a-murine-ommaya-xenograft-model-to-study-direct-targeted-therapy

A Murine Ommaya Xenograft Model to Study Direct-Targeted Therapy of Leptomeningeal Disease

Leptomeningeal disease (LMD) is an uncommon type of central nervous system (CNS) metastasis to the cerebral spinal fluid (CSF). The most common cancers ...

H. Lee Moffitt Cancer Center & Research Institute

We previously demonstrated a progressive loss of the anti-human epidermal growth factor receptor 2 (HER2) CD4+ T-helper type 1 (Th1) response during HER2 breast tumorigenesis. This loss is associated with residual disease following neoadjuvant therapy and increased risk of recurrence. In this study, we assessed the fate of anti-HER3 Th1 immunity during breast tumorigenesis.

Loss of Anti-HER-3 CD4+ T-Helper Type 1 Immunity Occurs in Breast Tumorigenesis and is Negatively Associated with Outcomes.

In human epidermal growth factor 2-positive breast cancer (HER2BC), neoadjuvant chemotherapy and anti-HER2-targeted therapy (nCT) achieves a complete pathologic response (pCR) in 40-67% of patients. Posttreatment magnetic resonance imaging (pMRI) is considered the gold standard, with high specificity but lower sensitivity for assessing response. The authors previously determined that anti-HER2Th1 immune response is associated with pathologic response after nCT in HER2BC patients. This study contrasted pMRI with anti-HER2Th1 response for assessing pCR in HER2BC.

Anti-HER2 CD4 T-Helper Type 1 Immune Response is Superior to Breast MRI for Assessing Response to Neoadjuvant Therapy in Patients with HER2-Positive Breast Cancer.

 Vaccination with HER2 peptide-pulsed DC1s stimulates a HER2-specific T-cell response. This randomized trial aimed to establish safety and evaluate immune and clinical responses to vaccination via intralesional (IL), intranodal (IN), or both intralesional and intranodal (ILN) injection. Fifty-four HER2 patients [42 pure ductal carcinoma  (DCIS), 12 early invasive breast cancer (IBC)] were enrolled in a neoadjuvant HER2 peptide-pulsed DC1 vaccine trial. Patients were randomized to IL ( = 19), IN ( = 19), or ILN ( = 16) injection. Immune responses were measured in peripheral blood and sentinel lymph nodes by ELISPOT or  sensitization assay. Pathologic response was assessed in resected surgical specimens. Vaccination by all injection routes was well tolerated. There was no significant difference in immune response rates by vaccination route (IL 84.2% vs. IN 89.5% vs. ILN 66.7%;  = 0.30). The pathologic complete response (pCR) rate was higher in DCIS patients compared with IBC patients (28.6% vs. 8.3%). DCIS patients who achieved pCR ( = 12) and who did not achieve pCR ( = 30) had similar peripheral blood anti-HER2 immune responses. All patients who achieved pCR had an anti-HER2 CD4 immune response in the sentinel lymph node, and the quantified response was higher by response repertoire ( = 0.03) and cumulative response ( = 0.04). Anti-HER2 DC1 vaccination is a safe and immunogenic treatment to induce tumor-specific T-cell responses in HER2 patients; immune and clinical responses were similar independent of vaccination route. The immune response in the sentinel lymph nodes, rather than in the peripheral blood, may serve as an endpoint more reflective of antitumor activity. .

Dendritic Cell Vaccination Enhances Immune Responses and Induces Regression of HER2 DCIS Independent of Route: Results of Randomized Selection Design Trial.

Although immunotherapy is making rapid inroads as a major treatment method for melanoma, lung, bladder, and hereditary colon cancer, breast cancer (BC) remains one of the tumors yet to experience the cellular immunology explosion despite the fact that heavy lymphocyte responses in breast tumors improve response to therapy and can predict for long-term survival.

Immunotherapy for Breast Cancer is Finally at the Doorstep: Immunotherapy in Breast Cancer.

Vaccines can be a cost effective preventive measure for both primary prevention of disease and prevention of disease recurrence. Several vaccines targeting breast cancer oncodrivers are currently being tested in clinical trials. Whereas clinical response rates to breast cancer vaccines have been modest despite the induction of strong antitumor T cell responses, it is through these approaches that valuable insight and knowledge have been gained about tumor immunology. With the emergence of new immunotherapies, there is renewed excitement for effective breast cancer vaccine development.

