A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer

Abstract

A phase 1 clinical trial was conducted to assess the safety, tolerability, and preliminary efficacy of a heterologous prime-boost strategy involving plasmid DNA (pHM-GM-CSF, expressing truncated human epidermal growth factor receptor 2 (HER2) and granulocyte macrophage colony-stimulation factor (GM-CSF) as a bicistronic message) and an adenoviral vector (Ad-HM, containing the same modified HER2 sequence only), in patients with stage III–IV metastatic breast cancer expressing HER2. Nine eligible subjects were divided into three cohorts based on the dosages (2, 4, and 8 mg/patient/visit) of pHM-GM-CSF used as the primer, which was intramuscularly injected three times at weeks 0, 2, and 4. It was followed by a single injection of Ad-HM (3 × 109 virus particles), used as a booster, at week 6. During the 6-month follow-up period, adverse events (AEs), pharmacokinetics and pharmacodynamics, and HER2-specific cellular and humoral immune responses were evaluated. Seven cases of minor grade 1 toxicities in four of nine subjects and no serious drug-related AEs were reported. HER2-specific cell-mediated or humoral immunity was produced in all (100%) or three subjects (33%), respectively. One subject showed a partial response, and seven subjects had stable diseases. However, there were no differences in clinical tumor response and HER2-specific immune responses among the cohorts. These results showed that intramuscular injections of pHM-GM-CSF and Ad-HM were well tolerated and safe.

Combination of vasculature targeting, hypofractionated radiotherapy, and immune checkpoint inhibitor elicits potent antitumor immune response and blocks tumor progression

“…11 17 18 DNA prime followed by boosting with viral vectors has been used to enhance immune responses against malaria, 23 viruses, 24 25 and cancers. [26][27][28][29] Heterologous injections with plasmid-DNA vaccine followed by adenoviral (Ad5) vaccine, both encoding guanylyl cyclase C (GUCY2C), have been shown to effectively control CT26 tumor progression. 44 Similarly, a protocol consisting of priming with plasmid-DNA vaccine followed by boost injections with an adenoviral vaccine, both expressing a truncated human epidermal growth factor receptor 2 (HER2), has been shown to elicit Her-2/neu-specific humoral and cellular immune responses without causing severe adverse effects in monkeys.…”

“…In line with the preclinical data, HER2-specific cell-mediated and humoral responses was reported in some patients leading to objective responses without serious adverse events. 26 Based on our previous findings that heterologous prime/boost vaccination can enhance vaccine efficacy, 20 22 we cloned the TEM1 insert into a replication-deficient Ad5 adenoviral vector and then tested the novel vaccination protocol. We found that priming with the TEM1 plasmid-DNA followed by two boosts with TEM1 Ad5 bolstered the immune response against TEM1-specific peptides and improved DNA vaccine antitumor effects.…”

“…DNA prime followed by boosting with viral vectors has been used to enhance immune responses against malaria, 23 viruses, 24 25 and cancers. [26][27][28][29] We and other have previously demonstrated that heterologous vaccination with plasmid-DNA followed by adenoviral vectors increase the magnitude of the immune response against the target antigen. 19 20 22 Therefore, we cloned the expression cassette of TEM1 (tem1 cDNA fused to TT) into a replication-deficient, human type 5 recombinant adenovirus (TEM1 Ad5) and tested the impact of vaccination using regimens consisting of: (1) three prime-boost injections with the TEM1 plasmid-DNA alone; or (2) three prime-boost injections with TEM1 Ad5 alone; (3) priming with the TEM1 plasmid-DNA followed by two boosts with TEM1 Ad5.…”

Heterologous prime-boost immunization co-targeting dual antigens inhibit tumor growth and relapse

“…35 In many cases, a heterologous prime-boost administered with different types of vaccines containing the same antigens was more immunogenic than a homologous prime-boost that was repeatedly administered with the same type of vaccine. In combinations of heterologous prime-boost strategies, a DNA prime followed by boosting with viral vectors have enhanced immune responses to malaria, 36 viruses, 37,38 and cancers 25,26,39,40 .…”

Strong antigen-specific T-cell immunity induced by a recombinant human TERT measles virus vaccine and amplified by a DNA/viral vector prime boost in IFNAR/CD46 mice

“…DNA vaccines offer numerous advantages such as their capacity to readily incorporate multiple genes, their easy engineering and their stability [24]. Heterologous prime-boost strategies using a DNA prime followed by boosting with viral vectors have been shown to increase the magnitude of immune responses to HIV [25], Chikungunya virus [26], melanoma [27] or breast cancer [28]. Here, we have developed a recombinant MV vector expressing the insert of INVAC-1, which is a modified ubiquitin-hTERT fusion protein, as immunotherapeutic agent.…”