Correspondence
Biomarkers for immune checkpoint inhibitors We read with interest Luana Calabrò and colleagues’1 phase 2 study, which investigated the efficacy, safety, and immunological activity of tremelimumab, an anti-CTLA4 monoclonal antibody, in patients with advanced malignant mesothelioma.1,2 They noted disease control in nine (31%) of the 29 enrolled patients, and proposed CD4-positive, ICOS-positive T cells as a predictive marker of treatment outcome. Although these results are promising, we believe that studies concerning biomarkers for immune checkpoint inhibitors should take another direction. Different checkpoint-targeting drugs have been developed and investigated to overcome the inhibitory signalling pathways that switch off T cells. Besides treatments that act on CTLA4, drugs targeting the programmed death (PD) protein 1 or its ligands PD-L1 and PD-L2, LAG3, HAVCR2, IDO1, CD276, and VTCN1 have now been tested for a wide variety of different cancers.3 However, in view of the low response rates and potential serious side-effects, the development of robust predictive biomarkers is needed. The authors made a clear effort to identify lymphocyte subsets as biomarkers of response. Intriguingly, the increase in peripheral CD4positive, ICOS-positive T cells 30 days after treatment was shown to be a potential predictive marker of tremelimumab treatment outcomes in patients with mesothelioma. An increase in peripheral CD4positive, ICOS-positive T cells after treatment with tremelimumab provides information regarding the T-cell activation induced by CTLA4 blockade. Differences in these T-cell counts after treatment imply differences in the proportion of immunosuppression attributable to CTLA4 expression. www.thelancet.com/oncology Vol 15 January 2014
However, in the present approach the underlying cause of differences in peripheral T-cell activation after treatment with tremelimumab remains unclear and this result can only be obtained after the start of therapy. The investigators did investigate several lymphocyte subgroups at baseline, but the selected populations are non-specific and are not related to the treatment approach. It would have been very informative if the investigators had reported data regarding CTLA4 expression in the tumour or peripheral blood before treatment to gain insights into the mechanisms of treatment response. Without a doubt, biomarkers that can predict response to these checkpoint inhibitors before use are desirable. The part played by different immunosuppressive mechanisms can change during treatment and disease progression dependent on cellular interactions and local signals, clearly affecting the efficacy of any immunotherapy.4 Proper biomarkers for the different immune checkpoint inhibitors enable the selection of the appropriate inhibitors for an optimised, patient-tailored treatment.5 The search for these biomarkers is now warranted by the encouraging clinical activity of tremelimumab in patients with chemotherapy-resistant advanced malignant mesothelioma. We declare that we have no conflicts of interest.
Lysanne A Lievense, Joost P J J Hegmans, *Joachim G J V Aerts [email protected] Department of Pulmonary Medicine, Erasmus MC Cancer Institute, Rotterdam, Netherlands 1
2
3
Calabrò L, Morra A, Fonsatti E, et al. Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. Lancet Oncol 2013; 14: 1104–11. Nowak AK. Immunological checkpoint inhibitors enter adolescence. Lancet Oncol 2013; 14: 1035–07. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12: 252–64.
4
5
Aerts JG, Hegmans JP. Tumor-specific cytotoxic T cells are crucial for efficacy of immunomodulatory antibodies in patients with lung cancer. Cancer Res 2013; 73: 2381–88. Hegmans JP, Aerts JG. Immunological profiling as a means to invigorate personalized cancer therapy. Oncoimmunology 2013; 2: e25236.
