559 Biomarker correlates of clinical response with FLT3L/nivo backbone treatment in the multi-cohort phase 1 PORTER platform trial in metastatic castration-resistant prostate cancer patients (original) (raw)
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Journal for ImmunoTherapy of Cancer, 2019
Background: Clinical benefit of cellular immunotherapy has been shown in patients with castration-resistant prostate cancer (CRPC). We investigated the immunological response and clinical outcome of vaccination with blood-derived CD1c + myeloid dendritic cells (mDCs; cDC2) and plasmacytoid DCs (pDCs). Methods: In this randomized phase IIa trial, 21 chemo-naive CRPC patients received maximally 9 vaccinations with mature mDCs, pDCs or a combination of mDCs plus pDCs. DCs were stimulated with protamine/mRNA and loaded with tumor-associated antigens NY-ESO-1, MAGE-C2 and MUC1. Primary endpoint was the immunological response after DC vaccination, which was monitored in peripheral blood and in T cell cultures of biopsies of post-treatment delayed-type hypersensitivity-skin tests. Main secondary endpoints were safety, feasibility, radiological PFS (rPFS) and overall survival. Radiological responses were assessed by MRIs and contrast-enhanced 68 Ga-prostate-specific membrane antigen PET/CT, according to RECIST 1.1, PCWG2 criteria and immune-related response criteria. Results: Both tetramer/dextramer-positive (dm +) and IFN-γ-producing (IFN-γ +) antigen specific T cells were detected more frequently in skin biopsies of patients with radiological non-progressive disease (5/13 patients; 38%) compared to patients with progressive disease (0/8 patients; 0%). In these patients with vaccination enhanced dm + and IFN-γ + antigen-specific T cells median rPFS was 18.8 months (n = 5) vs. 5.1 months (n = 16) in patients without IFN-γ-producing antigen-specific T cells (p = 0.02). The overall median rPFS was 9.5 months. All DC vaccines were well tolerated with grade 1-2 toxicity.
International Journal of Molecular Sciences, 2019
Currently, there are two Food and Drug Administration (FDA)-approved drugs for androgen deprivation therapy (ADT) of metastatic castration-resistant prostate cancer (mCRPC) patients: abiraterone and enzalutamide. However, our understanding of the effect of these therapies on the immune system in mCRPC patients remains limited. Here, we examined how abiraterone and enzalutamide treatment affects levels of soluble immune mediators in plasma and in circulating immune cells of 44 mCRPC patients. We found that the baseline levels of cytokines fibroblast growth factor (FGF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 10 (IL-10), and IL-6 were significantly lower in ADT-sensitive compared to de novo resistant patients. In addition, resistant patients showed significantly lower T cell frequencies. When comparing the levels of cytokines over the course of treatment, we observed that the levels of proinflammatory mediators, such as interferon-γ (IFN-γ), IL-5, macrophage inflammatory protein 1 alpha (MIP-1α), and tumor necrosis factor alpha (TNFα), were significantly increased in the ADT-sensitive patients. At the same time, the abiraterone/enzalutamide therapy did not reduce the percentage of tolerogenic myeloid cell populations, such as polymorphonuclear myeloid-derived suppressor cells, which retained unaltered expression of programmed death-ligand 1 (PD-L1) and B7-H3. Overall, our results suggest that certain immune markers, such as IL-6 and the frequency of effector T cells, could be predictive of therapeutic response to ADT therapies in mCRPC patients.