Vaccine Therapies for Breast Cancer.

Breast cancer, one of the leading causes of death in women in the United States, challenges therapeutic success in patients due to tumor heterogeneity, treatment resistance, metastasis and disease recurrence. Knowledge of immune system involvement in normal breast development and breast cancer has led to extensive research into the immune landscape of breast cancer and multiple immunotherapy clinical trials in breast cancer patients. However, poor immunogenicity and T-cell infiltration along with heightened immunosuppression in the tumor microenvironment have been identified as potential challenges to the success of immunotherapy in breast cancer. Oncodrivers, owing to their enhanced expression and stimulation of tumor cell proliferation and survival, present an excellent choice for targeted immunotherapy development in breast cancer. Loss of anti-tumor immune response specific to oncodrivers has been reported in breast cancer patients as well. Dendritic cell vaccines have been tested for their efficacy in generating anti-tumor T-cell response against specific tumor-associated antigens and oncodrivers and have shown improved survival outcome in patients. Here, we review the current status of immunotherapy in breast cancer, focusing on dendritic cell vaccines and their therapeutic application in breast cancer. We further discuss future directions of breast cancer immunotherapy and potential combination strategies involving dendritic cell vaccines and existing chemotherapeutics for improved efficacy and better survival outcome in breast cancer.

Immunotherapy in breast cancer: Current status and future directions.

HER2 breast cancer (BC) remains a significant problem in patients with locally advanced or metastatic BC. We investigated the relationship between T helper 1 (Th1) immune response and the proteasomal degradation pathway (PDP), in HER2-sensitive and -resistant cells. HER2 overexpression is partially maintained because E3 ubiquitin ligase Cullin5 (CUL5), which degrades HER2, is frequently mutated or underexpressed, while the client-protective co-chaperones cell division cycle 37 (Cdc37) and heat shock protein 90 (Hsp90) are increased translating to diminished survival. The Th1 cytokine interferon (IFN)-γ caused increased CUL5 expression and marked dissociation of both Cdc37 and Hsp90 from HER2, causing significant surface loss of HER2, diminished growth, and induction of tumor senescence. In HER2-resistant mammary carcinoma, either IFN-γ or Th1-polarizing anti-HER2 vaccination, when administered with anti-HER2 antibodies, demonstrated increased intratumor CUL5 expression, decreased surface HER2, and tumor senescence with significant therapeutic activity. IFN-γ synergized with multiple HER2-targeted agents to decrease surface HER2 expression, resulting in decreased tumor growth. These data suggest a novel function of IFN-γ that regulates HER2 through the PDP pathway and provides an opportunity to impact HER2 responses through anti-tumor immunity.

Article	Year
Loss of Anti-HER-3 CD4+ T-Helper Type 1 Immunity Occurs in Breast Tumorigenesis and is Negatively Associated with Outcomes. Annals of surgical oncology\| PubMed ID: 27663569	2017
Anti-HER2 CD4 T-Helper Type 1 Immune Response is Superior to Breast MRI for Assessing Response to Neoadjuvant Therapy in Patients with HER2-Positive Breast Cancer. Annals of surgical oncology\| PubMed ID: 27826664	2017
Dendritic Cell Vaccination Enhances Immune Responses and Induces Regression of HER2 DCIS Independent of Route: Results of Randomized Selection Design Trial. Clinical cancer research : an official journal of the American Association for Cancer Research\| PubMed ID: 27965306	2017
Immunotherapy for Breast Cancer is Finally at the Doorstep: Immunotherapy in Breast Cancer. Annals of surgical oncology\| PubMed ID: 30014455	2018
Vaccine Therapies for Breast Cancer. Surgical oncology clinics of North America\| PubMed ID: 31079793	2019
Immunotherapy in breast cancer: Current status and future directions. Advances in cancer research\| PubMed ID: 31202361	2019
Th1 cytokine interferon gamma improves response in HER2 breast cancer by modulating the ubiquitin proteasomal pathway. Molecular therapy : the journal of the American Society of Gene Therapy\| PubMed ID: 33412308	2021

Brian Czerniecki

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