Exceptional Immunotherapy Response Triggers Search for the Cause

  • In order for immunotherapy checkpoint blockers to work, the tumor has to be recognized as foreign by the immune system.
  • Most brain tumors, however, lack large numbers of mutations — making the tumors less covered with neoantigens, red flags signaling cancer.
  • However, some high-grade meningiomas are different, harboring mutations that produce neoantigens. They have been found to harbor mutations that produce neoantigens, making them potentially vulnerable to treatment with checkpoint blocking immunotherapy drugs.

Six years’ worth of repeated surgeries, radiation, and chemotherapy with three different agents failed to halt the growth of Frances Zichichi’s brain tumor. As it kept recurring and more surgeries were required, Zichichi lost the use of her left side. Eventually the cancer formed masses under her scalp, causing pain, which was dulled only with narcotics, and intense headaches, which were treated with steroid drugs.

Then, in 2016, she went on a new clinical trial. She received the checkpoint blocker drug nivolumab, an immunotherapy drug which releases the immune system from molecular “brakes” that keep it from attacking cancer cells. Over the next few weeks and two doses of nivolumab, however, the tumors continued to grow. Her scalp pain and headaches got even worse.

“Her physical exam and MRI appeared consistent with progressive disease, and we withheld further nivolumab,” wrote the researchers, led by David Reardon, MD, clinical director of the Center for Neuro-Oncology at Dana-Farber Cancer Institute, in a report in JCO Precision Oncology.

David A. Reardon, clinical director of the Center for Neuro-Oncology at Dana-Farber Cancer Institute

Surgeons then performed a “debulking” procedure to remove the scalp tumor, and when the tissue was examined by pathologists, it yielded a big surprise. That night Reardon got a phone call from the lead surgeon who was very excited to report that everything that was removed was dead tumor. What had looked like worsening disease was “pseudo-progression.” The nivolumab had worked – and worked dramatically.

“Ever since that day, she’s been tumor-free,” said Joseph Zichichi. Frances continued with nivolumab treatment every other week for two years and last September, she and her husband, in consultation with Reardon, decided to stop it – though she still is observed with periodic imaging scans.

Zichichi’s type of cancer, a meningioma, is the most common primary tumor of the central nervous system, diagnosed in about 28,000 people a year in the United States. Meningiomas tend to be slow-growing but can cause problems if they expand and press on crucial parts of the brain. A subset of meningiomas, like Frances’, can be quite aggressive. There are no approved systemic therapies for meningiomas that keep recurring after surgery or radiation.

Immunotherapy checkpoint blockers only work if the tumor can be recognized as foreign by the immune system. The reason behind this, scientists are learning, is that the more DNA mutations a tumor has, the more it will be studded with “neoantigens” that are like red flags signaling cancer: This increases the chance that the immune system will recognize the tumor as foreign and launch an attack. Unfortunately, because most brain tumors lack large numbers of mutations they generally don’t respond to treatment with checkpoint blockers.

However, high-grade meningiomas such as Zichichi’s are different. They have been found to harbor mutations that produce neoantigens, making them potentially vulnerable to treatment with checkpoint blocking immunotherapy drugs. This was the thinking behind the clinical trial that tested nivolumab in patients with high-grade meningiomas that recurred following surgery and radiation therapy.

The results from the phase 2 trial haven’t been published yet, but Reardon says 25 percent of patients in the trial have had their tumor progression stabilized for at least six months. Zichichi is the only patient in the trial who has experienced such a dramatic outcome. That makes her an “exceptional responder” in the parlance of clinical trials, and the researchers launched an effort to discover the source of her tumor’s vulnerability to the drug.

Using the Oncopanel DNA sequencing platform, part of Dana-Farber’s Profile genetic screening research program, scientists analyzed samples of Zichichi’s tumor taken at different points in her treatment, looking for mutations and copy number variations in 447 cancer genes. The investigators were especially interested in the “tumor mutational burden,” or TMB, a measure of the number of mutations that could produce immune-stimulating neoantigens. They also homed in on immune cell activity in tumor specimens taken before and after she began immunotherapy with nivolumab.

With these and other methods, the researchers created a molecular profile of Zichichi’s tumor that revealed factors in its exquisite sensitivity to nivolumab immunotherapy. The meningioma tumor cells were found to be lacking the normal repair mechanism that enables them to heal breaks in DNA – making them more susceptible to cancer therapies. In addition, the tumors had a high tumor mutational burden – much higher than the average TMB in 228 meningioma samples analyzed in the Profile project. Together, the defective repair mechanism and high number of mutations in Zichichi’s tumor are believed to account for her exceptional response to nivolumab.

With these clues in hand, the scientists analyzed samples of 1,080 meningiomas and found that only a small minority – about 2.5 percent – exhibited high tumor mutational burden. Still, they said in their report, this dramatic response to nivolumab “indicates that screening meningiomas is warranted to identify a molecularly-defined subtype likely responsive to immunotherapy.”

Other authors of the report include Sandro Santagata, MD, PhD, and Ian F. Dunn, MD, of Dana-Farber and Brigham and Women’s Hospital; and Ziming Du, MD, PhD, of Brigham and Women’s.

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