“In cancer vaccines people have been looking for targets – things that are different between the patient and the tumor. And there are a lot of targets. For a long time, these targets were sort of old timey things like PSMA and PSA, which are known to be overexpressed by a [prostate cancer] tumor, that we would try to target the immune system against. And the response has been okay, but not great.” – Lisa Butterfield
“Vaccines can do a lot. They can start a new immune response, they can boost an existing response, and they can make a broader immune response that recognizes lots of proteins.” – Lisa Butterfield
“Perhaps vaccines, even if they don’t fully work on their own, can initiate that response or boost it to then set the stage for a better response to something else.” – Lisa Butterfield
Advanced cancer patients see immunotherapies as offering one of the best paths to a durable response. Cancer vaccines have a lot of potential because they offer a possible treatment option to nearly every cancer patient. And immunotherapies offer the promise of durable responses — they are fighting a biological system (the cancer) with another system (the immune system), rather than the hit and miss, less durable paradigm of targeting a biomarker with a single drug.
Lisa Butterfield, PhD, Consultant in Immuno-Oncology, Adjunct Professor of Microbiology and Immunology, University of California San Francisco, is uniquely positioned to share the state of the art on cancer vaccines. Besides being a leading researcher, she brings the patient and caregiver perspective. Her husband had pancreatic cancer, and she was his patient advocate and caregiver. She experienced the extremely difficult challenges of trying to navigate this for him.
Her research is focused on cancer vaccines, immune profiling and cellular therapies for melanoma, hepatocellular cancer, and other tumor types. She was most recently Vice President, Research and Development at the Parker Institute for Cancer Immunotherapy, where she supported cell therapy initiatives and clinical trial biospecimen and biomarker projects.
Lisa was previously a tenured Professor of Medicine, Surgery, Immunology and Clinical and Translational Science at the University of Pittsburgh and Director of the Hillman Cancer Center Immunologic Monitoring and Cellular Products Laboratory; she earned a PhD in Biology from UCLA, followed by postdoctoral fellowships in Cellular Immunology and Cancer Gene Therapy also at UCLA.
She was the first female President of the Society of Immunotherapy of Cancer (SITC) and a member of the SITC Executive Committee. She also previously led the Immunology Reference Lab for the ECOG-ACRIN NCI cooperative group and collaborated on biomarker studies in many clinical trials.
She has published over 185 peer-reviewed manuscripts, reviews and book chapters, and mentored over 20 students and postdocs. She currently chairs the FDA Cell, Tissue and Gene Therapy Advisory Committee, co-leads the SITC Women’s Leadership Institute and is a co-Editor of the SITC textbook “Cancer Immunotherapy: Principles and Practice” 1st and 2nd editions.
How does your immune system fight cancer?
The immune system has evolved to protect us from pathogens such as bacteria, viruses, and fungus. When an infection arises, the immune response is triggered, all of the infection is eliminated, and then the immune response goes back down. But a memory of the infection persists, and you get a healthy memory cell, so that if you see that pathogen again, it can react quickly. But that doesn’t happen in cancer, because if the tumor doesn’t completely go away early in the process, the immune cells become exhausted, and are just not as functional. So they may need to be reactivated, or even worse, the immune system never saw the tumor in the first place, because tumors can be clever, perhaps able to block recognition by the immune system. So there are a lot of hurdles: tumor evolution, tumor heterogeneity, different cells expressing different things and then this exhaustion phenomenon from the cells seeing the antigen too much.
How do immunotherapies work in cancer?
The idea is to try to find what’s different about the tumor. Sometimes the tumor turns things back on that are generally turned off in people, sometimes it turns up the volume on things that are generally turned down. So if you can find these reactivated genes, you can perhaps get the immune system to recognize them and attack them. But the immune system doesn’t usually recognize them without a vaccine because a successful tumor shields itself from the immune system by being a terrible antigen-presenting cell.
All of the cancer vaccines are focused on T cells. Decades of studies have shown us that the T cell is the one that kills the tumor. If you can get CD8 killer T cells and CD4 helper T cells to work together, it’s even better. If you can add B cells and antibodies, that is a bonus. But all of these cancer vaccines are T-cell focused, which is why they’re hard, because they have to be matched to you. An antibody is matched to a pathogen. If it’s all the same pathogen, you get all the same antibodies.
What are the benefits of cancer vaccines?
Vaccines can start a new immune response, boost an existing response, and make a broader immune response that recognizes lots of proteins.
How do cancer vaccines work?
Cancer vaccines look for targets – things that are different between the patient and the tumor. There are a lot of targets. For a long time, these targets were sort of old timey things like PSMA and PSA, which are known to be overexpressed by a [prostate cancer] tumor, that we would try to target the immune system against.
How successful have cancer vaccines been to-date?
The response has been okay, but not great. There’s one cancer vaccine approved, and it is in prostate cancer. It’s not great for survival, but it is a shift away from chemotherapy, a little more time, and for the most part, non-toxic time. Once in a while cancer vaccines have had safe and immunogenic results. Some T cells were poked, but that doesn’t really mean much to the tumor, and therefore, to the patient.
Who’s going to benefit?
People who already have the specific T cells in their circulation maybe just need a checkpoint blockade. But if you don’t have those specific T cells, then a vaccine could reduce recurrence or mediate tumor progression. When you look at the side effects of cancer vaccines, they are minor compared to most other treatments.
When should a cancer vaccine be tried?
Cancer vaccines are still experimental. People want to get the standard of care first and something experimental later. The problem with that, for an immunotherapy vaccine, is you need your immune system to be able to respond. If you get chemotherapy, radiotherapy, steroids, or other standard treatments, your immune system is beat up. If you can, it would be better to get a cancer vaccine quickly (which can be done with RNA), and then wait a few weeks before getting the standard of care. If you’ve had standard treatments, try to reset your immune system as best as you can to be able to get the most from a cancer vaccine.
It looks like getting a cancer vaccine before a checkpoint blockade is better, but this needs to be tested.
How can you access a personalized cancer vaccine?
There’s a cancer vaccine trial at UC San Diego run by Ezra Cohen and his partner Steve Schoenberger, which has been treating a number of solid tumors with low tumor mutation burden. The other clinician involved at UC San Diego is Aaron Miller. Another resources is Nina Bhardwaj at Mount Sinai, who helped design a cancer vaccine trial in prostate cancer.
What’s new and exciting in research on cancer vaccines?
The exciting new cancer vaccine research is looking at combinations of cancer vaccines with other therapies. The hope is that cancer vaccines, even if they don’t fully work on their own, can initiate or boost a response to then set the stage for better response to something else. For example, a BioNTech mRNA vaccine study showed that a cancer vaccine plus checkpoint blockade is better. The study saw infiltration of the tumor with activated T cells. What’s great about RNA as a platform is that it’s fast. You sequence the tumor, tell the computer what sequences of RNA to make, and it does it, which is how we got a COVID vaccine so quickly.
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