missteps could offer the next big step forward in cancer control. ■ The Lancet Oncology
J C Revy, ISM/Science Photo Library
Cancer immunotherapy: enthusiasm and reality aligning at last
See Review page e234
475
