By the time Anita Adler made her way to Smilow Cancer Hospital in July of 2013 with stage IV non-small cell lung cancer (NSCLC), she had already heard the words every patient dreads. “My doctor told me there was nothing more they could do,” Mrs. Adler said, now 80, a substitute teacher and mother of four who has been married to her husband Russ for 61 years.
Mrs. Adler had always been physically strong. Even in her 70s, she was an avid swimmer who religiously did laps in her local pool in winter and swam in the Long Island Sound during the summer. But in the fall of 2013, she was exhausted from several rounds of chemotherapy and radiation, frail, in need of oxygen, and fighting a chronic cough. “I had every side effect from chemo listed,” she explained. “And I couldn’t bring myself to eat much. The silly thing is, like many women, I spent so much time trying to lose weight, then with the cancer, I lost 40 pounds in one month.” Mrs. Adler had one thing in her favor, however: Her doctor referred her to Scott Gettinger, MD, Associate Professor of Medicine (Medical Oncology) at Yale Cancer Center and the Disease Aligned Research Team Leader for the Thoracic Oncology Program at Smilow Cancer Hospital.
Dr. Gettinger is used to tough cases. Since 2009, he has been investigating the effectiveness of immunotherapy drugs against lung cancer. “There was pessimism about using immunotherapy for lung cancer back then, with several clinical trials failing to demonstrate effectiveness. Most had given up on this approach,” said Dr. Gettinger.
When Dr. Gettinger decided to try using checkpoint inhibitors to treat patients with advanced lung cancer, his colleagues were skeptical. Simply put, checkpoint inhibitors relieve brakes put on the body’s immune system by cancer, thereby allowing immune cells to do what they were meant to do–attack cancer. “No one thought they would work for lung cancer,” he admitted. But in 2009, he started enrolling select patients to a trial evaluating the checkpoint inhibitor drug Nivolumab. He was at first impressed by the tolerability of Nivolumab, with most patients experiencing little or no side effects. Then, he saw the responses. “Prognosis for these patients was on the order of 3-6 months, with few patients expected to live beyond a year. Five years later though, 16 percent of patients were alive. I am still following some of these patients today.”
Flash forward to 2018: The treatment Dr. Gettinger pioneered is now available as a first line therapy option for lung cancer. “The success of these medications has radically changed the treatment paradigm for lung cancer,” he said. That was good news for Anita Adler, who, despite her weakened physical state, says she felt more optimistic the moment she came to Smilow Cancer Hospital. “Everyone was just wonderful. I drew confidence from the environment,” she said. Dr. Gettinger started her on a trial randomizing patients to standard salvage chemotherapy or immunotherapy. Mrs. Adler was randomized to chemotherapy. After that failed, Dr. Gettinger told Mrs. Adler that it was time to consider another clinical trial that was testing a combination of two immunotherapy drugs. Instead of chemotherapy, she would get an infusion of an immunotherapy regimen every three weeks.
Soon after beginning the new treatment in early 2014, Mrs. Adler’s appetite returned. Shortly after that, she was out of her wheelchair, off oxygen, teaching again— and more. “I’ll never forget when Anita’s son showed me a video of Anita during one of her treatment visitsthere she was, swimming in the Long Island Sound!” Dr. Gettinger recalled.
That was memorable for Mrs. Adler, too. “Every August, we have a family beach day, when everyone comes home,” said Mrs. Adler. “My son always takes pictures of me swimming!” Within a few months, Mrs. Adler’s cancer was totally gone. “Dr. Gettinger called me at 8:30 one night after a CT scan, and said he couldn’t believe what he was seeing,” she recalled. But Mrs. Adler’s cancer would not be vanquished so easily. Four or five months into her treatment, a PET scan turned up signs of cancer in a lymph node. “I could always tell when the cancer was returning because I’d feel that exhaustion,” she explained. Surgery to remove the affected and surrounding lymph nodes left her without evidence of disease, and after a year of continued immunotherapy and no sign of cancer, Mrs. Adler went off the treatment, as the trial required.
Yet, less than a year later, the cancer again returned in her lymph nodes. Once again, the immunotherapy beat it back. Along the way, Dr. Gettinger was taking samples of Mrs. Adler’s tumor—at the beginning of treatment, and each time her cancer returned. His goal: to understand why certain tumors seemed to acquire resistance to the immunotherapy. “Like Anita, most patients with response to these therapies inevitably develop resistance when cancer recurs,” explained Dr. Gettinger. “We want to understand why.” To do that, Dr. Gettinger compared Mrs. Adler’s initial tumor to ones that appeared later, after periods of successful therapy.