Authors’ reply As Lysanne Lievense and colleagues correctly point out, the search for biomarkers that are predictive of response to immune-checkpointblocking monoclonal antibodies is an area of active investigation; however, despite these efforts, no markers to select patients who respond well to treatment with this new category of therapeutic antibodies have yet been identified. Expression of programmed cell death (PD) ligand 1 (PD-L1) by tumour cells seemed to represent an absolute biomarker predictive of response to PD1 and PD-L1 blockade,1 but a sizeable proportion of patients with PD-L1-negative tumours efficiently respond to blocking of PD1 and PD-L1.2 With regards to CTLA4 expression by tumour cells, to the best of our knowledge, no clear-cut data have been reported for cell-surface expression on neoplastic cells; we also investigated the expression of CTLA4 on a panel of nine human mesothelioma cell lines, without identifying it (Calabrò L, Maio M, unpublished data). Nevertheless, even if CTLA4 was expressed on the mesothelioma cells of patients treated in our study, it probably would not have given any therapeutic advantage because of the IgG2 isotype of tremelimumab, which prevents efficient antibody-dependent and complement-dependent cytotoxicity. We have thoroughly investigated the expression of CTLA4 on peripheral blood mononuclear cells collected at baseline from patients with cutaneous melanoma treated with the anti-CTLA4 drug ipilimumab, and did not note any correlation with clinical outcome (Calabrò L, Maio M, unpublished data). e1
Biomarkers for immune checkpoint inhibitors We read with interest Luana Calabrò and colleagues’1 phase 2 study, which investigated the efficacy, safety, and immunological activity of tremelimumab, an anti-CTLA4 monoclonal antibody, in patients with advanced malignant mesothelioma.1,2 They noted disease control in nine (31%) of the 29 enrolled patients, and proposed CD4-positive, ICOS-positive T cells as a predictive marker of treatment outcome. Although these results are promising, we believe that studies concerning biomarkers for immune checkpoint inhibitors should take another direction. Different checkpoint-targeting drugs have been developed and investigated to overcome the inhibitory signalling pathways that switch off T cells. Besides treatments that act on CTLA4, drugs targeting the programmed death (PD) protein 1 or its ligands PD-L1 and PD-L2, LAG3, HAVCR2, IDO1, CD276, and VTCN1 have now been tested for a wide variety of different cancers.3 However, in view of the low response rates and potential serious side-effects, the development of robust predictive biomarkers is needed. The authors made a clear effort to identify lymphocyte subsets as biomarkers of response. Intriguingly, the increase in peripheral CD4positive, ICOS-positive T cells 30 days after treatment was shown to be a potential predictive marker of tremelimumab treatment outcomes in patients with mesothelioma. An increase in peripheral CD4positive, ICOS-positive T cells after treatment with tremelimumab provides information regarding the T-cell activation induced by CTLA4 blockade. Differences in these T-cell counts after treatment imply differences in the proportion of immunosuppression attributable to CTLA4 expression. www.thelancet.com/oncology Vol 15 January 2014
However, in the present approach the underlying cause of differences in peripheral T-cell activation after treatment with tremelimumab remains unclear and this result can only be obtained after the start of therapy. The investigators did investigate several lymphocyte subgroups at baseline, but the selected populations are non-specific and are not related to the treatment approach. It would have been very informative if the investigators had reported data regarding CTLA4 expression in the tumour or peripheral blood before treatment to gain insights into the mechanisms of treatment response. Without a doubt, biomarkers that can predict response to these checkpoint inhibitors before use are desirable. The part played by different immunosuppressive mechanisms can change during treatment and disease progression dependent on cellular interactions and local signals, clearly affecting the efficacy of any immunotherapy.4 Proper biomarkers for the different immune checkpoint inhibitors enable the selection of the appropriate inhibitors for an optimised, patient-tailored treatment.5 The search for these biomarkers is now warranted by the encouraging clinical activity of tremelimumab in patients with chemotherapy-resistant advanced malignant mesothelioma. We declare that we have no conflicts of interest.
Lysanne A Lievense, Joost P J J Hegmans, *Joachim G J V Aerts [email protected] Department of Pulmonary Medicine, Erasmus MC Cancer Institute, Rotterdam, Netherlands 1
2
3
Calabrò L, Morra A, Fonsatti E, et al. Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. Lancet Oncol 2013; 14: 1104–11. Nowak AK. Immunological checkpoint inhibitors enter adolescence. Lancet Oncol 2013; 14: 1035–07. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12: 252–64.
4
5
Aerts JG, Hegmans JP. Tumor-specific cytotoxic T cells are crucial for efficacy of immunomodulatory antibodies in patients with lung cancer. Cancer Res 2013; 73: 2381–88. Hegmans JP, Aerts JG. Immunological profiling as a means to invigorate personalized cancer therapy. Oncoimmunology 2013; 2: e25236.
Authors’ reply As Lysanne Lievense and colleagues correctly point out, the search for biomarkers that are predictive of response to immune-checkpointblocking monoclonal antibodies is an area of active investigation; however, despite these efforts, no markers to select patients who respond well to treatment with this new category of therapeutic antibodies have yet been identified. Expression of programmed cell death (PD) ligand 1 (PD-L1) by tumour cells seemed to represent an absolute biomarker predictive of response to PD1 and PD-L1 blockade,1 but a sizeable proportion of patients with PD-L1-negative tumours efficiently respond to blocking of PD1 and PD-L1.2 With regards to CTLA4 expression by tumour cells, to the best of our knowledge, no clear-cut data have been reported for cell-surface expression on neoplastic cells; we also investigated the expression of CTLA4 on a panel of nine human mesothelioma cell lines, without identifying it (Calabrò L, Maio M, unpublished data). Nevertheless, even if CTLA4 was expressed on the mesothelioma cells of patients treated in our study, it probably would not have given any therapeutic advantage because of the IgG2 isotype of tremelimumab, which prevents efficient antibody-dependent and complement-dependent cytotoxicity. We have thoroughly investigated the expression of CTLA4 on peripheral blood mononuclear cells collected at baseline from patients with cutaneous melanoma treated with the anti-CTLA4 drug ipilimumab, and did not note any correlation with clinical outcome (Calabrò L, Maio M, unpublished data). e1
