A randomized phase II study of chemoradiation and pembrolizumab for locally advanced cervical cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS5601-TPS5601 ◽  
Author(s):  
Linda R. Duska ◽  
Timothy Norman Showalter ◽  
Gina R. Petroni ◽  
Timothy Bullock
Keyword(s):  
Cervical Cancer ◽  
Immune Response ◽  
T Cells ◽  
Regulatory T Cells ◽  
Cancer Patients ◽  
Phase Ii ◽  
Cd8 T Cells ◽  
Cytotoxic T Cells ◽  
Hpv Dna ◽  
Randomized Phase Ii

TPS5601 Background: The standard of care for patients with LACC is concurrent chemoradiation therapy (CRT) with weekly cisplatin. Five-year disease overall survival after contemporary CRT for LACC is only 66%. Human Papillomavirus (HPV) DNA is detected in virtually all cervical cancers, and HPV specific CD4+ helper and CD8+ cytotoxic T cells are found in cervical tumors, indicating the inherent immunogenicity of these tumors. The failure of the immune system to eradicate HPV DNA integration is thought to be associated with the cancer cells’ acquisition of mechanisms to avoid cytotoxic T cells, including, but not limited to, the expression of checkpoint inhibitory molecules such as PD-L1 and the recruitment of FoxP3+ immunosuppressive regulatory T cells. Low ratios of CD8+ T cells: regulatory T cells are associated with poor survival for cervical cancer patients, suggesting that strategies to enhance immune response would be effective. Additionally, in cervical cancer, PD-1 is expressed by the majority of infiltrating CD8+ T cells, suggesting that blocking of PD-1 could have therapeutic potential, inducing tumor-specific immunity in cervical cancer patients. We hypothesized that CRT may increase tumor responsiveness to anti-PD-1 therapy by enhancing antigen availability and disrupting immune-regulatory networks. However, it is unclear how treatment with cisplatin and/or ionizing radiation could influence the quality and quantity of the immune response. Methods: A randomized Phase II open-label multi-center study was designed in which 88 eligible subjects with LACC will be treated with standard CRT plus the PD-1 monoclonal antibody pembrolizumab. The primary objectives in the study are to estimate the safety and immune response to pembrolizumab given either sequentially or concurrently with CRT. Secondary objectives will evaluate the metabolic response and rates of distant metastases following treatment with pembrolizumab given sequentially or concurrently with CRT. The study design also affords the opportunity to characterize the effect of treatment on immune response pathways by estimating the effects of treatment on specific immune markers. Clinical trial information: NCT02635360.

scholarly journals The Role of T Lymphocytes in Cancer Patients Undergoing Immunotherapy with Autologous Dendritic Cells

2011 ◽  
Vol 5 ◽  
pp. CMO.S6927 ◽  
Author(s):  
Cláudia M. Rodrigues ◽  
Bruna F. Matias ◽  
Eddie F.C. Murta ◽  
Márcia A. Michelin
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Dendritic Cells ◽  
T Lymphocytes ◽  
Regulatory T Cells ◽  
Cancer Patients ◽  
Cytotoxic T Cells ◽  
Cell Populations ◽  
Tnf Α ◽  
Ifn Γ

Introduction Cancer stems from mutations in specific genes that induce uncontrolled cell proliferation. Dendritic cells (DCs) are important immunologic cells and play a crucial role in the induction of an antitumour response. Patients and Methods We examined the immune response mediated by T lymphocytes, helper T cells, cytotoxic T cells, and regulatory T cells, as well as the cytokines [interleukin (IL)-2, IL-12, interferon (IFN)-γ, tumour necrosis factor (TNF)-α and IL-10], produced by these cell populations, in cancer patients (N = 7) undergoing immunotheraphy with autologous DCs. Results We observed an initial increase in T helper cells (CD4+) expressing IL-2, IFN-γ, IL-12, TNF-α, and IL-10 after initiation of treatment, with statistically significant for the cytokines IL-2, TNF-α and IL-10. A similar significant effect was observed for IL-2-expressing cytotoxic T cells (CD8+). The percentage of total T cells (CD3+) remained elevated throughout immunotherapy. Regulatory T cells (CD25+/FOXP3+) only showed high percentage of their maximum value when analyzed the pretreatment levels, with statistically significant. Conclusion Immunotherapy with DCs stimulated the immune response, as evidenced by an increase in percent fluorescence of most cell populations investigated during the specified treatment period.

