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

Patients with metastatic HER2 breast cancer (MBC) often become resistant to HER 2 targeted therapy and recur. 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) concurrent 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. Both 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 tumor growth inhibition or enhanced survival compared to individual administration. Interestingly class II HER2- DC1 led to both increased CD4 and CD8 T cells into 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 HER2-DC1 vaccine could improve the efficacy of HER2-DC1 vaccines as measured by tumor growth, survival, infiltration of tumors by T cells and systemic anti-HER2 immune responses. Depletion of CD4+ T cells abrogated the anti-tumor efficacy of c...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research

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Conclusion MTDH is pro-oncogenic factor playing multifaceted and diverse roles in cancer progression. Its association and central role in regulating signaling pathways such a MAPK, wnt/β-catenin, PI3K/AkT, NF-κβ pathways in various cancers shows that it plays a vital role in metastasis. MTDH contribution to chemo and radiotherapy resistance provides a new direction for the development of anticancer therapeutics. Multiple mechanisms converge to promote expression of MTDH in cancers. Further studies are therefore warranted to determine whether the elevated MTDH expression has prognostic value for development...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
In this study, we evaluated the therapeutic benefit of combining the TAB004 antibody with Liposomal-MSA-IL-2 in immune competent and human MUC1 transgenic (MUC1.Tg) mouse models of PDA and investigated the associated immune responses. Treatment with TAB004 + Lip-MSA-IL-2 resulted in significantly improved survival and slower tumor growth compared to controls in MUC1.Tg mice bearing an orthotopic PDA.MUC1 tumor. Similarly, in the spontaneous model of PDA that expresses human MUC1, the combination treatment stalled the progression of pancreatic intraepithelial pre-neoplastic (PanIN) lesion to adenocarcinoma. Treatment with t...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Conclusion Several TISC-based immunotherapeutic approaches are under development in various stages of preclinical studies. As outlined in this review article, a careful and more exhaustive genetic and metabolic understanding of TISC-associated phenotypes is critical to develop novel TISC based immunotherapies. Various components within the tumor microenvironment such as tumor cells, infiltrating immune cells, and supporting stromal cells impact the TISC metabolism. This unique metabolic profile leads to upregulation of certain enzymes and proteins such as ALDH1, CEP55, IDO COA1 etc., which can be utilized for development ...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
In conclusion, CAR-T treatment combined with intratumoral delivery of poly I:C resulted in synergistic antitumor activity. We thus provide a rationale to translate this immunotherapeutic strategy to solid tumors. Introduction Adoptive T cell immunotherapy has been demonstrated to be a new way to fight malignancies. In particular, T lymphocytes engineered to express chimeric antigen receptor (CAR) have shown great promise in treating hematological malignancies (1). CD19-targeted CAR-T cells have been approved by FDA to treat relapsed B cell acute lymphoblastic leukemia (B-ALL) and Diffuse Large B-cell lymphoma (DLBC...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Conclusions: CAR T cell therapies have demonstrated the clinical benefits of harnessing our body's own defenses to combat tumor cells. Similar research is being conducted on lesser known modifications and gene-modified immune cells, which we highlight in this review. Introduction Chimeric antigen receptors and engineered T cell receptors (based on previously identified high affinity T cell receptors) function by redirecting T cells to a predefined tumor-specific (or tumor-associated) target. Most of these modifications use retroviral or lentiviral vectors to integrate the construct, and most of the receptors ...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Laure Garnier*, Anastasia-Olga Gkountidi and Stephanie Hugues* Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland The lymphatic system comprises a network of lymphoid tissues and vessels that drains the extracellular compartment of most tissues. During tumor development, lymphatic endothelial cells (LECs) substantially expand in response to VEGFR-3 engagement by VEGF-C produced in the tumor microenvironment, a process known as tumor-associated lymphangiogenesis. Lymphatic drainage from the tumor to the draining lymph nodes consequently increases, powering inters...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
Conditions:   Anatomic Stage IV Breast Cancer AJCC v8;   Estrogen Receptor Negative;   HER2/Neu Negative;   Metastatic Triple-Negative Breast Carcinoma;   Progesterone Receptor Negative;   Prognostic Stage IV Breast Cancer AJCC v8 Interventions:   Drug: Carboplatin;   Biological: Durvalumab;   Drug: Gemcitabine Hydrochloride;   Drug: Nab-paclitaxel;   Biological: Personalized Synthetic Long Peptide Vaccine;   Drug: Poly ICLC Sponso...
Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
Conditions:   Breast Cancer;   Breast Cancer Female;   Breast Cancer, Male;   Invasive Breast Cancer;   HER2-positive Breast Cancer;   HER2 Positive Breast Carcinoma;   Stage II Breast Cancer;   Stage III Breast Cancer Interventions:   Biological: Dendritic Cell Vaccine (DC1);   Drug: Neoadjuvant Chemotherapy;   Procedure: Curative Surgery Sponsor:   H. Lee Moffitt Cancer Center and Research Institute Not yet recruiting
Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
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