January 2015, Vol. 2, No. 1

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The Future of Immunotherapy in Breast Cancer

Breast Cancer

The oncology community is abuzz with the promise of immunotherapy, sparked by the success of immunotherapeutic approaches in advanced melanoma. There is major interest in studying immunotherapy in other cancers, including breast and lung cancer.

At the 2014 Chemotherapy Foundation Symposium, Heather L. McArthur, MD, MPH, a medical oncologist in the Breast Medicine Service, Memorial Sloan Kettering Cancer Center (MSKCC) in New York City, updated listeners on a novel approach being studied at her institution for the treatment of breast cancer using cryoablation in combination with anti–PD-1 and anti–CTLA-4 inhibitors. Thus far, preliminary results suggest that this is a worthy strategy to pursue.

“Immune checkpoint inhibition in breast cancer is an unbelievably exciting topic right now,” McArthur said. But, she cautioned, “Immunology is complicated and intimidating. I’ve been designing these studies for more than 5 years, and I still come out of meetings saying this is exciting and complex. The future of this field requires a multidisciplinary effort, so we need to create building blocks for the conversations we need to have.”

The CTLA-4 inhibitor ipilimumab and the PD-1 inhibitor nivolumab achieved an unprecedented survival improvement in melanoma, with 1-year survival of 94%, McArthur said.

“We need to have a balance of immune activation and immune suppression. The ‘gas’ to the system is kept in check with the ‘brakes,’ and the brakes are PD-1. If the brakes are removed by anti–PD-1 agents, then you have immune stimulation to fight the tumor,” she explained.

Studies provide hints that anti–PD-1 checkpoint inhibitors may be worth pursuing in breast cancer, particularly in triple-negative and HER2-positive breast cancers, she said.

Tumor-infiltrating lymphocytes (TILs) are prognostic in triple-negative and HER2-positive breast cancer. The 2013 GeparSixto study showed that TILs predicted response to carboplatin in triple-negative and HER2-positive breast cancer. TILs also predict response to trastuz­umab, McArthur added.

“The next question is, ‘If modern immune strategies work in melanoma and we have predictive markers [ie, TILs], can we expect immune approaches to work in breast cancer?’” she asked.

In pilot studies at MSKCC, CTLA-4 blockade achieved stable disease in breast cancer, but not the dramatic responses seen in melanoma. “This could be because breast cancer does not have as high a mutational load as melanoma,” McArthur suggested.

The next step was to determine how to optimize the immune response. The investigators hypothesized that cryoablation and anti–CTLA-4 therapy could be a good combination in breast cancer. The thinking was that cryoablation of the tumor would create tumor fragments, optimizing tumor antigen presentation; then, immune modulation could enable an immune response that is specific to an individual’s tumor.

In a pilot study of 18 women with planned mastectomy, 6 women had cryoablation alone, 6 received anti–CTLA-4 treatment with ipilimumab, and 6 received the combination before surgery.

Cryoablation was performed with MRI guidance, and after a series of freeze and thaw cycles, tumor fragments were seen. The procedure was well tolerated. Biopsies were obtained up front, and the mastectomy sample was analyzed.

More absolute numbers of T cells and more diverse T cells were present in triple-negative and HER2-positive samples compared with normal tissue. In the tumor bed, the ratio of types of T cells changed after ipilimumab and cryoablation. In the periphery, serum T cells were activated by ipilimumab.

“Cryoablation changes the clonal evolution of the T cells. This is exciting and innovative, and we have much to learn,” McArthur told listeners.

Building on the pilot study, the MSKCC investigators have planned a randomized study of ipilimumab plus nivolumab and cryoablation in early-stage breast cancer. Future strategies could include combining immunotherapy with conventional therapies, radiation, and other ablative strategies, McArthur said.

“Given the success of immunotherapy in melanoma and some solid tumors, and that TILs are predictive and prognostic in breast cancer, and preliminary data that we can alter tumor, stromal, and blood immune elements, there is good reason to be optimistic about immunotherapy approaches in breast cancer,” McArthur stated.

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