A Randomized Phase II Trial of Idiotype Vaccination and Adoptive Autologous T-Cell Transfer in Multiple Myeloma patients

Blood ◽  
2021 ◽  
Author(s):  
Muzaffar H Qazilbash ◽  
Neeraj Y Saini ◽  
Cha Soung-chul ◽  
Zhe Wang ◽  
Edward Stadtmauer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Phase Ii ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Phase Ii Trial ◽  
Ex Vivo ◽  
Vaccine Strategy ◽  
Randomized Phase Ii

We hypothesized that combining adoptively transferred autologous T cells with a cancer vaccine strategy would enhance therapeutic efficacy by adding anti-myeloma idiotype-keyhole limpet hemocyanin (Id-KLH) vaccine to vaccine-specific co-stimulated T cells. In this randomized, phase II trial, eligible patients received either the control (KLH only) or Id-KLH vaccine, an auto-transplant, vaccine-specific co-stimulated T-cells expanded ex-vivo, and two booster doses of the assigned vaccine. In 36 patients (20 in KLH, 16 in Id-KLH) enrolled, no dose-limiting toxicity was seen in either arm. At last evaluation, 6 (30%) and 8 (50%) had achieved complete remission in KLH-only and Id-KLH, respectively (p=0.22) and no difference in 3-year progression-free survival was observed (59% and 56%, respectively; p=0.32). In a 594 Nanostring nCounter gene panel analyzed for immune reconstitution (IR), compared with KLH-only patients, there was a greater change in IR genes in T-cells in Id-KLH patients relative to baseline. Specifically, upregulation of genes associated with activation, induction of effector function, and generation of memory CD8+ T cells after Id-KLH, but not after KLH control vaccination, was observed. Similarly, responding patients across both arms were associated with upregulation of genes associated with T-cell activation. At baseline, all patients had greater expression of CD8+ T-cell exhaustion markers. These changes were associated with functional Id-specific immune responses in a subset of Id-KLH patients analyzed. In conclusion, in this combination immunotherapy approach, we observed a significantly more robust IR in CD4+ and CD8+ T cells in the Id-KLH arm, supporting further investigation of vaccine and adoptive immunotherapy strategies.

scholarly journals 323 Systemic administration of ladiratuzumab vedotin alone or in combination with pembrolizumab results in significant immune activation in the tumor microenvironment in metastatic breast cancer patients

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A349-A349
Author(s):  
Lajos Pusztai ◽  
Hailing Lu ◽  
Christopher Hale ◽  
Anne Grosse-Wilde ◽  
Jennifer Specht ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Immune Response ◽  
T Cells ◽  
Metastatic Breast Cancer ◽  
Cancer Patients ◽  
Cd8 T Cells ◽  
Immune Activation ◽  
Metastatic Breast ◽  
Breast Cancer Patients

