Dissecting the therapeutic effects of anti-CTLA-4 and ADT in a murine hormone-sensitive prostate cancer.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 61-61
Author(s):  
Sumit Kumar Subudhi ◽  
Welby Montalvo-Ortiz ◽  
Howard I. Scher ◽  
James Patrick Allison
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
Tumor Growth ◽  
Murine Model ◽  
Immune Checkpoint ◽  
Treatment Initiation ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Ifn Gamma ◽  
Hormone Sensitive

61 Background: Immune checkpoint blockade with anti-CTLA-4 has emerged as a successful, novel form of cancer immunotherapy that acts directly on activated T cells instead of on cancer cells. CTLA-4 blockade can result in durable, long-term responses, but only a subset of patients treated benefit from this approach. Androgen deprivation therapy (ADT) is the first-line treatment for advanced prostate cancer, and it produces some of the most dramatic responses in clinical oncology. Clinically, the combination of ADT and anti-CTLA-4 was found to be more effective than ADT alone. To optimize the development of combination regimens, we examined the kinetics of the immune effects of ADT ± anti-CTLA-4 in a murine model of hormone-sensitive prostate cancer. Methods: Mice with established Myc-CaP prostate tumors were divided into 4 treatment groups: 1) untreated, 2) degarelix, 3) anti-CTLA-4, or 4) degarelix plus anti-CTLA-4. Tumor growth was measured biweekly. Tumor-infiltrating lymphocytes and T cell cytokine production was determined by flow cytometric analysis and serum IFN-gamma levels were assessed by ELISA. Results: We found that degarelix rapidly induces castrate levels of testosterone within 24 hours in mice and maintains these levels for at least 35 days. The combination of degarelix and anti-CTLA-4 improved median overall survival compared to degarelix alone (P<0.030, Mantel-Cox log-rank test). Tumor regression was associated with the production of the Th1-cytokines, IFN-gamma and TNF-alpha by tumor-infiltrating CD4+ and CD8+ T cells within 1 week of treatment initiation. This response peaked at 2 weeks after treatment initiation and was associated with elevated levels of serum IFN-gamma levels. In this model, anti-CTLA-4 monotherapy had no effect on tumor growth rates or intratumoral/sera cytokine levels. Conclusions: The combination of immune checkpoint blockade with anti-CTLA-4 and medical castration with degarelix is therapeutically effective in a murine model of hormone-sensitive prostate cancer, likely through an IFN-gamma-dependent manner. This model can be used to better identify potential post-treatment biomarkers that can be studied for associations with clinical outcomes.

scholarly journals Combination of vasculature targeting, hypofractionated radiotherapy, and immune checkpoint inhibitor elicits potent antitumor immune response and blocks tumor progression

2021 ◽  
Vol 9 (2) ◽  
pp. e001636
Author(s):  
Stefano Pierini ◽  
Abhishek Mishra ◽  
Renzo Perales-Linares ◽  
Mireia Uribe-Herranz ◽  
Silvia Beghi ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Combination Therapy ◽  
Tumor Growth ◽  
Tumor Progression ◽  
Immune Checkpoint ◽  
Blood Perfusion ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Triple Combination Therapy

BackgroundTumor endothelial marker 1 (TEM1) is a protein expressed in the tumor-associated endothelium and/or stroma of various types of cancer. We previously demonstrated that immunization with a plasmid-DNA vaccine targeting TEM1 reduced tumor progression in three murine cancer models. Radiation therapy (RT) is an established cancer modality used in more than 50% of patients with solid tumors. RT can induce tumor-associated vasculature injury, triggering immunogenic cell death and inhibition of the irradiated tumor and distant non-irradiated tumor growth (abscopal effect). Combination treatment of RT with TEM1 immunotherapy may complement and augment established immune checkpoint blockade.MethodsMice bearing bilateral subcutaneous CT26 colorectal or TC1 lung tumors were treated with a novel heterologous TEM1-based vaccine, in combination with RT, and anti-programmed death-ligand 1 (PD-L1) antibody or combinations of these therapies, tumor growth of irradiated and abscopal tumors was subsequently assessed. Analysis of tumor blood perfusion was evaluated by CD31 staining and Doppler ultrasound imaging. Immunophenotyping of peripheral and tumor-infiltrating immune cells as well as functional analysis was analyzed by flow cytometry, ELISpot assay and adoptive cell transfer (ACT) experiments.ResultsWe demonstrate that addition of RT to heterologous TEM1 vaccination reduces progression of CT26 and TC1 irradiated and abscopal distant tumors as compared with either single treatment. Mechanistically, RT increased major histocompatibility complex class I molecule (MHCI) expression on endothelial cells and improved immune recognition of the endothelium by anti-TEM1 T cells with subsequent severe vascular damage as measured by reduced microvascular density and tumor blood perfusion. Heterologous TEM1 vaccine and RT combination therapy boosted tumor-associated antigen (TAA) cross-priming (ie, anti-gp70) and augmented programmed cell death protein 1 (PD-1)/PD-L1 signaling within CT26 tumor. Blocking the PD-1/PD-L1 axis in combination with dual therapy further increased the antitumor effect and gp70-specific immune responses. ACT experiments show that anti-gp70 T cells are required for the antitumor effects of the combination therapy.ConclusionOur findings describe novel cooperative mechanisms between heterologous TEM1 vaccination and RT, highlighting the pivotal role that TAA cross-priming plays for an effective antitumor strategy. Furthermore, we provide rationale for using heterologous TEM1 vaccination and RT as an add-on to immune checkpoint blockade as triple combination therapy into early-phase clinical trials.

