Micrograph of malignant melanoma (copyright 2010, Nephron)

What Determines Whether a Melanoma Patient Will Respond to Checkpoint Blockade Drugs?

Of all cancer types, melanoma is the most investigated in terms of its potential to be treated through immune system-based approaches. More immunotherapy drugs are approved for melanoma than for any other type of cancer, and more are in development. Recent additions to the immunotherapy arsenal are the ‘anti-PD-1’ immune checkpoint blockade drugs pembrolizumab (Keytruda) and nivolumab (Opdivo).

Compared to older immunotherapy drugs—IL-2, interferon, and the older checkpoint drug ipilimumab (Yervoy)—anti-PD-1 drugs produce responses that are much more impressive in both their frequency and durability. However, the fact is they still do not work for all patients. Only about 30% to 35% of patients respond to anti-PD-1 drugs; even when Opdivo is combined with Yervoy, the number rises to just above 60%.

Intensive work is being done to figure out how to predict a patient’s response to immune checkpoint blockade. There is no reason to give these drugs to patients whose tumors have characteristics that make them unlikely to respond. And, of course, once the factors that make tumors resistant to immune checkpoint blockade are identified, researchers could develop ways to try to overcome the resistance.

Here is an overview of what has emerged from preclinical and clinical research so far:

1. Yervoy, the older checkpoint drug that disables the inhibitory protein CTLA-4 on T cells, produces responses in only about 10% to 15% of patients with metastatic melanoma. A large study has found that responses to Yervoy correlate with the number of mutations in any given tumor. After treatment with Yervoy, patients whose tumors had more than 100 mutations survived much longer than those whose tumors had fewer mutations. However, this correlation was not perfect. Also, it is not currently practical to prepare and analyze mutational tumor profiles for most melanoma patients.

2. Another study found that melanomas with mutations in the gene NRAS tend to have better responses to all kinds of immunotherapies (IL-2, interferon, Yervoy, and both PD-1 and ‘PD-L1’ blockade). In particular, 73% of patients with NRAS-mutant melanoma responded to PD-1 and PD-L1 blockade, versus 35% of patients whose tumors had normal NRAS. NRAS-mutant tumors tend to express more of the protein PD-L1, which could be related to their better response.

3. In lung cancer, expression of PD-L1 in tumors is a fairly reliable predictive marker of response to PD-1 blockade, but in melanoma the situation is more complex. In general, the presence of PD-L1 signals that T cells present in a tumor have been inhibited by the tumor, keeping them from playing their normal role as cancer cell killers. But it is possible to ‘awaken’ these dormant T cells through treatment interventions such as inhibition of PD-1 or PD-L1.

4. Well before the era of immunotherapies, it was recognized that the mere presence of infiltrating (invading) T cells in or very close to a tumor is generally a good prognostic marker. It is an indication that the immune system has been alerted to the presence of a tumor, even though the T cells may be prevented from attacking cancer cells by tumor-generated factors (such as PD-L1). Melanomas with T cell invasion respond much better to immune checkpoint blockade than melanomas without infiltrating T cells.

5. Why do some melanomas have T cells while others do not? A recent study made a major breakthrough in this problem. A molecular comparison of a large number of melanomas with or without T cells found a big difference in the activity of a certain cellular pathway known as β-catenin. This pathway was highly active in melanomas without T cells, but not in melanomas with T cells.

The researchers created two types of mice that had melanoma tumors with or without activated β-catenin. The mouse experiments confirmed that high β-catenin in melanoma tumors prevented invasion of T cells. Moreover, mouse tumors with high β-catenin did not respond to PD-1 inhibitors, but those with low β-catenin shrank after treatment. The underlying reason is that high β-catenin tumors failed to recruit not only T cells, but also specialized dendritic cells. Dendritic cells present tumor antigens to T cells, and are absolutely necessary for T cell recruitment. High β-catenin melanomas fail to attract dendritic cells and, as a consequence, T cells.

The researchers are now trying to figure out ways to inhibit β-catenin with targeted drugs and to evaluate if this will help tumors respond to PD-1 blockade. Meanwhile, they have found that irradiation of high β-catenin tumors leads to the influx of dendritic cells, followed by T cells. This is a welcome confirmation of the rationale for the already ongoing trials that combine radiation therapy with PD-1 blockade.

To summarize, we now have several approaches to predictive testing for immune checkpoint blockade in melanoma. Factors that predict a good response include the presence of T cells, a high number of tumor mutations, and NRAS mutation. A high level of β-catenin predicts a poor response, but carries with it a hope for future interventions to break resistance.

Image Credit: Micrograph of malignant melanoma (copyright 2010, Nephron)