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Advances in Immuno-Oncology: Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer—Introduction
Advances in Immuno-Oncology: Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer—Introduction
A
lthough immunotherapy, in the form of cytokines, has been used for decades to fight cancers considered to be immunogenic, such as melanoma and renal cell carcinoma, it has historically failed to move beyond this niche. However, great strides have been made in the field of immunotherapy in the past 5 years, with the approval of the first therapeutic cancer vaccine and the dramatically successful introduction of immune checkpoint inhibitors. For the first time, immunotherapy has demonstrated efficacy outside of traditional immunogenic tumors, with the approval of the sipuleucel-T vaccine in prostate cancer and the immune checkpoint inhibitor nivolumab in nonsmall cell lung cancer (NSCLC). Immune checkpoint molecules are important to the T-cell anti-tumor response. During the priming phase, T cells require two signals from the dendritic cells for activation, one from the antigen itself and a second costimulatory signal. After activation, the T cell upregulates immune checkpoint proteins on its surface, blocking the second costimulatory signal, thereby shortening the duration of the T-cell activation. Tumor cells themselves can upregulate immune checkpoint ligands on their cell surfaces, triggering the immune checkpoint pathway to reduce T-cell activation. Immune checkpoint inhibitors, by disrupting this dampening signal, can effectively release the brakes on the activation process to enhance T-cell activity. While first finding success in melanoma, immune checkpoint inhibition is the newest approach to be approved for NSCLC. The advent of nivolumab in advanced squamous NSCLC has heralded an explosion of immunotherapy agents Financial support for this supplement was provided by an educational grant from Merck & Co. Inc. Conflict of interest: Dr Socinski has disclosed that he has performed contracted research for AstraZeneca, Celgene, Clovis, Genentech, GlaxoSmithKline, Pfizer, and Synta. Dr Socinski also disclosed that he received fees for non-CME services received directly from Celgene and Genentech. 0093-7754/ - see front matter & 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.seminoncol.2015.09.018
for the treatment of this disease, with 6 other immune checkpoint inhibitors currently in phase III NSCLC trials, thus far showing promising efficacy and safety both as monotherapy and as part of chemoimmunotherapy regimens. This has produced a great deal of enthusiasm for the potential roles of immune checkpoint inhibitors in both squamous and non-squamous NSCLC. Although initially tested only for the treatment of advanced, refractory disease, these agents are now being evaluated in the first-line setting, as well as in the earlier stages of disease. One of the missing pieces to the puzzle of immune checkpoint inhibitors is the lack of a reliable biomarker. While some evidence supports the use of programmed death ligand 1 (PD-L1) as a biomarker, there is conflicting evidence as well; it is clear that more work needs to be done to validate and optimize this biomarker to select those patients most likely to respond to immunotherapy. Although the enthusiasm surrounding this class of agents in NSCLC is justified, it does bring a set of unique challenges to the clinic. Immunotherapies have a distinct response pattern that involves slower-than-expected kinetics, with tumor regression sometimes occurring after apparent clinical progression. This delayed pattern of response, which is likely related to the time needed for clonal T-cell expansion and filtration, can result in premature discontinuation of this approach when assessed using traditional response criteria. Thus, new immune-related response criteria have been instituted that allow for these delayed kinetics. In addition to these response differences, immunotherapies also have unique immune-related toxicities. Because both the unique response and safety profiles of these agents are unfamiliar to most physicians treating NSCLC, these physicians will require education on the proper assessment of response to immunotherapies and the identification and management of immune-related adverse events. The future of checkpoint inhibitors in NSCLC does hold great promise, assuming the challenges of validating a biomarker and educating physicians on
Seminars in Oncology, Vol 42, No 5, Suppl 2, October 2015, pp S1-S2
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new response criteria and unfamiliar immunerelated toxicities can be overcome. The next several years will certainly shape the niche of immunotherapy in NSCLC, refining for whom and at what stage this approach provides the greatest benefit.
