Pepinemab/Trastuzumab With Dendritic Cell Vaccine and Adoptive T-Cell Therapy Under Evaluation in HER2+ Breast Cancer

A treatment regimen consisting of pepinemab plus trastuzumab (Herceptin) and a dendritic cell (DC) vaccine, followed by autologous CD4-positive T cells, is under investigation in a phase 1 trial (NCT05378464 ) in patients with metastatic HER2-positive breast cancer, according to a poster presentation given at the 2023 ASCO Annual Meeting.¹

Previous data have demonstrated that HER2 peptide–pulsed type I DCs (HER2-DC1) restored anti-HER2 CD4-positive Th1 immune responses and improved pathologic complete responses in patients with HER2-positive breast cancer.² Additionally, the tumor microenvironment has been shown to be modulated by SEMA4D antibodies through an increase in effector cell infiltration and a reduction in immunosuppression.³

Preclinical mouse models have also demonstrated that the combination of anti-SEMA4D and HER2-DC1 led to an improvement in DC homing, expansion of CD4-positive T cells, and complete tumor regression in HER2-positive tumors compared with either treatment alone.¹

“In preclinical studies, we have seen great tumor regression with treatment of pepinemab in combination with trastuzumab and DC vaccines in patients with HER2-positive breast cancer,” lead author Heather Han, MD, said in an interview with OncLive^®. “With [this rationale in mind], we designed this clinical trial using immunotherapy with DC vaccines, pepinemab, and trastuzumab to help patients with metastatic HER2-positive breast cancer.”

Han is a research director and a medical oncologist in the Department of Breast Oncology at Moffitt Cancer Center, in Tampa, Florida.

The open-label study is enrolling patients with histologically confirmed HER2-positive breast cancer who experienced disease progression while receiving trastuzumab for HER2-positive metastatic disease. Moreover, a maximum of 3 prior lines of cytotoxic chemotherapy in the metastatic setting is allowed, and patients are required to have an ECOG performance status of 0 or 1.

Patients are not eligible for the study if they present with uncontrolled brain metastases or leptomeningeal disease, or if they have a second invasive malignancy requiring active treatment.

The treatment regimen begins with 20 mg/kg of intravenous (IV) pepinemab once every 3 weeks for 2 cycles, IV trastuzumab once every 3 weeks for 2 cycles, and a DC vaccine at 1 to 2 x 10⁷ cells as an intranodal or intratumoral administration once weekly for 6 weeks. Notably, trastuzumab is being given at 8 mg/kg in cycle 1 and 6 mg/kg in cycle 2.

Between the 2 cycles of immunotherapy, T cells will be collected from patients and expanded. After the second cycle of immunotherapy, patients will receive 300 mg/m2 of cyclophosphamide 1 day before being infused with CD4-positive T cells at 1 of 3 dose levels: 0.05 to 0.25 x 10⁹ cells, 0.25 to 1.20 x 10⁹ cells, or 0.50 to 2.50 x 10⁹ cells.

Patients will then continue on treatment with 20 mg/kg of IV pepinemab and 6 mg/kg of IV trastuzumab every 3 weeks, plus a DC vaccine booster every 3 weeks for 3 total doses.

The primary end points of the study are safety and tolerability, and to establish the maximum tolerated dose (MTD) of expanded CD4-positive T cells. Secondary end points include clinical benefit rate at 6 months and progression-free survival per RECIST v1.1 criteria, as well as HER2-specific T-cell immune responses and a biomarker analysis.

The 3 dose-escalation cohorts will include 3 to 6 patients. The study will then proceed to dose expansion, where 10 additional patients will receive CD4-positive T cells at the MTD, which will be defined as the highest dose that leads to dose-limiting toxicities in less than 2 of 6 patients in a given cohort.

“This clinical trial is ongoing. Thus far, we have evaluated first cell levels and are planning to expand with escalated the T-cell dose until determination of optimal dose to expand further treatment for this patient population,” Han concluded.

References

1. Han HS, Costa RL, Soliman HH, et al. Phase I study of adoptive T cell therapy following HER2-pulsed dendritic cell vaccine and pepinemab/trastuzumab in patients with metastatic HER2-positive breast cancer (MBC). J Clin Oncol. 2023;41(suppl 16):TPS1113. doi:10.1200/JCO.2023.41.16_suppl.TPS1113.
2. Lowenfeld L, Mick R, Datta J, et al. Dendritic cell vaccination enhances immune responses and induces regression of HER2^pos DCIS independent of route: results of randomized selection design trial. Clin Cancer Res. 2017;23(12):2961–2971. doi:10.1158/1078-0432.CCR-16-1924.
3. Patnaik A, Weiss, GJ, Leonard JE, et al. Safety, pharmacokinetics, and pharmacodynamics of a humanized anti-semaphorin 4D antibody, in a first-in-human study of patients with advanced solid tumors. Clin Cancer Res. 2016;22(4):827–836. doi:10.1158/1078-0432.CCR-15-0431.