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The failure of immune checkpoint blockade in multiple myeloma with PD-1 inhibitors in a phase 1 study

Leukemia volume 29, pages 1621–1622 (2015)Cite this article

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The failure of significant clinical responses to immune checkpoint blockade in multiple myeloma in comparison with other lymphoid malignancies (especially Hodgkin’s lymphoma) raises considerable questions as to our understanding of human T-cell anti-tumour responses in myeloma. The report by Ray et al.1 presented in vitro data, which suggested that the inhibition of PD-1/ PD-L1 ligation would be a potentially useful therapeutic modality in myeloma. Although this appears to be supported by preclinical murine studies, this data is at variance to the observations being reported in clinical studies in myeloma.2 For immune checkpoint inhibition to be a successful modality, there must be immune recognition of malignant myeloma cells and the presence of T cells that are capable of being activated. Such activation requires T cells to have an exhausted phenotype rather than an anergic or senescent phenotype as it is the reversal of exhausted T cells rather than the generation of new T cells reacting to the tumour, which is thought to be the key to therapeutic response. The possibility that cytotoxic T cells against common pathogens may be cross reacting with neoantigens from the tumour has been raised in melanoma,3 and it remains a possibility that cytotoxic T cells can be activated by checkpoint blockade that cross react against myeloma. It has certainly been possible to educate and generate T cells from myeloma patients to malignant plasma cell lines and tumour lysates in vitro, but whether such in vitro recognition and activation reflects the situation in vivo is unclear.

The non-clonal T cells (CD8+TCRVβ−CD57+) in myeloma are unlikely to be tumour reactive but the specific phenotype of the clonal T cells (CD8+TCRVβ+CD57+CD28−) suggest antigen specific, terminally differentiated, senescent cells that have lost their ability to proliferate under stimulation. Studies that use pooled cytotoxic CD8+ T cells will contain both clonal and non-clonal T cells and therefore may not be of clinical significance.

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  1. Institute of Haematology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia

    H Suen, R Brown, S Yang, P J Ho, J Gibson & D Joshua

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Correspondence to H Suen.

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Suen, H., Brown, R., Yang, S. et al. The failure of immune checkpoint blockade in multiple myeloma with PD-1 inhibitors in a phase 1 study. Leukemia 29, 1621–1622 (2015). https://doi.org/10.1038/leu.2015.104

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