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Resistance to PD-1 blockade in melanoma
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A new study by Antoni Ribas and colleagues has identified two likely mechanisms for the development of resistance to PD-1 blockade in patients with melanoma. The investigators did whole-exome sequencing on tumour samples taken from four patients with metastatic melanoma who had relapsed after treatment with pembrolizumab. The patients had all shown an objective response to pembrolizumab for at least 6 months and mean time to relapse was 624 days (range 419–888). Biopsies were taken before treatment began and after disease progression. The tumours in two of the patients showed over 90% of the same mutations both before and after treatment. But their relapsed tumours had developed mutations in the JAK1 and JAK2 genes, respectively. “These were both loss-of-function mutations that had become
homozygous after losing the wild type copy”, explained co-author Jesse Zaretsky (University of California, Los Angeles, Los Angeles, CA, USA). “The tumours had worked very hard to get rid of those genes.” JAK1 and JAK2 are crucial for mediating interferon-related signalling. The third patient’s relapsed tumour showed a mutation in B2M, the gene for beta-2-microglobulin, which has been previously implicated in immunotherapy resistance. Without this protein, tumour cells no longer present antigens to T cells. So whereas mutations in JAK1 and JAK2 suggest that the tumour is insensitive to T cells inhibition, a mutation in B2M means the T-cells cannot recognise the tumour in the first place. The fourth patient had no apparent mutations related to acquired resistance to T cells. Zaretsky cautioned that the sample size precludes drawing
conclusions on the frequency of these mutations in relapsed patients. “It is also possible that other resistance mechanisms or immune suppressive factors could be at play at the same time”, he said. Ramesh Rengan (University of Washington, Seattle, WA, USA) wondered whether the same resistance pathway is activated at all sites of disease within the same patient. “It would be very difficult to re-establish the interferon-signalling pathway”, he explained. “But if we bring the patient to a reasonable response from the immunotherapy, if we see isolated progression, we could try a different approach.” If immunotherapy is no longer viable, this approach might be radiotherapy, or a therapy that specifically targets the cancer cells.
Steve Gschmeissner/Science Photo Library
Resistance to PD-1 blockade in melanoma
Lancet Oncol 2016 Published Online July 21, 2016 http://dx.doi.org/10.1016/ S1470-2045(16)30372-2 For the study by Zaretsky and colleagues see NEJM 2016; published online July 13. DOI:10.1056/NEJMoa1604958
Talha Khan Burki
www.thelancet.com/oncology Published online July 21, 2016 http://dx.doi.org/10.1016/S1470-2045(16)30372-2
1
A new study by Antoni Ribas and colleagues has identified two likely mechanisms for the development of resistance to PD-1 blockade in patients with melanoma. The investigators did whole-exome sequencing on tumour samples taken from four patients with metastatic melanoma who had relapsed after treatment with pembrolizumab. The patients had all shown an objective response to pembrolizumab for at least 6 months and mean time to relapse was 624 days (range 419–888). Biopsies were taken before treatment began and after disease progression. The tumours in two of the patients showed over 90% of the same mutations both before and after treatment. But their relapsed tumours had developed mutations in the JAK1 and JAK2 genes, respectively. “These were both loss-of-function mutations that had become
homozygous after losing the wild type copy”, explained co-author Jesse Zaretsky (University of California, Los Angeles, Los Angeles, CA, USA). “The tumours had worked very hard to get rid of those genes.” JAK1 and JAK2 are crucial for mediating interferon-related signalling. The third patient’s relapsed tumour showed a mutation in B2M, the gene for beta-2-microglobulin, which has been previously implicated in immunotherapy resistance. Without this protein, tumour cells no longer present antigens to T cells. So whereas mutations in JAK1 and JAK2 suggest that the tumour is insensitive to T cells inhibition, a mutation in B2M means the T-cells cannot recognise the tumour in the first place. The fourth patient had no apparent mutations related to acquired resistance to T cells. Zaretsky cautioned that the sample size precludes drawing
conclusions on the frequency of these mutations in relapsed patients. “It is also possible that other resistance mechanisms or immune suppressive factors could be at play at the same time”, he said. Ramesh Rengan (University of Washington, Seattle, WA, USA) wondered whether the same resistance pathway is activated at all sites of disease within the same patient. “It would be very difficult to re-establish the interferon-signalling pathway”, he explained. “But if we bring the patient to a reasonable response from the immunotherapy, if we see isolated progression, we could try a different approach.” If immunotherapy is no longer viable, this approach might be radiotherapy, or a therapy that specifically targets the cancer cells.
Steve Gschmeissner/Science Photo Library
Resistance to PD-1 blockade in melanoma
Lancet Oncol 2016 Published Online July 21, 2016 http://dx.doi.org/10.1016/ S1470-2045(16)30372-2 For the study by Zaretsky and colleagues see NEJM 2016; published online July 13. DOI:10.1056/NEJMoa1604958
Talha Khan Burki
www.thelancet.com/oncology Published online July 21, 2016 http://dx.doi.org/10.1016/S1470-2045(16)30372-2
1