Source: The Inquire, philly.com
Author: Marie McCullough
The patient’s head and neck cancer came roaring back, spreading to his lymph nodes and skin, which developed bleeding tumors. Yet despite a grim prognosis, that man is alive and cancer-free more than two years later.
In a study led by the University of Pennsylvania and published Friday, researchers hypothesize that his remarkable remission is due to a promising combination: an experimental cancer vaccine that activated his disease-fighting T cells, plus Opdivo, one of the revolutionary “checkpoint inhibitor” drugs that cut a brake on the immune system.
“Of course, I’m biased,” said Charu Aggarwal, the Penn oncologist who led the study. “In my career, I haven’t seen a vaccine as impactful as this.”
However, the remission may have been due to Opdivo alone; the study lacks data to rule out that possibility.
Robert Ferris, director of the University of Pittsburgh Medical Center’s Hillman Cancer Center and head of the pivotal study leading to approval of Opdivo, called the Penn-led study “an important intermediate step exploring a strategy that we hope will work.”
Conventional vaccines prevent diseases by priming the immune system to recognize the distinctive “antigens” on invading microbes. Therapeutic cancer vaccines, like the one in this study, are intended to work after cancer develops by provoking a heightened immune response.
Despite decades of research, this approach remains experimental. The only approved product, the prostate cancer vaccine Provenge, was barely effective; the maker filed for bankruptcy in 2015.
A major obstacle to treatment vaccines is the fact that cancer arises from the body’s own cells. Although cancer cells produce antigens as they mutate, using these telltale proteins as targets for the immune system has proved to be very difficult.
Even so, at least four pharmaceutical groups are developing therapeutic vaccines that target human papillomavirus, HPV, the sexually transmitted virus that causes cervical cancer, head and neck cancer, and some rare genital cancers.
These diseases can be warded off with the preventive HPV vaccine that is recommended for all adolescents, but it didn’t exist until 12 years ago. Much to the dismay of public health authorities, vaccination rates remain low. And while screening can detect and treat cervical precancers, there are no early detection methods for head and neck cancers; experts call the surging incidence of these malignancies an “epidemic.”
The vaccine in the new study, called MEDI0457, was originally developed by Inovio with technology pioneered at Penn. In 2015, MedImmune, which is part of AstraZeneca, acquired exclusive rights to the drug.
MEDI0457 contains a DNA ring called a plasmid that programs the patient’s cells to produce two HPV antigens. The vaccine is injected into the patient’s muscle and enters cells with the help of a small electrical pulse applied to the skin. When the cells make the antigens, this triggers the immune system to activate disease-fighting white blood cells, so-called “killer” T cells.
For the study, published Friday in Clinical Cancer Research, 22 patients with head and neck cancer received conventional treatment — either surgery or chemotherapy and radiation — that eliminated all signs of cancer. This was supplemented by four doses of the experimental vaccine, which caused no serious side effects.
Eighteen patients, or 80 percent, showed elevated T cell activity that lasted at least three months after the final vaccine dose. While that is an encouraging sign, the study was too preliminary to detect clinical effectiveness such as tumor shrinkage or improved survival.
In the one patient who relapsed, cancer recurred seven months after vaccine treatment and spread to his lymph nodes and skin. He was given Opdivo and, eight weeks later, the cancer was gone.
Aggarwal and her co-authors note that such remarkable remissions do occasionally occur with checkpoint inhibitors. But they speculate that the vaccine revved up the patient’s T cells, then Opdivo removed the immune brake, enabling the T cells to attack the cancer.
“The response suggests the vaccine may in some manner prime the immune system, potentially boosting the effects of subsequent [checkpoint inhibitor] therapy,” Aggarwal said.
Rajarsi Mandal, director of the head and neck cancer immunotherapy research program at Johns Hopkins University, took a more conservative view: “They demonstrated vaccine specific T cell proliferation very nicely. But there is not a lot of data to suggest the vaccine is inducing any clinical response in these patients. Overall, it’s very interesting, but future studies are needed to demonstrate definitive clinical responses to the vaccine.”
Still, the combination approach is sufficiently promising that MedImmune is now funding a Penn-led clinical trial of MEDI0457 and MedImmune’s own experimental checkpoint inhibitor.
Ferris, meanwhile, said he is part of a trial of a competing experimental vaccine for HPV-related cancers, plus the approved checkpoint inhibitor Keytruda.