Targeting the immune system to fight cancer is not new: in 1891, New York bone sarcoma surgeon William B. Coley injected a patient with an inoperable malignant tumor with streptococcal organisms. His theory was that the resulting severe bacterial infection, erysipelas, would stimulate the immune system, shrinking the tumor.
His hunch was right, and over the next 40 years he treated nearly 1000 patients with bone and soft tissue sarcoma with what became known as “Coley’s Toxins.”
Dr Coley’s work has now earned him the title of “Father of Immunotherapy,” foreshadowing today’s research in several immunotherapeutic approaches, including vaccines.1
“Vaccines have great potential in this modern era of cancer prevention and therapy, both used alone and in combination with other types of therapeutics,” Keith Knutson, PhD, professor of immunology and director of the discovery and translational laboratories cancer research program at the Mayo Clinic in Jacksonville, Florida, told Cancer Therapy Advisor.
“We have only begun to understand how to make them and how to test in the clinic. Most prior vaccines were tested in advanced, bulky, heavily pretreated cancer, which we know now is not the appropriate setting for any type of vaccine, including those that target infectious disease.”
Several phase 1 and 2 clinical trials are evaluating 2 approaches for developing vaccines to treat and prevent breast and ovarian cancer. Both stimulate the immune system, 1 by reintroducing cells derived from a patient’s tumor along with a tumor-specific antigen, and the other by boosting T cell activity to recognize and attack tumors as well as residual cells.
Brian Czerniecki, MD, PhD, chair and senior member in the Moffitt Cancer Center department of breast oncology in Tampa, Florida, maintains that “vaccines would work best as adjuvants or in very early disease.” In fact, “vaccines have [a] very limited role in cancer immunotherapy. It is not simply ‘create a vaccine and it will automatically improve outcomes,’” he said in an interview with Cancer Therapy Advisor. “The type and stage of disease, the type of vaccine, antigens targeted, and staging can all affect outcomes of vaccines.”
In addition to having developed a dendritic cell (DC) vaccine targeting HER2/neu that regresses ductal carcinoma in situ (DCIS), Dr Czerniecki is pursuing the role of a HER2 pulsed DC vaccine in 2 trials to prevent invasive breast cancer recurrence, the first as an adjuvant (ClinicalTrials.gov Identifier: NCT02063724) and the second as a neoadjuvant treatment after chemotherapy (ClinicalTrials.gov Identifier: NCT02061423).
“We use the oncodriver HER2 because it is the main driver of the disease and eliminating it cripples cells,” he said. In DCIS, “our vaccine particularly targeted CD4 Th1 cells, which appear to be lost in HER2-expressing breast cancer.
“It appears these vaccines work best in early DCIS and may have an impact in preventing recurrence in patients with residual disease following neoadjuvant therapy. They will not work alone in active invasive breast cancer but may be critical to make other therapies like chemotherapy and HER2 targeted therapies more effective.”
Dr Czerniecki said he believes many vaccine trials have failed to date specifically because they lacked a critical target. “If you take it in the connotation of ‘just target anything, just because it’s on the cell,’ if it’s not important to the tumor, it doesn’t care about it. If you have an immune response against the tumor, it will just downregulate that protein if it doesn’t need it.
“What we haven’t paid so much attention to in the vaccine world is really going after drivers that the tumor needs to go,” he said.
Dr Knutson is conducting 2 phase 2 clinical trials using vaccines from TapImmune Inc., an immuno-oncology company based in Jacksonville, Florida, which licensed the technology from the Mayo Clinic in 2012. The vaccines — TPIV 110 and TPIV 200 — comprise proprietary peptide antigens that elicit both CD8+ and CD4+ immune responses.
In March, TapImmune received a $3.7 million grant from the US Department of Defense (DOD) for a phase 2 clinical study of women with DCIS using the company’s peptide HER2/neu-targeted T cell vaccine, TPIV 110. The trial, set to begin in the fall, will enroll 40 to 50 women with DCIS, which accounts for approximately 20% of US breast cancer cases. The vaccine will be administered 6 weeks prior to standard surgical resection.
“There are several vaccine approaches that are being tested in companies and academia that may be competitive for DCIS,” Dr Knutson said. “This, however, is a new indication for which there are few candidates.”
Glynn Wilson, PhD, chairman, president, and CEO of TapImmune, said in an interview with Cancer Therapy Advisor that results of a phase 1 study were presented at the 2015 San Antonio Breast Cancer Symposium and are expected to be published by the end of the year.2
The second phase 2 study, of which Dr Knutson is principal investigator, will use TapImmune’s TPIV 200 vaccine targeting folate receptor alpha to determine whether triple-negative breast cancer recurrence can be prevented.
