330 research outputs found
Abstract KP03: NOVEL IMMUNOTHERAPEUTICS FOR OVARIAN CANCER
No full textAbstract
In the last decade we have seen significance advances in the understanding of how the immune system modulates the ovarian tumor microenvironment and cancer growth. A number of studies have shown that high levels of tumor infiltrating adaptive immune system cells (B-cells and T-cells) found in ovarian cancer are associated with a favorable prognosis, especially if there is evidence of reduced regulatory T-cells. Robust T-cell tumor infiltration (TIL) is associated with PD-L1 upregulation. Almost half of ovarian cancers demonstrate enhanced PD-L1 expression on tumor cells and/or tumor infiltrating immune system cells. Immune checkpoint inhibitor monoclonal antibodies block receptors such as PD-1 and PD-L1 which suppress T-cell function. The largest study of immune checkpoint inhibition in ovarian cancer evaluated the blockade of PD-L1 using avelumab. In this phase I/II study 124 patients with recurrent disease, considered chemotherapy refractory, were treated with 10mg/kg avelumab every 2 weeks (65% of patients with 3 or greater salvage regimens). The overall response rate was 10% with a stable disease rate of 44% resulting in a disease control rate of 54%. Overall survival at 12 months was 44%. Clinical response did not correlate with either PDL-1 expression on tumor or immune infiltrating cells or BRCA mutation status. A randomized trial of avelumab in combination with pegylated liposomal doxorubicin in cisplatin refractory ovarian cancer has been initiated. Pre-clinical studies have shown that clinical responses to immune checkpoint inhibitor therapy in ovarian cancer may be enhanced by increasing Type I T-cell infiltration concurrent with therapy. Clinical strategies aimed at increasing TIL include the use of vaccines immunizing against ovarian cancer antigens to stimulate T-cells trafficking to tumor. Specific chemotherapy may result in increased TIL as some cytotoxic agents have been shown to modulate both the level and phenotype of TIL in ovarian cancer. An alternate approach is to suppress alternate pathways of tumor immune escape such as depletion of macrophage or inhibition of the IDO pathway to enhance immune activation. Several promising combination immunotherapy strategies are currently being evaluated in ovarian cancer.
Citation Format: Mary L. Disis, MD. NOVEL IMMUNOTHERAPEUTICS FOR OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr KP03.</jats:p
Abstract PR007: Candidate antigens for a ductal carcinoma in situ vaccine, essential for breast cancer cell survival across multiple subtypes, are immunogenic in DCIS and IBC
No full textVaccine therapy may to destroy the current ductal carcinoma in situ (DCIS), prevent recurrence, and have little risk of long-term complications. One of the limitations for a DCIS vaccine is identifying appropriate antigens which, when targeted, may be able to treat DCIS and prevent development of IBC. In this study, we identified proteins that were overexpressed in both DCIS and IBC tumors across fifteen human Geo and Array Express data sets. From the 68 candidate proteins, twelve proteins expression was necessary for cancer cell survival across breast cancer subtypes using a high throughput siRNA screen. We chose candidates that increased apoptosis and decreased cell survival in human HER2 positive (HER2), triple negative (TN), and hormone receptor positive HER2 negative (HR) human breast cancer cell lines with decreased expression of the target protein. Twelve proteins (AURKA, KIF11, NDC80, RRM2, SDC1, UBE2C, HJURP, CENPA, CENPF, HIST2H2AA3, KRT8, and TOP2A) were the twelve antigens developed for the vaccine. All twelve targets were immunogenic in women with DCIS and IBC as compared to age matched control women. For example, autoantibodies to four of the antigens (AURKA, NDC80, KRT8, and RRM2) predicted women with DCIS with AUC 0.69 (p=0.005 95% CI 0.56 to 0.80) and IBC with AUC 0.79 (p\u3c0.001 95% CI 0.66 to 0.90) as compared to age matched control women in a discovery set of 59 DCIS patients, 37 IBC patients, and 43 control women. In an independent validation set of serum samples of 50 DCIS, 60 IBC, and 50 control patients, autoantibodies to the four candidate antigens could predict women with DCIS with AUC 0.62 (p=0.04, 95% CI 0.51 to 0.73) and IBC with AUC 0.69 (p\u3c0.001, 95% CI 0.60 to 0.79). Autoantibodies to the four DCIS