A preclinical study showing that a vaccination with a recombinant adenovirus expressing a truncated ErbB-2 antigen can cure advanced established murine breast cancer as well as extensive established metastatic lung cancer led to the launch of a small phase I study investigating a therapeutic cancer vaccine targeting HER2-expressing cancers. In this early clinical trial, the vaccine provided clinical benefit in several patients with metastatic HER2-positive cancers that had progressed on at least one line of standard therapy.
The study researchers now plan to test the vaccine in combination with a checkpoint inhibitor to try to induce T-cell responses that turn “cold” tumors into “hot” ones amenable to checkpoint blockade immunotherapy. The study by Berzofsky et al was presented at the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival (Abstract A004).
The researchers enrolled patients with various metastatic HER2-positive cancers, including breast, ovarian, lung, colorectal, gastroesophageal, prostate, and bladder, among others, who had disease progression on treatment with at least one line of standard therapy. Part 1 of the phase I study was carried out in patients naive to trastuzumab (Herceptin) or other HER2-directed therapies to demonstrate safety in the absence of complicating effects of prior HER2-targeted therapies.
In the dose-escalation portion of the clinical trial, patients were injected with the cancer vaccine at its lowest dose, 5 million dendritic cells per injection, on weeks 0, 4, 8, 16, and 24. Although no responses were seen in 6 patients, at the second and third dose escalations, 10 and 20 million dendritic cells, respectively, of 11 evaluable patients, 6 (54%) achieved clinical benefit.
One patient with ovarian cancer experienced a complete response that lasted 89 weeks; 1 patient with gastroesophageal cancer had a partial response that lasted 16 weeks; and 4 patients—2 with colon cancer, 1 with prostate cancer, and 1 with ovarian cancer—had stable disease. Adverse reactions were limited to the injection site and did not require treatment, and there was no evidence of cardiotoxicity.
Based on these results and safety data, the dose of the vaccine was increased to 40 million dendritic cells per injection and part II of the trial was opened to patients, including those with metastatic breast and gastric cancers, who had disease progression after prior HER2-directed therapies, such as trastuzumab. Early results from part 2 of the study showed 2 patients had achieved stable disease.
“Moving forward, we would like to investigate whether we can increase the proportion of people who benefit from treatment with the vaccine by combining it with checkpoint inhibitor therapy,” said Jay A. Berzofsky, MD, PhD, Chief of the Vaccine Branch at the Center for Cancer Research at the National Institutes of Health and senior author of the study.
The study was funded by the National Cancer Institute. Dr. Berzofsky declared no conflicts of interest.
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