The trial is expected to enroll 280 women and begin later this year. The study is fully funded by a $13.3 million, 5-year DOD Breakthrough Award grant. TapImmune is also conducting a phase 2 study of TPIV 200 as a standalone therapy in triple-negative breast cancer.
Dr Wilson said phase 1 results for the TPIV 200 vaccine, to be reported shortly, will show that some patients have immune responses going out to a year. “That’s a very long time in the vaccine field and we think that’s because broad stimulation of T cells that we’re seeing involves T memory cells.”
TapImmunue is also conducting 2 clinical trials of its TPIV 200 vaccine in ovarian cancer. The first, in collaboration with Memorial Sloan Kettering Cancer Center, is a phase 2 trial (ClinicalTrials.gov Identifier: NCT02764333) in combination with the PD-L1 checkpoint inhibitor, durvalumab, in women with platinum-resistant ovarian cancer.
The US Food and Drug Administration (FDA) granted Orphan Drug and Fast Track Designation for TPIV 200 in ovarian cancer. To date, the trial has more than 50% recruited, Dr Wilson said.
The company is also recruiting women with platinum-sensitive ovarian cancer for a phase 2 study (ClinicalTrials.gov Identifier: NCT02978222) of the TPIV 200 vaccine plus adjuvant GM-CSF vs GM-CSF alone.
“There is an added feature here which is very important,” Dr Wilson said. “If you look at the cancers we’re trying to treat — ovarian and breast cancer, whether it’s triple-negative or HER2 breast cancers…patients, after they have been treated, are at high risk of recurrence. So, one of the things we can do with a vaccine — it’s almost a perfect point to come in with a vaccine — is to stimulate the immune system to prevent recurrence. And, of course, that includes metastatic disease, too.”
To date, sipuleucel-T remains the first and only FDA-approved cancer treatment vaccine on the market and is used for some men with metastatic prostate cancer.3 Best estimates of clinical availability of a vaccine to treat breast and ovarian cancer range from 5 to 10 years.
Genentech, Inc., and Galena Biopharma are enrolling patients with HER2-positive breast cancer for 2 phase 2 trials (ClinicalTrials.gov Identifiers: NCT02297698 and NCT01570036) of the nelipepimut-S vaccine with trastuzumab vs trastuzumab plus GM-CSF alone in to prevent recurrence in the adjuvant setting.4
The National Cancer Institute is conducting a phase 2 study (ClinicalTrials.gov Identifier: NCT02636582) of nelipepimut-S plus GM-CSF in women with DCIS.
The National Cancer Institute is recruiting for a phase 1 trial (ClinicalTrials.gov Identifier: NCT01730118) of an adenoviral transduced autologous DC vaccine expressing human HER2/neu (AdHER2/neu) in adults with tumors — including breast, adenocarcinomas, and metastatic solid tumors characterized by HER2/neu expression — with 1 to 3-positive HER2/neu expression.
The University of Connecticut also recently announced open accrual of patients for “the world’s first personalized genomics-driven ovarian cancer vaccine clinical trial” using OncoImmune, which will be individualized for each patient.5
The phase 1 study (ClinicalTrials.gov Identifier: NCT02933073) will enroll up to 15 women with stage III/IV ovarian cancer in clinical remission after standard of care, with monitoring up to 5 years post-vaccination.
- McCarthy EF. The toxins of William B. Coley and the treatment of bone and soft-tissue sarcomas. Iowa Orthop J. 2006;26:154-8.
- Knutson KL, Kalli KR, Block MS, et al. Robust generation of T cell immunity to HER2 in HER2+ breast cancer patients with a degenerate subdominant HLA-DR epitope vaccine. Poster presented at: San Antonio Breast Cancer Symposium; December 10, 2015; San Antonio, Texas.
- PROVENGE (sipuleucel-T). Prescribing information. https://www.fda.gov/downloads/BiologicsBloodVaccines/ CellularGeneTherapyProducts/ApprovedProducts/UCM210031.pdf. US Food and Drug Administration website. Accessed May 2017.
- Galena Biopharma reports positive outcome from the data safety monitoring board on the two NeuVax (nelipepimut-S) clinical trials in combination with trastuzumab [news release]. San Ramon, CA: Galena Biopharma; February 6, 2016. https://globenewswire.com/news-release/2017/02/06/914171/0/en/Galena-Biopharma-Reports-Positive-Outcome-from-the-Data-Safety-Monitoring-Board-on-the-Two-NeuVax-nelipepimut-S-Clinical-Trials-in-Combination-with-Trastuzumab.html. Accessed May 2017.
- Woods L. Recruitment begins for world’s first ovarian cancer vaccine trial [news release]. Storrs, CT: University of Connecticut; April 20, 2017. http://today.uconn.edu/school-stories/recruitment-begins-worlds-first-ovarian-cancer-vaccine-trial/. Accessed May 2017.
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