Clinical Cancer Research, 2008
Purpose: CD4 + CD25 high FoxP3 + regulatoryTcells (Treg) have been shown to inhibit the activation and function of Tcells that participate in antigen-specific immune responses. Higher levels of Tregs have been reported in the peripheral blood of patients with several types of tumors. In this study, we investigated the number and functionality of CD4 + CD25 high FoxP3 + Tregs in patients with prostate cancer (PCa), and their potential role in inhibiting antitumor immune responses. Experimental Design: Levels of Tregs in the peripheral blood of healthy donors and patients with biochemically progressive, localized, and metastatic PCa were each measured by flow cytometry. The functional activity of Tregs was determined by their ability to suppress the proliferation of CD4 + CD25-T cells. Data were analyzed using Wilcoxon rank sum test and unpaired Student's t test. Results: Although levels of Tregs in the peripheral blood of patients with PCa were not significantly higher than those in healthy donors, Tregs in patients with PCa had significantly greater suppressive functionality than Tregs from healthy donors (P < 0.05). Additionally, there was a direct correlation between the serum levels of prostaglandin E 2 and Treg functionality in patients with localized PCa, using Pearson's product-moment correlation coefficient (R). Conclusions: These findings further show the potential importance of Tregs in modifying immune responses in patients with PCa. Although longer studies are necessary to confirm these findings, these studies also show for the first time the differences inTreg populations in patients with various stages of PCa, and thus, provide a basis for determining which PCa patient populations are best suited for immunotherapy trials involving the inhibition of Tregs.
Assessment of Immune Status in Dynamics for Patients with Cancer Undergoing Immunotherapy
Journal of Oncology, 2021
Immunotherapy using immune checkpoint inhibitors has revolutionized the treatment, and many types of cancer show a response rate of 20-40% and a significant increase in five-year survival. However, immunotherapy is expensive and may cause serious adverse events. erefore, a predictive method allowing identification of responding patients before starting the treatment would be very useful. In this study, we aimed to identify and implement other individual prognosis factors, factors that could lead to an improved clinical decision made in regard to the patient to establish an individualized treatment. Materials and Methods. All patients recruited from October 2018 to July 2019 were treated in OncoFort Hospital, Bucharest, with nivolumab or pembrolizumab. We investigated T lymphocyte CD3+, CD4+, CD8+, and CD4/CD8 cells by flow cytometry in patients before and after receiving treatment with anti-PD-1 agents. Results. We found that the responder group showed higher expression on CD4+ cells than the nonresponder group after the first cycle of immunotherapy. e prediction of the immunotherapeutic effect revealed that the elevation of T lymphocytes CD8+ and CD4+ after the first cycle of immunotherapy was followed by a decrease in their expression after the second cycle and was followed by a return almost to that one after the first administration. Conclusion. Our work indicates that the evaluation of the cells of the immune system in relation to the tumor and immunotherapy may lead to a better understanding of the pathogenic mechanisms and the identification of prognostic and predictive factors that will more effectively model the therapeutic approach.
Immunotherapy and Immunotherapy Combinations in Metastatic Castration-Resistant Prostate Cancer
Cancers
Although most prostate cancers are localized, and the majority are curable, recurrences occur in approximately 35% of men. Among patients with prostate-specific antigen (PSA) recurrence and PSA doubling time (PSADT) less than 15 months after radical prostatectomy, prostate cancer accounted for approximately 90% of the deaths by 15 years after recurrence. An immunosuppressive tumor microenvironment (TME) and impaired cellular immunity are likely largely responsible for the limited utility of checkpoint inhibitors (CPIs) in advanced prostate cancer compared with other tumor types. Thus, for immunologically “cold” malignancies such as prostate cancer, clinical trial development has pivoted towards novel approaches to enhance immune responses. Numerous clinical trials are currently evaluating combination immunomodulatory strategies incorporating vaccine-based therapies, checkpoint inhibitors, and chimeric antigen receptor (CAR) T cells. Other trials evaluate the efficacy and safety of t...
