Phase I Clinical Trial of an Autologous Dendritic Cell Vaccine Against HER2 Shows Safety and Preliminary Clinical Efficacy

Abstract

BackgroundDespite recent advances, there is an urgent need for agents targeting HER2-expressing cancers other than breast cancer. We report a phase I study (NCT01730118) of a dendritic cell (DC) vaccine targeting HER2 in patients with metastatic cancer or bladder cancer at high risk of relapse.Patients and MethodsPart 1 of the study enrolled patients with HER2-expressing metastatic cancer that had progressed after at least standard treatment and patients who underwent definitive treatment for invasive bladder cancer with no evidence of disease at the time of enrollment. Part 2 enrolled patients with HER2-expressing metastatic cancer who had progressed after anti-HER2 therapy. The DC vaccines were prepared from autologous monocytes and transduced with an adenoviral vector expressing the extracellular and transmembrane domains of HER2 (AdHER2). A total of five doses were planned, and adverse events were recorded in patients who received at least one dose. Objective response was evaluated by unidimensional immune-related response criteria every 8 weeks in patients who received at least two doses. Humoral and cellular immunogenicity were assessed in patients who received more than three doses.ResultsA total of 33 patients were enrolled at four dose levels (5 × 106, 10 × 106, 20 × 106, and 40 × 106 DCs). Median follow-up duration was 36 weeks (4–124); 10 patients completed five doses. The main reason for going off-study was disease progression. The main adverse events attributable to the vaccine were injection-site reactions. No cardiac toxicity was noted. Seven of 21 evaluable patients (33.3%) demonstrated clinical benefit (1 complete response, 1 partial response, and 5 stable disease). After ≥3 doses, an antibody response was detected in 3 of 13 patients (23.1%), including patients with complete and partial responses. Lymphocytes from 10 of 11 patients (90.9%) showed induction of anti-HER2 responses measured by the production of at least one of interferon-gamma, granzyme B, or tumor necrosis factor-alpha, and there were multifunctional responses in 8 of 11 patients (72.7%).ConclusionsThe AdHER2 DC vaccine showed evidence of immunogenicity and preliminary clinical benefit in patients with HER2-expressing cancers, along with an excellent safety profile. It shows promise for further clinical applications, especially in combination regimens.

The Potential of Dendritic Cell Subsets in the Development of Personalized Immunotherapy for Cancer Treatment

“…One patient achieved a complete response (CR), one achieved a partial response (PR), and five patients achieved disease stabilization (DS). Significantly, the study showed no AE with transduced DC therapy [109]. In the study NCT01826877, DCs delivering antigens via an adenoviral vector were also tested.…”

“…To date, a multitude of clinical trials have used different DC vaccines, with the majority of them utilizing monocyte-derived DCs for loading with antigens [60,62,108,109], while only a few highlight the use of neoantigens [61]. Some studies employ DCs of natural myeloid origin [110]; however, the method of generating DCs from monocytes is considered the most commonly encountered.…”

Targeting HER2-positive breast cancer: advances and future directions

“…The DC vaccine platform allows for antigen processing by the patient's own immune system, eliciting immunological responses against multiple epitopes on the target, versus a single epitope approach with an antibody or a small-molecule inhibitor. Preliminary studies using DC vaccines have been conducted in patients with invasive BC and even DCIS; the latter hinting at the potential for possible development of a vaccine for prevention of BC [196][197][198][199] . Although DC vaccines are a promising individualized strategy, the vaccine manufacturing process is complex and will need to be streamlined to make it more accessible.…”

Dendritic Cells in Cancer Immunology and Immunotherapy

“…To improve the DCV procedure, an antiFoxP3+ Treg depletion immunotoxin was administered before giving viral modified DCV, improving immunogenicity in advanced BC patients [ 54 ]. Another group treated metastatic HER2-positive bladder and BC patients with DCs transduced with an adenoviral vector expressing different HER2 domains, demonstrating clinical benefits in up to one third of the patients, together with immune responses [ 55 ].…”

“…In a non-randomized clinical trial for early disease, Qi et al treated non-luminal BC patients with tumor lysate-pulsed DCV, showing benefits in 3-year PFS, although they found no impact on OS, with almost 60% of the patients showing immune delayed hypersensitivity responses [ 55 ]. Lowenfeld et al vaccinated ductal carcinoma in situ (DCIS) and early HER2-positive BC patients before breast surgery with HER2 peptide-pulsed DCV and showed 28% of pathological complete response (pCR) in DCIS (only 8.5% in BC), with immunogenic activity in the sentinel lymph nodes as well as in the systemic blood, with no adverse effects [ 56 ].…”