The news that agents effective in melanoma, renal cell, and non-small cell lung cancers can achieve complete remissions in heavily pretreated, mainly nodular sclerosis, Hodgkin’s lymphoma1 should surprise no one familiar with medical history.
All cancers were just cancers from the time of Hippocrates and not separated until the 19th century. In 1919, Dr. James Ewing’s 1,000-page book contained a detailed chapter for each tumor by organ. He envisioned the 20th century as “promising to widely separate many neoplastic diseases formerly held to be closely related…[and] proving to be the era of successful therapeutics and prophylaxis.”
His prediction came true; separation by tumor site led to some success and some knowledge about prevention, but not nearly all we need.
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Dr. Ewing did not foresee that our century’s therapeutic focus would turn from organ site classification back to the concept of “closely-related” cancers and the ancient Greek belief in a human body’s ability to heal itself, but using 21st century technology.
Focus is now back on the evident inability of the host to mount the immune response required to recognize cancer and eradicate it. Our target is now not the tumor, but the host. Means that tumors may use to escape immune surveillance include immune checkpoints such as CTLA-4 and PD1/PD-L1 (programmed death).
Regulatory T cells, activated B cells, and NK cells express the checkpoint receptor PD-1. Tumors that overexpress the ligands PD-L1 and PD-L2 can engage these receptors on activated T cells that can lead to so-called T-cell exhaustion, allowing unimpeded tumor growth. Tumor PD-L1 expression is correlated with poor prognosis in many tumors.
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Blocking the interaction of PD-1 and PD-L1 is the goal of new antibody therapies being rapidly developed, the first are nivolumab and pembrolizumab. Responses and their long durations have been great news in typically resistant tumors that bear PD-L1.
However, responses have also been seen among tumors considered PD-L1 negative, as in some significant radiologic response in PD-L1-negative melanoma.
