'Inhibit the inhibitor' - it's all about PD-(L)1 inhibitors in cancer treatment

PD-1 and PD-L1 inhibitors are the hot topic in oncology drug development at the moment, as underscored by numerous speakers during the TAT conference in Paris a few weeks ago. These type of immune-oncology drugs work by the concept of ‘inhibit the inhibitor’ instead of ‘activate the activator’.

The release of tumor associated antigens (TAAs) and the subsequent activation of dendritic cells/Antigen Presenting Cells (APCs) primes T cells to attack the tumor cells expressing these antigens. The supposed T cell-mediated tumor cell killing is however often inhibited by the tumor cells themselves: when the T cells infiltrate the tumor, the tumor recognition via MHC/antigen complex mediates both the release of IFNγ by the T cell, as well as the upregulation of PD-1 Ligand (PD-L1) on many tumor types. The PD-1/PD-L1 binding inhibits the T cell response and thereby also its tumor eradication effect. This may explain why many promising immunotherapies directed at the activation of T cells have not always shown the results that were expected or hoped for.

Blocking PD-1 and PD-L1 (‘inhibiting the inhibitor’) results in the reactivation of the T cell-mediated tumor killing and thus seems an attractive treatment method. Especially when considering that PD-1 inhibitors are found to specifically have their effect on the immune cells in the peripheral tumor micro-environment only, rather than systemically, which hopefully translates into fewer side effects.

The two PD1- inhibitors Keytruda® (pembrolizumab, Merck) and Opdivo® (nivolumab, Bristol-Myers Squibb) have been recently US FDA-approved for the treatment of metastatic melanoma, with Opdivo® also for squamous non-small cell lung cancer (NSCLC). The drugs are currently being tested in several clinical trials for other types of cancer as well including renal cell carcinoma (RCC) and Hodgkin lymphoma.

Although PD-1 inhibitors are (by some) thought to be the new blockbusters with an even greater impact than Avastin® (bevacizumab, Roche), some challenges remain to be solved. During TAT conference a few of them were mentioned. One of these challenges is to really understand the mode of action, thereby highlighting the importance of preclinical models. Second, synergistic combinations should be identified of which targeting innate immune cells (e.g. natural killer (NK) cells, Tumor-Associated Macrophages (TAMs)) to enhance antibody-dependent cell-mediated cytotoxicity (ADCC) was brought up. Third, we should understand how to overcome resistance to immune checkpoint blockade.

The last-mentioned challenge may be the most difficult and time-consuming one to tackle. It may take some additional years of research, efforts, and headaches, but if this would enable prolonged or even sustained responses it is worthwhile. After all, and I quote Hilary Calvert from the UCL Cancer Institute UK who gave the honorary award lecture at the TAT:

“Succeeding slowly is better than failing fast”