Editorial: Modulation of Human Immune Parameters by Anticancer Therapies
Frontiers in Immunology, 2020
Immunoncology is among the most important hallmarks of immunotherapy revolution of cancer medicine. Here, we compiled reviews and original research articles reflecting current developments in immunoncology. Novel therapies modulate the complex interaction between tumor and immune system (Figure 1). Multiparametric flow cytometry (FCM) is a key analytical tool contributing over 1,000 research articles/ year to the field. As a quantitative single-cell technology, FCM reliably and reproducibly identifies rare populations, detects subtle changes in modulatory signals, and assesses time-sensitive antigenic expression patterns. State-of-the-art equipment, fast sophisticated software, and flexibly labeled monoclonal antibodies allow rapid analyses with high sensitivity and specificity, even in routine applications. Lambert et al. explain how new analytes are added to the portfolio of diagnostic and research laboratories. Sample preparation, antibody titration, and appropriate controls are central in cytometric analysis and must be controlled with the necessary rigor and reproducibility (1). Although tumor cell analysis is a key application of cytometry (2, 3), this research topic is dedicated to the modulation of immune parameters, and we only included work focusing on tumorimmune-cell interaction and its disease-course impact. Dendritic cells (DCs) are crucial in tumor protection (4). Lu et al. dissect the interaction of DCs with non-small cell lung cancer (NSCLC) cells, which can induce an immunosuppressive microenvironment and evade immune surveillance. Analysis of costimulatory molecules and pro-/anti-inflammatory cytokines reveals new subpopulations of CD1c+ DCs in coculture with NSCLC. Particularly, the expression of signal molecules and pro-inflammatory cytokines are suppressed, whereas the secretion of anti-inflammatory cytokines by DCs is upregulated, suggesting that NSCLC can induce tolerogenic DCs, blocking DC-mediated anti-tumor immunity. Chemokines and their corresponding receptors play a pivotal role in orchestrating trafficking of immune cells to fulfill their next tasks. CXCL10 has been associated with T cell recruitment into
Cancer Immunology, Immunotherapy, 2019
Patients with non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) have shown benefit from anti-PD-1 therapies. However, not all patients experience tumor shrinkage, durable responses or prolonged survival, demonstrating the need to find response markers. In blood samples from NSCLC and RCC patients obtained before and after anti-PD-1 treatment, we studied leukocytes by complete blood cell count, lymphocyte subsets using flow cytometry and plasma concentration of nine soluble mediators, in order to find predictive biomarkers of response and to study changes produced after anti-PD-1 therapy. In baseline samples, discriminant analysis revealed a combination of four variables that helped differentiate stable disease-response (SD-R) from progressive disease (PD) patients: augmented frequency of central memory CD4 + T cells and leukocyte count was associated with response while increased percentage of PD-L1 + natural killer cells and naïve CD4 + T cells was associated with lack of response. After therapy, differential changes between responders and non-responders were found in leukocytes, T cells and TIM-3 + T cells. Patients with progressive disease showed an increase in the frequency of TIM-3 expressing CD4 + and CD8 + T cells, whereas SD-R patients showed a decrease in these subsets. Our findings indicate that a combination of immune variables from peripheral blood (PB) could be useful to distinguish response groups in NSCLC and RCC patients treated with anti-PD-1 therapy. Frequency of TIM-3 + T cells showed differential changes after treatment in PD vs SD-R patients, suggesting that it may be an interesting marker for monitoring progression during therapy.
The Prostate Cancer Immune Microenvironment, Biomarkers and Therapeutic Intervention
Uro
Advanced prostate cancers have a poor survival rate and a lack of effective treatment options. In order to broaden the available treatments, immunotherapies have been investigated. These include cancer vaccines, immune checkpoint inhibitors, chimeric antigen receptor T cells and bispecific antibodies. In addition, combinations of different immunotherapies and with standard therapy have been explored. Despite the success of the Sipuleucel-T vaccine in the metastatic, castrate-resistant prostate cancer setting, other immunotherapies have not shown the same efficacy in this population at large. Some individual patients, however, have shown remarkable responsiveness to these therapies. Therefore, work is underway to identify which populations will respond positively to therapy via the identification of predictive biomarkers. These include biomarkers of the immunologically active tumour microenvironment and biomarkers indicative of high neoantigen expression in the tumour. This review ex...