Has the Era of Dendritic Cell Vaccines Arrived for HER2-Positive Breast Cancer?

According to a study published on 5 December 2024 in JAMA Oncology , intratumoral administration of dendritic cells (cDC1) in early-stage ERBB2 (formerly HER2)-positive breast cancer stands out as a safe and effective approach that strengthens the immune response and promotes tumor shrinkage before chemotherapy.

ERBB2-positive breast cancer remains an important research area despite major advances in treatment outcomes. Although anti-ERBB2 antibodies such as trastuzumab and pertuzumab improve survival, the need for chemotherapy to achieve a pathological complete response carries substantial risks of adverse effects. New-generation immunotherapies are being investigated to improve efficacy and reduce adverse effects. This phase 1 clinical study at Moffitt Cancer Center in Tampa, Florida, evaluated the safety, immunogenicity, and antitumor activity of intratumoral (IT) cDC1 injections.

Study Design

This was a nonrandomized phase 1 clinical study involving 12 patients in 2021-2022. Participants had early-stage ERBB2-positive breast cancer with tumors measuring 1 cm or larger.

A dendritic cell vaccine boosts the immune system's ability to fight diseases such as cancer by using dendritic cells loaded with tumor antigens obtained from the patient and then returned to the body. This type of immunotherapy is prepared by collecting dendritic cell precursors from the patient's blood, combining them with suitable antigens in the laboratory, and activating them.

Treatment Protocol:

• Dendritic Cell Administration: Weekly intratumoral cDC1 injections for 6 weeks. Two dose levels were tested: 50 million cells - Dose Level 1, and 100 million cells - Dose Level 2.
• Antibody Treatment: Trastuzumab and pertuzumab were given intravenously every 3 weeks starting on the first day.
• Chemotherapy and Surgery: All patients underwent lumpectomy or mastectomy after 12 weeks of paclitaxel.

Main Outcomes:

• Primary Objectives: Safety and immune response.
• Secondary Objectives: Tumor response (breast MRI) and residual cancer burden after surgery.

Findings

Safety and Adverse Effects:

• Intratumoral dendritic cell vaccine administrations were generally well tolerated. No dose-related adverse effects were observed.
• The most commonly reported adverse effects were:
• Grade 1-2 chills (50 percent)
• Fatigue (41.7 percent)
• Headache (33 percent)
• Injection site reactions (33 percent)

Immunological Effect:

• Dose Level 2:
• Increased accumulation of adaptive immune cells (CD3, CD4, CD8 T cells, and B cells), as well as gamma delta T cells and natural killer (NK) T cells, was observed in the tumor microenvironment (TME).

Tumor Response:

• According to breast MRI:
• 9 objective responses (6 partial, 3 complete responses)
• 3 cases of stable disease
• After surgery, 7 of the 12 patients (58 percent) achieved a pathological complete response .
• All hormone receptor-negative patients (3 patients) achieved a complete response.
• A complete response was achieved in 4 hormone receptor-positive patients.

What Does a 58% Pathological Complete Response Rate Mean?

In patients with HER2-positive breast cancer, neoadjuvant treatment achieved a 58% pathological complete response (pCR) rate, a notable success in light of both historical data and current treatment approaches. The literature reports pCR rates generally ranging from 30% to 50% with neoadjuvant trastuzumab and chemotherapy combinations. For example, adding trastuzumab to taxane- and anthracycline-based chemotherapy regimens produced rates of 40-50%. However, advances in treatment, including dual-targeted HER2 therapies such as trastuzumab plus pertuzumab, have raised pCR rates above 50%.

Results and Clinical Significance

The study results show that intratumoral cDC1 injections combined with anti-ERBB2 antibodies offer a safe and effective treatment option. In particular, high-dose administration (100 million cells) produced strong immune cell infiltration in the tumor microenvironment and significant tumor regression before chemotherapy.

Overall, this approach holds promise as an immunotherapy that could reduce the need for chemotherapy and limit adverse effects. Efficacy and safety assessments will continue in the study's phase 2 stage with a larger group of patients (41 patients).