In NEJM, Clues to Which Melanomas Respond to Immunotherapy

Alexander M. Castellino, PhD

November 21, 2014

Immune checkpoint blockade has provided durable responses across several solid cancers. However, predicting who will respond has baffled clinicians since the launch of the first immunotherapy agent, ipilimumab, which blocks cytotoxic T-lymphocyte antigen 4 (CTLA-4).

Now a team led by scientists at the Memorial Sloan Kettering Cancer Center in New York City have provided surprising insights into how a high mutational burden is associated with more robust responses to ipilimumab in patients with metastatic melanoma. The report was published online November 19 in the New England Journal of Medicine (NEJM).

"We have begun to understand why some tumors respond to immunotherapy and others don't. There is a genetic basis rooted in passenger mutations, which have the opportunity to make the tumor more foreign to the immune system," Jedd D. Wolchok, MD, PhD, chief, Melanoma and Immunotherapeutics Service, and Lloyd J. Old Chair for Clinical Investigation, told Medscape Medical News.

Geneticist Timothy A. Chan, MD, PhD, vice chair, Department of Radiation Oncology and Director, Translational Oncology Division, echoed similar sentiments. He told Medscape Medical News: "Immunotherapies were developed in an ad hoc manner. This is the first paper to identify how response to immune-based drugs may be written in the DNA of the tumor."

Dr Wolchok and Dr Chan are from the Memorial Sloan Kettering Cancer Center and are co-corresponding authors on the NEJM report.

A major hurdle in tumor immunotherapy is the fact that mechanisms of self-tolerance that prevent autoimmunity also impair T-cell responses against tumors, which do not differ substantially from self, writes Vassiliki A. Boussiotis, MD, PhD, professor in medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, in an accompanying editorial in the journal.

The genetic landscape of melanoma and other cancers, which show a high mutational burden associated with environmental exposure to ultraviolet light and smoking, now suggests that mutational epitopes resembling those of bacteria and viruses emerge, she told Medscape Medical News. The emergence of these potentially potent "neoepitopes" is associated with treatment success, she added.

The Memorial Sloan Kettering Study

For the discovery set, researchers undertook whole-exome sequencing of tumor DNA and matched normal blood from 25 patients treated with ipilimumab. Exome sequencing provides sequences for all protein-coding genes in the DNA. Eleven of these patients were exceptional responders to ipilimumab and 14 were not.

The researchers correlated the mutational load seen in the exome sequence with response to therapy. They found that patients with a high mutational load showed long-term benefits with ipilimumab. Patients with a low mutational load showed minimal or no benefit. In fact, a mutational load greater than 100 was correlated with significantly better overall survival compared with a mutational load of under 100.

Using a bioinformatics approach developed by Dr Chan, the researchers identified mutations in the exomes and determined their ability to activate an immune response. A "neoepitope signature," which conferred long-term benefit, was identified. This signature was common to all tumors from patients who experienced long-term benefits with ipilimumab.

These observations were validated in a separate set of 39 patients, of whom 5 were treated with another CTLA-4–blocking antibody, tremelimumab.

Explaining Exceptional Responses

Dr Boussiotis writes in her editorial: "[In] order for a CTLA-4 checkpoint blockade to mediate clinical benefit, T cells must be activated in the context of tumor-associated antigens."

For immunotherapies to work, the tumor must be recognized as nonself. The neoepitopes, which include recurrent distinctive stretches four amino acids long ("tetrapeptide"), provide a core of the necessary context for T cells to recognize melanoma as nonself.

The immune system surveys structure, not function. It has to look like a target it is designed to recognize. Apart from oncogenic driver mutations and otherwise oncogenic "silent passenger"' mutations, tumor cells look like normal cells, said Dr Wolchok. The tetrapeptide sequence in exceptional responders is homologous to sequences in bacteria and viruses that the immune system evolved to recognize and eliminate, he added.

If one had to choose a single term to describe what immunotherapy is ultimately targeting, it would be "genetic diversity," Dr Chan explained.

Both Dr Boussiotis and Dr Wolchok shared insights into why a higher mutational load provides a higher likelihood of response to immunotherapies.

Melanoma, lung cancer, head and neck cancer, renal cell carcinoma, and bladder cancer have a high mutational burden. That is why immunotherapies work in these disease settings, Dr Wolchok said. The genetic instability of tumors is the immunotherapist's best friend, he added.

Mutational burden also increases with age, Dr Boussiotis indicated. However, a mutational load in and of itself is insufficient to impart a clinical benefit. It is the quality, not the number, of mutations that has the highest predictive value for treatment success, Dr Boussiotis said. The likelihood of obtaining quality mutations increases with the mutational load, she added.

She went a step further in explaining response to immunotherapy. A responder's immune system was possibly activated in early life when exposed to certain bacteria and viruses leading to the generation of memory T cells. In the context of neoantigens homologous to bacteria and viruses, these memory T cells activate the immune response, and blockade of CTLA-4 provides the best clinical benefit.

What's Next for Predicting Response to Immunotherapies?

This report was the first to show why some patients treated with ipilimumab have shown exceptional responses.

In their report, the investigators write that their use of whole-exome sequencing to identify a genetic basis associated with a benefit from CTLA-4 blockade provides proof of principle that tumor genomics can inform responses to immunotherapies.

Dr Chan said, "We will soon offer patients an opportunity to obtain a mutational profile, which can guide patients to appropriate clinical trials and to the correct choice for immunotherapy. Our goal is to move rapidly to make this available to patients so that we can determine who can benefit from ipilimumab and who would not and thus, perhaps, should try other immunotherapy agents."

The goal may now be to identify peptide signatures in good responders and make a panel that could be used in a test, Dr Boussiotis added.

These observations also have implications for predicting responses to other immunotherapies across other solid tumors, said Dr Chan. He indicated that they are using a similar approach to identify neoepitopes in patients with lung cancer who have responded to immunotherapy with PD-1 inhibitors.

Several authors on the article report a pending patent related to determinants of cancer response to immunotherapy; some report personal fees, grant support, and/or nonfinancial support from industry. Dr Boussiotis has disclosed no relevant financial relationships.

N Engl J Med. Published online November 19, 2014. Abstract Editorial


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