scholarly journals Immune checkpoint blockade impairs immunosuppressive mechanisms of regulatory T cells in B-cell lymphoma

2021 ◽  
Vol 14 (9) ◽  
pp. 101170
Author(s):  
Vera Bauer ◽  
Fatima Ahmetlić ◽  
Nadine Hömberg ◽  
Albert Geishauser ◽  
Martin Röcken ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
B Cell ◽  
Immune Checkpoint ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

scholarly journals Autophagy inhibition by targeting PIKfyve potentiates response to immune checkpoint blockade in prostate cancer

Nature Cancer ◽  
2021 ◽  
Author(s):  
Yuanyuan Qiao ◽  
Jae Eun Choi ◽  
Jean C. Tien ◽  
Stephanie A. Simko ◽  
Thekkelnaycke Rajendiran ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Autophagy Inhibition

scholarly journals A TLR4 agonist improves immune checkpoint blockade treatment by increasing the ratio of effector to regulatory cells within the tumor microenvironment

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
A. Farias ◽  
A. Soto ◽  
F. Puttur ◽  
C. J. Goldin ◽  
S. Sosa ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Therapeutic Effect ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Combined Treatment ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Regulatory Cells ◽  
Ifn Γ

AbstractBrucella lumazine synthase (BLS) is a homodecameric protein that activates dendritic cells via toll like receptor 4, inducing the secretion of pro-inflammatory cytokines and chemokines. We have previously shown that BLS has a therapeutic effect in B16 melanoma-bearing mice only when administered at early stages of tumor growth. In this work, we study the mechanisms underlying the therapeutic effect of BLS, by analyzing the tumor microenvironment. Administration of BLS at early stages of tumor growth induces high levels of serum IFN-γ, as well as an increment of hematopoietic immune cells within the tumor. Moreover, BLS-treatment increases the ratio of effector to regulatory cells. However, all treated mice eventually succumb to the tumors. Therefore, we combined BLS administration with anti-PD-1 treatment. Combined treatment increases the outcome of both monotherapies. In conclusion, we show that the absence of the therapeutic effect at late stages of tumor growth correlates with low levels of serum IFN-γ and lower infiltration of immune cells in the tumor, both of which are essential to delay tumor growth. Furthermore, the combined treatment of BLS and PD-1 blockade shows that BLS could be exploited as an essential immunomodulator in combination therapy with an immune checkpoint blockade to treat skin cancer.

scholarly journals IMMU-19. TARGETING GLIOBLASTOMA IMMUNOSUPPRESSION AND TREATMENT RESISTANCE WITH IBRUTINIB IN COMBINATION WITH STEREOTACTIC RADIATION AND IMMUNE CHECKPOINT BLOCKADE

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii108-ii108
Author(s):  
Jayeeta Ghose ◽  
Baisakhi Raychaudhuri ◽  
Kevin Liu ◽  
William Jiang ◽  
Pooja Gulati ◽  
...  
Keyword(s):  
T Cells ◽  
Combination Therapy ◽  
Median Survival ◽  
Immune Checkpoint ◽  
Survival Benefit ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Control Group ◽  
Triple Combination ◽  
Triple Combination Therapy

Abstract BACKGROUND Glioblastoma (GBM) is associated with systemic and intratumoral immunosuppression. Part of this immunosuppression is mediated by myeloid derived suppressor cells (MDSCs). Preclinical evidence shows that ibrutinib, a tyrosine kinase inhibitor FDA approved for use in chronic lymphocytic leukemia and known to be CNS penetrant, can decrease MDSC generation and function. Also, focal radiation therapy (RT) synergizes with anti-PD-1 therapy in mouse GBM models. Thus, we aimed to test the combination of these approaches on immune activation and survival in a preclinical immune-intact GBM mouse model. METHODS C57BL/6 mice intracranially implanted with the murine glioma cell line GL261-Luc2 were divided into 8 groups consisting of treatments with ibrutinib, RT (10 Gy SRS), or anti-PD-1 individually or in each combination (along with a no treatment control group). Immune cell subset changes (flow-cytometry) and animal survival (Kaplan-Meier) were assessed (n=10 mice per group). RESULTS Median survival of the following groups including control (28 days), ibrutinib (27 days), RT (30 days) or anti-PD-1 (32 days) showed no significant differences. However, a significant improvement in median survival was seen in mice given combinations of ibrutinib+RT (35 days), ibrutinib+anti-PD-1 (38 days), and triple therapy with ibrutinib+RT+anti-PD-1 (48 days, p &lt; 0.05) compared to controls or single treatment groups. The reproducible survival benefit of triple combination therapy was abrogated in the setting of CD4+ and CD8+ T cell depletion. Contralateral intracranial tumor re-challenge in long-term surviving mice suggested generation of tumor-specific immune memory responses. The immune profile of the tumor microenvironment (TME) showed increased cytotoxic CD8+ T cells and decreased MDSCs and regulatory T cells in the triple combination therapy mice compared to controls. CONCLUSION The combination of ibrutinib, focal RT, and anti-PD-1 immune checkpoint blockade led to a significant survival benefit compared to controls in a preclinical model of GBM.

Sign in / Sign up

Export Citation Format

Share Document