“By comparing the specimens we can see what has changed that might be rendering the cancer resistant,” he explained. His team is also studying cells from tumors of patients who don’t respond to immunotherapy at all, as well as from patients who seem to respond robustly and indefinitely. “We’ve collected a cohort of what we call ‘exceptional responders,’ who show no evidence of active disease at least three years after starting treatment. We are tracking 30 or so patients in this group to see what’s unique about their tumors.” By 2017, Mrs. Adler’s cancer had recurred again.
The good news was that Dr. Gettinger and his team, who had been doing biopsies of Mrs. Adler’s tumors all along, now had more information about her cancer cells. “We looked at the tumors on a molecular level, studying changes in DNA and RNA, and additionally at Anita’s immune cells within the tumor,” Dr. Gettinger explained. Even more remarkable: Each time Dr. Gettinger and his team biopsied Mrs. Adler’s various tumors, they injected samples of that tumor into laboratory mice, creating mice models that now had growing tumors identical to Mrs. Adler’s. “We created a litter of mice with Anita’s tumors that could be interrogated further, and treated them with different therapies designed to counteract resistance to the immunotherapy Anita received.”
Yet one crucial element was missing in that experiment. To truly get a complete picture of how these tumors interacted with the immune system, and learn why some seemed to grow resistant to treatment, Dr. Gettinger’s team needed mice that not only had Mrs. Adler’s tumors but also had her immune system—what Dr. Gettinger refers to as a humanized mouse model. To do that, he needed to take early progenitor cells from Mrs. Adler’s bone marrow to recreate her immune system in the mice.
While Mrs. Adler was happy to contribute pieces of her tumor and submit to biopsies–“If it’s going to advance science, I’m excited about it,” she said--she was nervous about donating her bone marrow cells. “My sister died from bone cancer, so getting near my bones frightened me,” she said. “But in my heart, I knew I wanted to do it.” Once Mrs. Adler gave her consent, Dr. Gettinger and his team aspirated her bone marrow cells during one of her tumor biopsy procedures— “I was under anesthesia; it was all fine,” Mrs. Adler recalled—and they could now inject those cells and create a mouse with Mrs. Adler’s immune system. “That meant we could replicate how the tumors and the immune system were interacting,” said Dr. Gettinger.
When Mrs. Adler’s cancer returned, and her tumors looked as if they were now resistant to treatment, Dr. Gettinger went back to the lab and discovered something that had not been described before. “We saw that Anita’s tumor was further thwarting her body’s immune system, evading detection by altering certain markers on its surface.” Normally, when a cancer cell or virus camouflages itself in this way, there are specialized immune cells that can sense the deception, and decimate the altered cancer cells. These extra-alert immune cells are known as natural killer cells. By using flow cytometry on one of the tumor specimens they had collected from her, Dr. Gettinger and his team discovered that Mrs. Adler’s tumor was expressing keys on its surface that turned off the natural killer cells, thus explaining their resistance to treatment. Based on those results, Dr. Gettinger tried a combination immunotherapy treatment through a clinical trial.
“We were participating in a phase one study evaluating a new medication that could potentially release Anita’s natural killer cells from the restraints used by the lung cancer,” he explained. In November of 2017, Mrs. Adler began this therapy. “Not only did she respond, but she had a complete response, which is rare,” said Dr. Gettinger, still jubilant. “No remaining tumors could be found on imaging studies.” That was more than a year ago. Aside from some skin side effects that are now subsiding, Mrs. Adler is once again swimming laps, teaching, and enjoying her family. Thanks to her generosity and willingness to participate in Dr. Gettinger’s research, there is also more hope for all patients with advanced NSCLC. “Anita let us go one step beyond,” said Dr. Gettinger. “We learned a great deal from her tumor and immune system, and were able to recommend a therapy based on our discoveries that resulted in clearance of her lung cancer. Anita’s contribution has paved the way to new discoveries that will benefit many. Seeing her enjoying life is an indescribable reward that pushes us to do more.” Which is why Mrs. Adler gathered with her family this past Thanksgiving, felt especially grateful. “I am very lucky to have been sent to Yale,” she said. “I’m grateful to the doctors, and I feel good about what I’m doing for them. But I feel twice as good about what they have done for me.”