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    CIM CON day 1 – Precision cancer care: ‘So much power’

Article by Barbara Toman

Individualizing Medicine Conference 2018

Unlocking the secrets of the genetic blueprint may hold the key to both detecting and effectively treating cancer. Researchers from around the world are discussing new ways to diagnose and treat cancer at the Individualizing Medicine Conference: Advancing Care through Genomics, which started today. The Mayo Clinic Center for Individualized Medicine (CIM) is hosting the conference this week at the Mayo Civic Center in Rochester, Minnesota.

Specific topics include a novel treatment that harnesses the power of the immune system to attack cancer, and two types of testing to uncover the unique genetic makeup of an individual's tumor. Three conference speakers outline these developments.

Weaponizing the immune system

The name is complicated — chimeric antigen receptor (CAR) T-cell therapy — but the idea behind this new cancer treatment is straightforward. Cells in the immune system, known as T- cells, are genetically modified to equip them to recognize and destroy cancer cells.

Yi Lin, M.D., Ph.D.

"We've seen very impressive results. CAR T-cell therapy is a living drug that relies on the innate ability of the patients' own immune cells to sense what's around them and to respond," says Yi Lin, M.D., Ph.D., chair of the Cellular Therapeutics Cross-Disciplinary Group in the Mayo Clinic Cancer Center, who spoke this morning as one of the conference's main speakers. "These cells are a smart and living drug, and we hope they can last a long time in a patient's body and have a durable effect."

CAR T-cell therapy was approved by the Food and Drug Administration last year to treat two types of blood cancer — relapsed B-cell acute lymphoblastic leukemia and relapsed B-cell non-Hodgkin's lymphoma. Less than 15 percent of people who experience recurrence of those cancers respond completely to existing treatments. Up to 90 percent of people respond to CAR T-cell therapy, with 40 to 50 percent experiencing remission.

"Of course, this therapy is so new that we are still learning how durable that response will be," Dr. Lin says.

Other challenges remain. CAR T-cell therapy causes severe side effects that sometimes require management in the intensive care unit and, rarely, can be fatal. With support from CIM, the researchers are working to find biomarkers that could identify individuals likely to experience severe side effects or to have a durable response to the therapy.

The researchers also hope to simplify the complex processes involved in CAR T-cell therapy to improve patients' experience. In addition, laboratory work is underway to develop a next generation of CAR T-cell therapy that would have fewer side effects and would kill other blood-based cancers and solid tumors.

Dr. Lin expects multiple myeloma to be the next cancer type to gain FDA approval for CAR T-cell therapy.

"We have a lot to learn," Dr. Lin says. "But we know CAR T-cell therapy is a good platform to develop more innovations."

Genetic fingerprints to guide treatment

A genetic test developed at Memorial Sloan Kettering (MSK) Cancer Center can profile the unique genetic makeup of an individual's cancer — information that physicians can use to select the best treatment for that person. The MSK-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) can detect genetic changes in 468 genes associated with common and rare cancers.

Michael Berger, Ph.D.

"Almost 40 percent of patients tested with MSK-IMPACT have a DNA alternation that can be targeted by an approved or investigational therapy. Those patients can then receive targeted treatment or be enrolled in a clinical trial," says Michael Berger, Ph.D., associate director of the Marie-Josée and Henry R. Kravis Center for Molecular Oncology at MSK Cancer Center.

Dr. Berger, who spoke at the conference today, led the development of MSK-IMPACT, which offers a more comprehensive view of an individual's tumor than smaller gene panel tests. "We've begun extracting even more information from MSK-IMPACT data, looking beyond individual mutations to the more complex signatures of mutations that sometimes affect response to immunotherapy," he says.

In his conference presentation, Dr. Berger cited a 67-year-old woman who had been successfully treated several years earlier for breast cancer but subsequently developed a tumor in a lymph node. That tumor was considered a recurrence of breast cancer — until the woman had MSK-IMPACT testing.

"Based on mutations and other genomic signs, we realized there was a 96 percent chance that this wasn't breast cancer but a lung cancer," Dr. Berger says. "As a result of this new diagnosis, she was treated with chemotherapy instead of hormone therapy."

CT sequences DNA from patients' blood as well as their tumors. The blood sequencing tests can detect mutations associated with a predisposition to cancer. "That has implications for family members, who might benefit from screening or genetic counseling," Dr. Berger says.

By focusing on genetic alterations shared by various tumor types, MSK-IMPACT can boost the power of clinical trials for new cancer therapies. "After MSK-IMPACT testing, you might have patients in a clinical trial with lung cancer, breast cancer or any other cancer type who share a specific genomic alternation that can be targeted by the drug under investigation," Dr. Berger says. "The more accessible this testing becomes, the more effectively we can choose the best therapies for patients based on the genetic makeup of their tumors."

A deeper dive with RNA sequencing

To further guide cancer treatment, researchers are diving even more deeply into the expressed genes of tumor cells, using RNA sequencing. It's a technology that provides a wealth of information, including detecting the fusion of two previously separate genes. Fusions of cancer-related genes can contribute to tumor formation and progression.

"Identifying gene fusions can help with diagnosis and can help predict whether a person will respond to certain cancer therapies," says Kevin C. Halling, M.D., Ph.D., a consultant in Mayo Clinic's Division of Laboratory Genetics and Genomics, who spoke at the conference today.

RNA sequencing is currently used mostly to help with diagnosis of sarcomas — cancers that occur in the bones and soft tissues. But it also shows promise for the diagnosis of certain blood and lung cancers with gene fusions.

Kevin Halling, M.D., Ph.D.

"There's so much power to this RNA sequencing technology. It seems like almost every time we run it, we're discovering something new," Dr. Halling says. "There's a lot we have to discover yet before we can understand the precise applications for this technology. But I'm confident that drugs are going to become available that work on these fusions. The work we're doing now will pay off later."

The Individualizing Medicine Conference continues tomorrow. Highlights tomorrow include presentations on the Human Genome Project and its impact on precision medicine, as well as the use of big data to understand genetic links to disease and breakout sessions on artificial intelligence (also known as augmented human intelligence), pharmacogenomics, and the microbiome and its influence on diet and health.

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