M.A. Socinski
Mark A. Socinski, MD Co-Leader, UPCI Lung Cancer Program University of Pittsburgh Medical Center Pittsburgh, PA Guest Editor
A
lthough immunotherapy, in the form of cytokines, has been used for decades to fight cancers considered to be immunogenic, such as melanoma and renal cell carcinoma, it has historically failed to move beyond this niche. However, great strides have been made in the field of immunotherapy in the past 5 years, with the approval of the first therapeutic cancer vaccine and the dramatically successful introduction of immune checkpoint inhibitors. For the first time, immunotherapy has demonstrated efficacy outside of traditional immunogenic tumors, with the approval of the sipuleucel-T vaccine in prostate cancer and the immune checkpoint inhibitor nivolumab in nonsmall cell lung cancer (NSCLC). Immune checkpoint molecules are important to the T-cell anti-tumor response. During the priming phase, T cells require two signals from the dendritic cells for activation, one from the antigen itself and a second costimulatory signal. After activation, the T cell upregulates immune checkpoint proteins on its surface, blocking the second costimulatory signal, thereby shortening the duration of the T-cell activation. Tumor cells themselves can upregulate immune checkpoint ligands on their cell surfaces, triggering the immune checkpoint pathway to reduce T-cell activation. Immune checkpoint inhibitors, by disrupting this dampening signal, can effectively release the brakes on the activation process to enhance T-cell activity. While first finding success in melanoma, immune checkpoint inhibition is the newest approach to be approved for NSCLC. The advent of nivolumab in advanced squamous NSCLC has heralded an explosion of immunotherapy agents Financial support for this supplement was provided by an educational grant from Merck & Co. Inc. Conflict of interest: Dr Socinski has disclosed that he has performed contracted research for AstraZeneca, Celgene, Clovis, Genentech, GlaxoSmithKline, Pfizer, and Synta. Dr Socinski also disclosed that he received fees for non-CME services received directly from Celgene and Genentech. 0093-7754/ - see front matter & 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.seminoncol.2015.09.018
for the treatment of this disease, with 6 other immune checkpoint inhibitors currently in phase III NSCLC trials, thus far showing promising efficacy and safety both as monotherapy and as part of chemoimmunotherapy regimens. This has produced a great deal of enthusiasm for the potential roles of immune checkpoint inhibitors in both squamous and non-squamous NSCLC. Although initially tested only for the treatment of advanced, refractory disease, these agents are now being evaluated in the first-line setting, as well as in the earlier stages of disease. One of the missing pieces to the puzzle of immune checkpoint inhibitors is the lack of a reliable biomarker. While some evidence supports the use of programmed death ligand 1 (PD-L1) as a biomarker, there is conflicting evidence as well; it is clear that more work needs to be done to validate and optimize this biomarker to select those patients most likely to respond to immunotherapy. Although the enthusiasm surrounding this class of agents in NSCLC is justified, it does bring a set of unique challenges to the clinic. Immunotherapies have a distinct response pattern that involves slower-than-expected kinetics, with tumor regression sometimes occurring after apparent clinical progression. This delayed pattern of response, which is likely related to the time needed for clonal T-cell expansion and filtration, can result in premature discontinuation of this approach when assessed using traditional response criteria. Thus, new immune-related response criteria have been instituted that allow for these delayed kinetics. In addition to these response differences, immunotherapies also have unique immune-related toxicities. Because both the unique response and safety profiles of these agents are unfamiliar to most physicians treating NSCLC, these physicians will require education on the proper assessment of response to immunotherapies and the identification and management of immune-related adverse events. The future of checkpoint inhibitors in NSCLC does hold great promise, assuming the challenges of validating a biomarker and educating physicians on
Seminars in Oncology, Vol 42, No 5, Suppl 2, October 2015, pp S1-S2
S1
S2
new response criteria and unfamiliar immunerelated toxicities can be overcome. The next several years will certainly shape the niche of immunotherapy in NSCLC, refining for whom and at what stage this approach provides the greatest benefit.
M.A. Socinski
Mark A. Socinski, MD Co-Leader, UPCI Lung Cancer Program University of Pittsburgh Medical Center Pittsburgh, PA Guest Editor