Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:O76050 (neu)
 3,969 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients with metastatic HER2 breast cancer (MBC) often become resistant to HER 2 targeted therapy and have recurrence of disease. The Panacea trial suggested that HER2 MBC patients were more likely to respond to checkpoint therapy if TIL were present or if tumor expressed PD-L1. We assessed whether type I polarized dendritic cells (DC1) could improve checkpoint therapy in a preclinical model of HER2+ breast cancer. TUBO bearing mice were vaccinated with either MHC class I or class II HER2 peptide pulsed DC1 (class I or class II HER2-DC1) concurrently or sequentially with administration of anti-PD-1 or anti-PDL1. Infiltration of tumors by immune cells, induction of anti-HER2 immunity and response to therapy was evaluated. Class I or class II HER2-DC1 vaccinated mice generated anti-HER2 CD8 or CD4+ T cell immune responses and demonstrated delayed tumor growth. Combining both MHC class I and II HER2-pulsed DC1 did not further result in inhibition of tumor growth or enhanced survival compared to individual administration. Interestingly class II HER2-DC1 led to both increased CD4 and CD8 T cells in the tumor microenvironment while class I peptides typically resulted in only increased CD8 T cells. Anti-PD-1 but not anti-PD-L1 administered sequentially with class I or class II HER2-DC1 vaccine could improve the efficacy of HER2-DC1 vaccine as measured by tumor growth, survival, infiltration of tumors by T cells and increase in systemic anti-HER2 immune responses. Depletion of CD4+ T cells abrogated the anti-tumor efficacy of combination therapy with class II HER2-DC1 and anti-PD-1, suggesting that tumor regression was CD4 dependent. Since class II HER2-DC1 was as effective as class I, we combined class II HER2-DC1 vaccine with anti-rat neu antibodies and anti-PD-1 therapy. Combination therapy demonstrated further delay in tumor growth, and enhanced survival compared to control mice. In summary, Class II HER2-DC1 drives both a CD4 and CD8 T cell tumor infiltration that leads to increased survival, and in combination with anti-HER2 therapy and checkpoint blockade can improve survival in preclinical models of HER2 positive breast cancer and warrants exploration in patients with HER2 MBC.
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PMID:Sequential Anti-PD1 Therapy Following Dendritic Cell Vaccination Improves Survival in a HER2 Mammary Carcinoma Model and Identifies a Critical Role for CD4 T Cells in Mediating the Response. 3147 2

Esophageal cancer (EC) is among the most frequent and deadly cancers around the world. While esophageal adenocarcinoma (EAC) has one of the fastest-growing incidences amongst cancers in the US, it also has one of the lowest survival rates due to the limited effective treatment options. Fortunately, in the past decade, two targeted therapies and an immunotherapy agent have been approved by the FDA for metastatic EAC and esophageal squamous cell carcinoma (ESCC), with several more currently being considered for approval. In terms of immunotherapies, in July 2019, the FDA approved the PD1 inhibitor pembrolizumab for second-line treatment of PDL1-positive, advanced or metastatic ESCC. Two years before, pembrolizumab had been approved for the third-line treatment of PDL1-positive EAC. The PD1 inhibitor nivolumab, which was found in one study to outperform chemotherapy irrespective of PDL1 status, has yet to secure FDA approval. In terms of targeted therapies, although as many as 90% of EC cases show upregulated EGFR, anti-EGFR therapy has not been shown to improve survival. Ramucirumab, an antibody targeting both VEGF and HER2/neu receptors, has been approved for the treatment of refractory EAC, while the anti-HER2 monoclonal antibody (mAb) trastuzumab has been approved as front-line treatment for HER2-positive cases which account for approximately 20% of ECs. Although these targeted therapies and immunotherapies have resulted in significant improvements in survival for specific patient populations that are positive for certain biomarkers, such as PDL1 and HER2/neu, the survival rates remain low for a large proportion of the metastatic EC patient population, necessitating the development of further targeted treatment options.
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PMID:Targeted Therapies and Immunotherapies in the Treatment of Esophageal Cancers. 3156 65