Cancer patients and researchers alike have been dreaming of the day when treatments can be developed that are not only effective, but also are affordable with low toxicity- luxuries that haven’t typically accompanied effective cancer therapeutics in the past. Recent work from the University of Washington’s Cancer Vaccine Institute (CVI), part of the Cancer Consortium Breast & Ovary Cancers Program, shows that that day might not be as far off as it might seem. In their recently published JAMA Oncology study, the CVI team showed promising results from a phase I nonrandomized clinical trial for a breast cancer vaccine in advanced stage HER2-positive breast cancer patients. With a 10 year post-vaccine follow up period, this DNA vaccine proved both safe and effective with most participating women still cancer-free today. Although limited to a small number of patients, the results from this trial are very promising.
Breast cancer is just one of six solid tumor cancers that the UW Cancer Vaccine Institute is targeting for vaccine development, with additional efforts aimed at treating ovarian, colon, lung, bladder and prostate cancers. CVI Director Dr. Mary (Nora) Disis was one of the pioneering investigators to identify HER2 as a tumor antigen and developing a vaccine against breast cancer was an initial focus of the institute. In addition to her work at CVI, Disis is the UW School of Medicine Associate Dean for Translation Science and a jointly affiliated Professor at UW and Fred Hutch. The mission of the CVI “is to use cancer vaccines and other therapies that ignite the immune system to end cancer,” explained Executive Director of CVI, Dr. Kiran Dhillon. Dhillon went on to describe the unique streamlined structure of CVI, which consists of five principal investigators and core facilities where “everything we do is designed to go to clinic.” “We’ve disrupted the traditional lab model by connecting the early discovery, translational research, and clinical trial work under one roof,” she added.
Before they were able to develop the promising HER2 DNA vaccine highlighted in this study, figuring out how to make an effective vaccine against cancer took some trial and error. Dhillon explained that “the real breakthrough came about eight years ago when we developed an understanding of how the same protein, or antigen, could have different responses from the immune system.” For instance, one part of the protein may elicit a strong tissue destructive response that kills off cancer cells, while another part may promote disadvantageous immune suppression. Excitingly, Dhillon exclaimed “we’ve figured out this system and now we’ve got a hammer to combat cancer.” Knowing that each cancer comes with unique treatment challenges, the CVI researchers designed vaccines to work at three stages of cancer therapy: cancer prevention, treatment, and recurrence. While these vaccines aren’t designed to work quite like our yearly flu shot, they’re aimed to either help prevent cancer in high-risk patients (prevention or interception), work in conjunction with current chemotherapies to boost their effectiveness (treatment) or help keep cancers from coming back after they’re initially treated (recurrence). Cancer vaccines all generally work by “training the immune system to recognize cancer cells expressing specific proteins as dangerous, setting off alarms and signaling to attack those cells,” Dhillon explained. These trained T cells survey the body including the brain, which is a common site of breast cancer metastasis and difficult to target since many drugs cannot cross the blood-brain barrier. Thus, this approach can overcome one of the current challenges of drug-based therapeutic regimens.
To focus on treating this aggressive breast cancer, with hammer in hand, Disis and the CVI research team developed a DNA vaccine encoding the HER2 protein intracellular domain (thus training the immune system to attack HER2-expressing cancer cells) to treat 66 patients with stage III or IV HER2-positive breast cancer. Prior to vaccination, all patients had been effectively cured of cancer through treatment with chemotherapy drugs like Trastuzumab. Although patients were technically cancer-free at this pre-vaccine stage, HER2-positive breast cancers are aggressive with a high probability of recurrence and metastasis. But this is where the vaccine steps in! The patients were given one of three monthly doses of this DNA vaccine over a 3-month period. Vaccines were found to be very safe with extremely mild adverse effects, similar to the aches and chills one might experience from COVID-19 or flu vaccines- a walk in the park compared to current, more toxic, cancer treatments. Disis and colleagues then assessed the patients’ immune responses to the vaccines by analyzing blood samples taken at various post-vaccination timepoints. Teaming up with Dr. Katherine Guthrie, a Professor in the Cancer Prevention Program at Fred Hutch, to analyze the patient data, the researchers observed a strong immune response to all doses of vaccines administered. However, the middle dose seemed to be the most effective with a sustained immune response over time. This immune response was accompanied by an increase in central memory T cells, which are important for long-term immunity. Furthermore, at this dose, the mean survival after a 10-year period for these late stage breast cancer patients was ~85% among stage III and IV patients, remarkably with all of the stage III women still alive today. Comparatively, the survival rate for stage III/IV breast cancer patients receiving currently available chemotherapies is only 50% at just 4.5 years post-treatment. The remarkable increased survival rates for this phase I clinical trial emphasize the effectiveness of vaccines for this aggressive breast cancer and bring hope that effective, affordable and accessible vaccine-based cancer treatments might be a future reality for other cancers. Partnering with Aston Sci., the vaccine developed at CVI is headed into phase II randomized clinical trials which will be expanded to include patients with other types of difficult-to-treat breast cancers who might benefit from a HER2-targeted therapeutic approach. It is important to note that final approval by the FDA for use outside of clinical trials will require even larger phase III randomized trials that rigorously test efficacy.
As an off the shelf cancer therapy, vaccines are emerging as a promising new treatment that could be broadly available, affordable, safe, and effective, with adverse effects being no worse than a COVID-19 shot. In addition to the research teams at CVI, these exciting breakthroughs would not have been possible without the work of several key players, including the UW/Fred Hutch/Seattle Children’s Cancer Consortium Women’s Cancer Program, which helped recruit patients for clinical trials, and Fred Hutch’s GMP facility which manufactured the vaccines for this work. While Dhillon is excited about the scientific results of this study, she emphasized how integral the patients are in this. Dhillon stressed how grateful CVI is for the patients, “as nothing we do would be possible without them. We keep the patients at the center of everything we do.” Living this value, the CVI team gives back to patients through hosting patient reunion and educational events to teach people about cancer vaccines and clinical trials, with a focus on holding these events for diverse communities that are not well represented in clinical trials. Underscoring the strong relationship CVI builds with their patients, Dhillon shared that more than 10 years after the HER2 vaccine clinical trial, one patient recently called her to say: “I’m still here!” This simple phone call may not have been possible without this breast cancer vaccine.
For those interested in learning more clinical trials, please check out the resources below!
-To learn more about current UW CVI clinical trials and the contact information for these studies for those interested in enrolling, see here.
-To learn more about how to participate in clinical trials and the risks and benefits involved, see here.
This work was supported by the National Institutes of Health, the National Cancer Institute, the National Center for Advancing Translational Sciences, the Helen B. Slonaker Endowed Professorship for Cancer Research and the American Cancer Society.
UW/Fred Hutch/Seattle Children’s Cancer Consortium members Mary (Nora) Disis, Katherine Guthrie, Andrew Coveler contributed to this work.
Disis MLN, Guthrie KA, Liu Y, Coveler AL, Higgins DM, Childs JS, Dang Y, Salazar LG. Safety and Outcomes of a Plasmid DNA Vaccine Encoding the ERBB2 Intracellular Domain in Patients With Advanced-Stage ERBB2-Positive Breast Cancer: A Phase 1 Nonrandomized Clinical Trial. JAMA Oncol. 2023 Jan 1;9(1):71-78. doi: 10.1001/jamaoncol.2022.5143.