BackgroundLadiratuzumab vedotin (LV) is an investigational antibody-drug conjugate (ADC) composed of a humanized anti-LIV-1 IgG1 conjugated with monomethyl auristatin E (MMAE), a microtubule-disrupting agent. LV targets LIV-1, a protein expressed by various cancers. Along with a cytotoxic effect, LV has been shown to induce immunogenic cell death (ICD) in preclinical studies. LV is currently being investigated as a monotherapy and in combination with pembrolizumab in patients with metastatic breast cancer and other solid tumors. This correlative biomarker study aims to assess the ability of LV to modulate the tumor microenvironment (TME) in breast cancer patients.MethodsIn the SGNLVA-001 trial, metastatic breast cancer patients, predominantly of the triple negative subtype (TNBC), received LV monotherapy (2.0 or 2.5 mg/kg, every 3 weeks [q3w]). In the SGNLVA-002 trial, patients with metastatic TNBC received LV (2.0 or 2.5 mg/kg, q3w) plus pembrolizumab (200 mg, q3w). To investigate the potential effect of LV or LV plus pembrolizumab on the TME, paired pre-treatment and on-treatment tumor biopsies (Cycle [C] 1 Day [D] 5 or C1D15) were collected and analyzed by RNAseq and immunohistochemistry (IHC) staining.ResultsGene expression analysis of paired biopsy TNBC samples (n=59; baseline and C1D5) showed that LV monotherapy treatment significantly induces immune response-related gene expression, MHC, co-stimulatory molecules, and PD-L1. Gene set enrichment analysis (GSEA) demonstrated enrichment of macrophage and tumor inflammation signature genes, supporting the induction of ICD and enhancement of innate immune response. Paired tumor samples from subjects treated with LV plus pembrolizumab (n=16; baseline and C1D15) showed a broader range of gene expression changes on RNAseq compared to LV monotherapy. GSEA evidenced enrichment of genes associated with cytotoxic CD8 T cells, CD4 T helper cells, dendritic cells, and macrophages, further demonstrating the induction of ICD and activation of an innate immune response. Importantly, the combination had a unique adaptive immune response induction signature. IHC analysis confirmed the increased infiltration of macrophages after LV monotherapy. The combination with pembrolizumab resulted in a further increase in macrophages and a prominent influx of CD8 T cells.ConclusionsSystemic administration of LV monotherapy resulted in immune activation in the TME and macrophage infiltration. The combination of LV plus pembrolizumab resulted in a more potent immune activation in the TME and a prominent influx of CD8 T cells in addition to macrophages. Together these results provide a rationale for the continued clinical investigation of LV alone or in combination with pembrolizumab.Trial RegistrationNCT01969643 and NCT03310957Ethics ApprovalThe study protocols for clinical trials represented in this publication were reviewed by the respective IRB/IEC at each study site and approved before trial participants were screened and enrolled.ConsentNot applicable.

scholarly journals High KDM1A Expression Associated with Decreased CD8+T Cells Reduces the Breast Cancer Survival Rate in Patients with Breast Cancer

2021 ◽  
Vol 10 (5) ◽  
pp. 1112
Author(s):  
Hyung Suk Kim ◽  
Byoung Kwan Son ◽  
Mi Jung Kwon ◽  
Dong-Hoon Kim ◽  
Kyueng-Whan Min
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
T Cells ◽  
Survival Rate ◽  
Immune Responses ◽  
Cancer Patients ◽  
Cd8 T Cells ◽  
Specific Gene ◽  
Breast Cancer Patients ◽  
Gene Sets

Background: Lysine-specific demethylase 1A (KDM1A) plays an important role in epigenetic regulation in malignant tumors and promotes cancer invasion and metastasis by blocking the immune response and suppressing cancer surveillance activities. The aim of this study was to analyze survival, genetic interaction networks and anticancer immune responses in breast cancer patients with high KDM1A expression and to explore candidate target drugs. Methods: We investigated clinicopathologic parameters, specific gene sets, immunologic relevance, pathway-based networks and in vitro drug response according to KDM1A expression in 456 and 789 breast cancer patients from the Hanyang university Guri Hospital (HYGH) and The Cancer Genome Atlas, respectively. Results: High KDM1A expression was associated with a low survival rate in patients with breast cancer. In analyses of immunologic gene sets, high KDM1A expression correlated with low immune responses. In silico flow cytometry results revealed low abundances of CD8+T cells and high programmed death-ligand 1 (PD-L1) expression in those with high KDM1A expression. High KDM1A expression was associated with a decrease in the anticancer immune response in breast cancer. In pathway-based networks, KDM1A was linked directly to pathways related to the androgen receptor signaling pathway and indirectly to the immune pathway and cell cycle. We found that alisertib effectively inhibited breast cancer cell lines with high KDM1A expression. Conclusions: Strategies utilizing KDM1A may contribute to better clinical management/research for patients with breast cancer.

scholarly journals A Randomized Phase II Trial of Multiepitope Vaccination with Melanoma Peptides for Cytotoxic T Cells and Helper T Cells for Patients with Metastatic Melanoma (E1602)

2013 ◽  
Vol 19 (15) ◽  
pp. 4228-4238 ◽  
Author(s):  
Craig L. Slingluff ◽  
Sandra Lee ◽  
Fengmin Zhao ◽  
Kimberly A. Chianese-Bullock ◽  
Walter C. Olson ◽  
...  
Keyword(s):  
T Cells ◽  
Metastatic Melanoma ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Cytotoxic T Cells ◽  
Helper T Cells ◽  
Randomized Phase Ii ◽  
Melanoma Peptides
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