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Although overall survival outcomes of HER2+ MBC have improved in HER2 targeted therapies, results have also shown significant toxicities and the development of progressive disease during treatment in many patients. Due to these outcomes, new and more effective therapeutic options are essential.

Moffitt’s Breast Oncology Department specialists conducted research on a novel approach evaluating whether the combination of three immunotherapies in addition to trastuzumab: dendritic cell (DC) vaccination, anti-SEMA4D blocking antibody (pepinemab) and CD4+ T cell adoptive transfer can lead to improved outcomes for patients with MBC refractory to HER2-targeted agents.

Breast cancer has been considered immunologically cold, attributing to immune evasion and suppression of host effector immune cells homing into tumor beds. Progressive loss of Th1 immunity against HER2 oncodriver correlates with poor prognosis. HER2 peptide-pulsed type I dendritic cells (HER2-DC1) restored anti-HER2 CD4+ Th1 immune response and improved pathologic complete response (pCR) in HER2+ BC.

Moreover, antibodies to SEMA4D have been shown to modulate the TME by increasing effector cell infiltration and reducing immunosuppression. In preclinical studies, treatment with anti-SEMA4D and HER2-DC1 in mice bearing established HER2+ tumors improved DC homing, expansion of CD4+ T cells, and complete tumor regression, compared to treatment with anti-SEMA4D or HER2-DC1 alone. Further, subsequent expansion and adoptive transfer of CD4+ T cells induced synergistic anti-tumor activity by activating CD8+ T mediated cytotoxicity. Pepinemab was well-tolerated and showed signs of anti-tumor activity in immunotherapy-resistant, PD-L1 negative/low non-small cell lung cancer patients when combined with checkpoint inhibitor (avelumab).

This innovative Phase 1 study enrolled 28 cohorts with HER2+ MBC. Patients are treated with six weekly injections of dendritic cell (DC1) vaccines in combination with trastuzumab and pepinemab. The researchers theorize these therapists may elicit CD4+ HER2-specific T-cell responses. HER2-specific T cells will be expanded ex vivo and subsequently infused to patients following lymphodepletion with cyclophosphamide. Trastuzumab and pepinemab will be given as maintenance in addition to booster DC1 vaccines.

Eligible patients must have had the disease progression while on trastuzumab for the treatment of HER2+ MBC and received no more than 3 lines of therapy in the setting of metastatic disease. Dose escalation will consist of 3-6 patients each with increasing amounts of transferred CD4+ T cells, followed by dose expansion of 10 patients at the MTD. The primary objective is safety and tolerability; secondary objectives will include evaluation of T cell immunity and immune subsets, efficacy, PK/PD/ADA of pepinemab, and biomarker assessments.

View the full abstract.

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