Gone are the iconic bald heads that immediately identified a person—inside or outside of the hospital—as a cancer patient. Like no other disease, cancer has traumatized the human population with its lethality and toxic treatments.
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As long as cancer has been a recognized disease, doctors have believed the power to eliminate it existed within the immune system, but attempt after attempt to unlock this potential has largely failed. The potential always existed, but the key information needed to turn this promise into real treatments was locked away inside the DNA of tumor and immune cells.
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Researchers and clinicians at the Kimmel Cancer Center have worked together with experts throughout Johns Hopkins, using science to follow the clues and bring the world what may be a universal treatment for cancer. Immune-based therapies reflect a different approach to treatment. Instead of targeting cancer cells, the new therapies target immune cells in and around cancers. Some treatments increase the number of immune cells summoned to the tumor, and others unleash the commands that send the immune cells to work against it. Leading the way are scientists, like Drew Pardoll and Elizabeth Jaffee, who have been at work for more than 30 years deciphering the mechanisms of the immune system, how it works and why it all too often does not work against cancer.
As students of the immune system, Pardoll, Jaffee, and others understood that the characteristics of the immune system should make it the perfect anticancer weapon, but if the cancer cell was complex in its molecular construction, the intricacies of the immune system were equally complicated.
Unlike viruses and bacteria that are easily recognized by our immune system because they are so different, cancer originates from our own cells. As a result, it has all of the cellular mechanisms that are used by normal cells at its disposal. Cancer co-opts them selectively, using them like superpowers to grow, spread, and cloak themselves from the immune system. It took time for the technology to catch up with the scientific ideas, but the invincible cancer cell may have finally met its match.
This Kimmel Cancer Center team of multispecialty collaborators—seasoned investigators and young clinician-scientists—have figured out how to reset the cellular controls hijacked by the cancer cell and restore power to the immune system. Utter destruction of the most resistant, lethal tumors is occurring across many cancer types and with few side effects.
Patients who were months, even weeks, from dying are alive and well, some five years or more after treatment. It was what Pardoll and Jaffee imagined three decades ago when they first began studying the immune system—perhaps even better.
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More than practicing oncologists and clinical cancer scientists from all over the world filled the lecture hall at the annual meeting of the American Society of Clinical Oncology ASCO. This time, cancer immunology expert Suzanne Topalian was there as the David A. It marks a changing tide in clinical cancer research.
Immunology studies had never before received this level of attention at ASCO meetings. With remarkable and lasting results in about 20 to 40 percent of patients with advanced cancers that resisted all other types of therapy, oncologists wanted to know more. Scholarly journals and the news media alike were reporting on drugs that caused lethal melanoma skin cancers, kidney cancers , and lung cancers to melt away and stay away.
The therapies are so new—first tested in patients in —that the Kimmel Cancer Center immunology team readily admits there is much left to learn. These long-lasting responses that continued even after therapy was stopped and caused few side effects are the reason the auditorium was filled to capacity with doctors anxious to learn how and when they could get this new therapy for their patients.
The source of the excitement is an immune target called PD-1 and a related partner protein on tumor cells called PD-L1. PD-1 is what immunology experts call an immune checkpoint. Pardoll stops short of calling it an immune system master switch, but the results in laboratory research and these early clinical trials point to it as one of the strongest influencers of an immune response to cancer identified so far.
There are two main actions at play in an immune reaction. One can think of DNA as the blueprint of a cell, and the proteins its genes encode are its building blocks. A protein from a mutated gene looks different than its normal counterpart. This is the go signal. These stop signals are controlled by immune checkpoints like PD They send a deceptive message to cancer-killing immune cells that there is no problem.
Immune cells arrive at the tumor, but they are duped with a false message that everything is OK. Taube and Anders describe a scenario in which a tumor is spreading, and as immune cells come in to try to remove the cancer, the cancer turns up the volume on PD-1, a signal that turns the immune cells off. In solid tumors, like melanoma and lung cancer, PD-L1 has received the most attention today, but PD-L2 appears to play an important role in cancers that start in the blood and lymph nodes, such as leukemia and lymphoma. When you see it through the microscope, it looks like someone outlined the cells with a marker.
It forms an armor that protects the cancer cell from the immune system. Giving patients a drug, known as an anti-PD-1 checkpoint blocker, for its ability to interrupt PD-1 signaling as well as the communication between PD-1 and PD-L1 and PD-L2, removes the stop signal and re-engages the immune system.
Among normal cells, PD-1 is not a bad actor, explains blood and bone marrow cancer expert and immunology collaborator Jonathan Powell. PD-1 is an immune mechanism that has been usurped by the cancer cell. Ryan, 71, began experiencing symptoms in when he coughed up a small amount of blood. The husband and father of eight thought it was strange, but with no pain or other symptoms he was stunned to learn he had the most advanced stage of a common form of lung cancer known as non-small cell lung cancer. The cancer had already spread to a rib.
