The advent of immune checkpoint inhibition and other immune-related therapies has produced a sea change in the treatment of a wide range of oncology indications. The impact of these new treatment options is powerfully illustrated here:
These charts show the overall survival for advanced melanoma patients treated with ipilimumab, and progression free survival for advanced melanoma patients treated with either ipilimumab or a combination of ipilimumab plus nivolumab.
There are two important takeaways from these charts. The first is that both show long tails. These represent patients showing no disease progression, for up to ten years after the initiation of treatment (chart on the left). We don’t use the word “cure” often in the setting of metastatic disease, but a patient who remains disease free after ten years can at least start thinking in those terms.
The second important point here is the proportion of patients—eighty percent in the ipilimumab-only arms—who do not seem to have benefited from therapy. We know at this point that immune therapy is extraordinarily powerful in many disease settings. Unfortunately, we also know that this is only so for a subset of patients. The challenge now is to identify subset of patients who are unlikely to benefit up front, so that they can immediately move to alternative therapy than waste time and suffer side effects related to treatments that will not help them.
Theoretically, this should be a fairly straightforward problem. Checkpoint inhibitors operate by binding to specific proteins that tumors use to avoid immune surveillance. Tumors that express these proteins on their surfaces should be vulnerable to treatment, while those that don’t should be resistant. When we assess target expression by tumor biopsy, the correlation with successful treatment has been far from ideal. The explanation for this contradiction is that biopsies only samples a very small portion of a single tumor, and we are learning now that checkpoint expression can vary widely, not only between patients, but between individual tumors within a patient, and within regions of a single tumor. As a result, what we really need is a comprehensive way to assess checkpoint expression across a patient’s entire disease burden.
To this end, a research group at BMS has been hard at work developing a positron emission tomography (PET) tracer designed to bind specifically to PD-L1 (the target of the checkpoint inhibitor nivolumab). David Leung of BMS recently presented preliminary results of these efforts at the Immune-Oncology 360 meeting in Manhattan, NY. As illustrated below, they have found a high correlation between tracer uptake at baseline, tumor accumulation of nivolumab, and successful response to therapy.
For all the promise shown already, it seems likely that we are still only scratching the surface of the immune system’s potential in this field. We currently have approved inhibitors to only two of the twenty or more known immune checkpoints. The challenge moving forward is to learn how to more precisely tune the body’s own defenses to attack tumor cells in as many settings as possible, while at the same time avoiding the sort of complete immune disinhibition that can result in autoimmune disease. Imaging tools such as those described here will play a critical role in achieving these goals.
- Schadendorf et al. (JCO 2015) and Postow et al., (NEJM 2015)