A treatment regimen consisting of pepinemab plus trastuzumab and a dendritic cell vaccine, followed by autologous CD4-positive T cells, is under investigation in a phase 1 trial in patients with metastatic HER2-positive 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.