Advances Improving & Prolonging Lives

There was a time when patients with newly diagnosed metastatic melanoma were told to get their affairs in order. Now, there is a different message, thanks to advances in immunotherapy, including developments from trials and research conducted at Yale Cancer Center and Smilow Cancer Hospital

“I tell them we’re going to push the envelope as much as we can and are hoping for a cure. I ask them to pay attention and to partner with us on this journey. And most of them are very happy to do that,” said Harriet Kluger, MD, director of Yale’s skin cancer program and Harvey and Kate Cushing Professor of Medicine (Oncology) and Dermatology, Yale School of Medicine.

Two decades ago, Dr. Kluger’s patients with late-stage melanomas usually had from six to nine months to live. A few years later, checkpoint inhibitors — a type of cancer treatment that help the body’s immune system fight cancer more effectively — were being offered and studied in clinical trials. Doctors noticed that median survival was increased to about a year. Then, with the introduction of a new class of inhibitors, called PD-1 inhibitors, the most broadly used immunotherapy, the median survival went up to three years.

“Now we know that at six-and-a-half years of follow-up for the longest running of the large dual checkpoint inhibitor trials, approximately half of our patients are alive, many of them off treatment,” Dr. Kluger said.

As with melanoma, advances in immunotherapy are improving outcomes for patients with many types of cancer.

Physicians at Yale Cancer Center and Smilow Cancer Hospital are at the forefront of cancer research, and new treatment approaches as they oversee clinical trials that give patients access to the latest immunotherapy drugs.

Among the pioneers of immunotherapy are Yale School of Medicine’s Lieping Chen, MD, PhD, United Technologies Corporation Professor in Cancer Research and Professor of Immunology, Dermatology and Medicine (Medical Oncology), and Roy Herbst, MD, PhD, Deputy Director of Yale Cancer Center, Ensign Professor of Medicine (Medical Oncology), and professor of pharmacology.

“Understanding lung cancer and what causes lung cancer patients to respond to immunotherapy, or not, has been a major effort of our research here at Yale. We’ve worked very closely with Dr. Chen and colleagues to understand this better,” Dr. Herbst said.

“The advantage of our program here at Yale has been the close proximity of our scientists and clinicians all working to target diseases such as lung cancer, melanoma, and renal cancer. This truly accelerates the pace at which we can bring new lab developments to clinic to fight these diseases with new immunologic advances.”

EARLY IMMUNOTHERAPY BREAKTHROUGH

Dr. Chen discovered that a molecule called PD-L1 could bind to a certain cell receptor (PD-1) and, in some cases, prevent the immune system from “seeing” and attacking cancerous tumors. That led to clinical trials that tested the drugs, called immune checkpoint inhibitors, designed to prevent the binding action of PD-L1. These drugs have given years of life to patients who respond to them. In 2013, Dr. Chen’s work in the discovery of the PD-1/PD-L1 pathway was cited as the #1 breakthrough of the year by Science magazine.

Checkpoint inhibitors have “made huge inroads into the treatment of cancer,” said Mario Sznol, MD, professor of medicine (medical oncology) and co-leader of the Cancer Immunology Research Program at YCC.

“It’s used in almost every cancer type so at least some subset of patients with most types of cancer receive some benefit from the drugs. In some diseases, these drugs provide enormous benefit, even cures. We still have a long way to go, but clearly the immune checkpoint inhibitors are one of the biggest advances in cancer treatment,” Dr. Sznol said.

A relatively new checkpoint inhibitor called Relatlimab, combined with the PD-1 inhibitor nivolumab, was approved in melanoma, and the combination is being studied in other tumor types.

“It raises the question of whether there are additional checkpoint inhibitors that are going to be helpful,” Dr. Kluger said. “We are working on some, both in the lab and in the clinic, but it’s a little early to say.”

Another development is using immunotherapy before surgery. Ongoing Yale trials in this area are showing promise in lung, head and neck, and other cancers. This approach is already standard therapy in triple negative breast cancer.

“The majority of immunotherapy is focused on late-stage cancer,” Dr. Chen said. “Now the idea is to give immunotherapy before surgery to prevent the metastasis and treat any smaller tumors left.”

Dr. Chen said he’s also working with Kurt Schalper, MD, PhD, associate professor of pathology, on the so-called ‘cold tumor’ in which a patient’s immune system seems to ignore the cancer. “We discovered several molecules, which are overexpressed by tumor cells and basically signal the immune cells not to come to the tumor. [The discovery] is pretty exciting,” Dr. Chen said.

STIMULATING IMMUNE CELLS

Another novel class of drugs being studied at Yale is cytokines, molecules that stimulate immune cells directly.

“Our cells make cytokines when we have an infection, and the cytokines direct the activation of our immune cells to clear the infectious organisms, such as viruses. So the question is whether this mechanism can be harnessed for cancer treatment,” Dr. Kluger said. “We’ve been trying to do it for years with modest success, partially because the amount of cytokines we can give is limited by side effects. But now it’s possible to engineer the cytokines to have effects more specific to the tumor microenvironment or certain immune cells so they don’t produce side effects in other parts of the body. This approach is really promising.”

A third type of immunotherapy, called T-cell engagers, recruit and activate T-cells, a type of white blood cell, to recognize and attack cancer cells. A T-cell engager, Tebentafusp, has been approved for melanoma, and in recent months

a drug called tarlatamab was approved for small cell lung cancer. T-cell engagers are also showing promise in patients with late-stage prostate cancer, and are already approved for treatment of lymphomas, Dr. Sznol said.

“The (tumor) response rate to some of the T-cell engagers is really remarkable,” he said. “As a class of drugs, T-cell engagers are very promising and will have a substantial impact. It could be the next major advance in immunotherapy of solid cancers.”

ANTIBODY DRUG CONJUGATES

Then there are antibody drug conjugates, which are not immunotherapies but use an immunotherapy concept by targeting chemotherapy to the tumor with an antibody. They attach a cancer-fighting chemotherapy drug to the antibody, which carries it directly into the tumor. Daniel P. Petrylak, MD, professor of medicine (medical oncology) and of urology, is a pioneer in the research and development of new cancer drugs, including the antibody drug conjugate enfortumab vedotin, used to treat urothelial (bladder) cancer.

“The gratifying thing is that patients who had no other options for treatment are now long-term survivors,” Dr. Petrylak said. “This opens avenues in other tumor types to deliver a chemotherapeutic agent directly to the cancer cell. Enfortumab really has changed the way oncologists treat bladder cancer. It’s now used in the front-line setting with results that are far superior than anything that was ever seen with chemotherapy.”

Additional approaches being studied at the bench and in the clinic include genetically engineering a patient’s own immune cells and stimulating various types of immune cells. Although progress in cancer treatment is incremental, physicians and scientists in oncology research are more excited for the future than ever before—and the ability to work at Yale.

“When you interact daily with brilliant bench researchers, you start thinking differently in the clinic,” Dr. Kluger said. “You start thinking about the biology of the cancer and the biology of the immune system. That’s what keeps us pushing the envelope. The onus is on us as clinical researchers to always improve on the standard of care and the quality of life for our patients.”