There are few diagnoses worse than late stage lung cancer. The cancer kills more people than any other type of cancer, and few patients survive once it has spread. At this stage, the cancer is treatment resistant, responding for a brief time to chemotherapy or cancer-gene-targeted therapies, but almost always resurging even stronger. For a time, the chemotherapy worked, but the treatment came at great physical cost, and these side effects were worsening.
The simplest tasks became difficult. His body was weakening, and worse, he learned his cancer was no longer responding. Genetic testing of his tumor did not reveal any mutations that would make him a candidate for targeted therapies. It seemed he was out of options, until his doctor suggested he go to the Kimmel Cancer Center and meet with lung cancer expert Julie Brahmer.
Brahmer was one of the lead investigators on an experimental clinical study of the anti-PD-1 therapy in a variety of advanced cancers. His only side effect was some minor skin irritations he compared to a mosquito bite. Ryan is not an isolated case. Topalian and Brahmer say about one-quarter of the lung cancer patients in their studies responded to the treatment.
The numbers are even higher for melanoma and kidney cancer patients. The first clinical reports of checkpoint inhibitors in melanoma were exciting and peaked interest, but excitement was tempered because the few successes in immune therapy over the last three decades had also been primarily in melanoma and kidney cancer.
There have been documented cases of these cancers occasionally going into spontaneous remission, so experts long maintained that, by nature, these types of cancers had a way of engaging the immune system. No other type of cancer was considered to be responsive to immune interventions.
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The new therapy was greeted with guarded optimism. That all changed in when the Kimmel Cancer Center group published the results of anti-PD-1 therapy in lung cancer patients. Lung cancer had never before responded to an immune therapy, and the remarkable activity of anti-PD-1 in a small number of lung cancer patients proved what Pardoll and other cancer immunologists long believed—if understood, the immune system could be used to fight any cancer. Although lung cancers had not responded to other past immune therapy attempts, this discovery provided new evidence that it had the potential to work and was the reason the Kimmel Cancer Center team included lung cancer patients in the first anti-PD-1 trial.
Powell is excited about the success of PD-1 in patients, but he is also enthusiastic about what he sees as a triumph of science. The problem is that the response is being blocked. That concept, and the fact that it is true in people, is exceedingly important. As soon as the components of the PD-1 pathway were discovered in , Pardoll, Topalian, Brahmer, and immunology and genitourinary cancer expert Chuck Drake, saw the potential of blocking it.
They began working with the small biotech company Medarex to develop the first anti-PD1 antibody in the laboratory and took it to patients. This was the moment Pardoll and Topalian, who are not only research partners but also husband and wife, were waiting for. It was a belief Pardoll had staked his career on, and one that caused Topalian to change course from a career as surgical oncologist to immunology, working as a National Cancer Institute scientist alongside cancer immunology pioneer Steven Rosenberg for 20 years before coming to the Kimmel Cancer Center.
To be fair, interleukin-2 treatment, while a difficult treatment for patients, continues to be used occasionally today and is highly effective in some patients with melanoma and kidney cancer. However, instead of being the blockbuster immune therapy people had hoped for, it was a start. In fact, many outside the field of cancer immunology had begun to doubt the promise of immune treatments in cancer.
Immunotherapy discussions at the large national cancer meetings were sparsely attended, and research funding was hard to come by. The Kimmel Cancer Center immunology team remained undeterred. They knew the power of the immune system and their convictions were cemented in this truth. The challenge was channeling this power into real therapies.
The promise of immune therapy is changing the way new therapies are studied and evaluated. Chemotherapy poisons cells dividing quickly, including immune cells. This toxic effect is the cause of the common side effects like hair loss, nausea, and infection risk due to a compromised immune system.
Some of this was learned almost serendipitously as cancers that initially looked like they were not responding to immune treatments, with more time began to shrink with more time. Eventually, it all rested upon what was learned with science and technology—powerful new ways to look inside the DNA of cancer cells and computerized data mining that measures and quantifies the subtlest of changes and differences among seemingly similar cancers.
The mechanisms that make therapy work in one patient and not in another are now being teased out. Treatments that worked only in a small subset of patients were once deemed failures. Now, in an era of precision medicine that uses molecular markers to identify the right treatment for each patient, the options are much broader and the outlook is significantly brighter. Cancer vaccines were one of the first immune treatments studied by Kimmel Cancer Center investigators. Early research on cancer vaccines by immunologist and pancreatic cancer expert Elizabeth Jaffee proved the ability to successfully recruit immune cells to tumors, and even had some therapeutic benefit.
All too often, however, the immune cells—called to the tumor by the vaccine in large numbers—did not fully attack the cancer. Vaccines can peak the immune response in days, calling immune cells to the tumor site. To reverse tolerance of the cancer—characterized by immune cells flooding to the tumor site but not taking action—can take time. It may also require additional kinds of immune therapies.