antigens could identify each subtype of breast cancer subtype as compared to control, HR+(n=20 patients) with AUC 0.69 (p=0.01, 95% CI 0.55 to 0.83), HER2+ (n=20 patients) with AUC 0.70 (p=0.01, 95% CI 0.55 to 0.84), and TN (n=20 patients) with AUC 0.74 (p=0.002, 95% CI 0.61 to 0.87). All these were IgG autoantibodies suggest pre-existing T cells that recognize the candidate antigens because Ig class switching from IgM to IgG requires antigen-specific T cells. These twelve candidate antigens, overexpressed in human breast cancer, are also overexpressed in the TgMMTV-neu and C3(1)Tag transgenic mouse mammary tumor models of breast cancer. Vaccination with human MHC Class II predicted epitopes from KRT8, conserved between mouse and human, inhibited tumor growth in TgMMTV-neu mice by 47% and C3(1)Tag by 62%. The KRT8- specific IFN-g immune response developed was associated with lower tumor volume with mice vaccinated with the human MHC Class II Th1 KRT8 epitopes with the KRT8-specific IFN-g immune response associated with smaller tumors in TgMMTV-neu mice (R2= 0.64, p=0.02). We plan to develop these antigens in a multi-antigen DCIS vaccine that may be able to destroy DCIS and prevent breast cancer across all breast cancer subtypes.
Citation Format: Sasha E. Stanton, Jason Schlumbohm, Mary L. Disis. Candidate antigens for a ductal carcinoma in situ vaccine, essential for breast cancer cell survival across multiple subtypes, are immunogenic in DCIS and IBC [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr PR007
Therapeutic Cancer Vaccines and Translating Vaccinomics Science to the Global Health Clinic: Emerging Applications Toward Proof of Concept
No full textSITC/iSBTc cancer immunotherapy biomarkers resource document: online resources and useful tools - a compass in the land of biomarker discovery
No full textRecent positive clinical results in cancer immunotherapy point to the potential of immune-based strategies to
provide effective treatment of a variety of cancers. In some patients, the responses to cancer immunotherapy are
durable, dramatically extending survival. Extensive research efforts are being made to identify and validate
biomarkers that can help identify subsets of cancer patients that will benefit most from these novel
immunotherapies. In addition to the clear advantage of such predictive biomarkers, immune biomarkers are
playing an important role in the development, clinical evaluation and monitoring of cancer immunotherapies. This
Cancer Immunotherapy Resource Document, prepared by the Society for Immunotherapy of Cancer (SITC, formerly
the International Society for Biological Therapy of Cancer, iSBTc), provides key references and online resources
relevant to the discovery, evaluation and clinical application of immune biomarkers. These key resources were
identified by experts in the field who are actively pursuing research in biomarker identification and validation. This
organized collection of the most useful references, online resources and tools serves as a compass to guide
discovery of biomarkers essential to advancing novel cancer immunotherapies
Related Articles from Enhancing Cancer Vaccine Efficacy via Modulation of the Tumor Microenvironment
No full textRelated Articles from Enhancing Cancer Vaccine Efficacy via Modulation of the Tumor Microenvironmen
Immune Regulation of Cancer
No full text Innate and adaptive immune system cells play a major role in regulating the growth of cancer. Although it is commonly thought that an immune response localized to the tumor will inhibit cancer growth, it is clear that some types of inflammation induced in a tumor may also lead to cancer proliferation, invasion, and dissemination. Recent evidence suggests, however, that some patients with cancer can mount an antitumor immune response that has the potential to control or eliminate cancer. Indeed, a so-called “immune response” signature has been described in malignancy that is associated with improved outcomes in several tumor types. Moreover, the presence of specific subsets of T cells, which have the capability to penetrate tumor stroma and infiltrate deep into the parenchyma, identifies patients with an improved prognosis. Immune-based therapies have the potential to modulate the tumor microenvironment by eliciting immune system cells that will initiate acute inflammation that leads to tissue destruction. </jats:p
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