Synergistic cytotoxicity of a prostate cancer-specific immunotoxin in combination with the BH3 mimetic ABT-737

AbstractIn many tumors, including prostate cancer, anti-apoptotic members of the Bcl-2 family are overexpressed and cause cell death resistance, which is a typical hallmark of cancer. Different therapeutic approaches, therefore, aim to restore the death mechanisms for enhanced apoptosis. Our recombinant immunotoxin D7(VL-VH)-PE40 is composed of the scFv D7(VL-VH) against the prostate-specific membrane antigen (PSMA) on the surface of prostate cancer cells and of the cytotoxic domain of the bacterial toxinPseudomonas Exotoxin A (PE40). SincePseudomonas Exotoxin A-based immunotoxins are known to preferentially inhibit the expression of the anti-apoptotic protein Mcl-1, the rationale was to test our immunotoxin in combination with the BH3 mimetic ABT-737, which specifically inhibits Bcl-2, Bcl-xl, and Bcl-w for enhanced induction of apoptosis in prostate cancer cells. The immunotoxin showed high and specific binding and cytotoxicity against PSMA expressing prostate cancer cells marked by a direct inhibition of Mcl-1. The combination of the immunotoxin with a subtoxic concentration of ABT-737 caused additive or even synergistic effects, which were based on an enhanced apoptosis induction as detected by poly(ADP-ribose) polymerase (PARP) and Caspase-3 cleavage in Western blot. Our study shows that the combination therapy of immunotoxin plus ABT-737 is a promising approach for the future treatment of advanced prostate cancer to improve therapeutic efficacy and to reduce adverse sid...
Source: Cancer Immunology, Immunotherapy - Category: Cancer & Oncology Source Type: research

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AbstractThe most common metastatic lesions of prostate cancer are in bone and can be classified into three distinct pathology subtypes: lytic, blastic, and an indeterminate mixture of both. We investigated a cohort of decalcified formalin-fixed and paraffin-embedded (FFPE) patient specimens from the bone that contained metastatic prostate cancer with lytic or blastic features. These tissue sections were utilized for immunohistochemistry (IHC) staining, isolation of RNA for gene expression, and Digital Spatial Profiling (DSP) of changes in both the tumor and microenvironment. A diverse set of unique immune cell populations ...
Source: Journal for Immunotherapy of Cancer - Category: Cancer & Oncology Source Type: research
Ferumoxytol capped antiprogrammed cell death ‐ligand 1 (PD‐L1) antibodies (aPD‐L1) loaded ultralarge pore mesoporous silica nanoparticles are delivered with image guidance after cabazitaxel (Cbz) chemotherapy for the treatment of prostate cancer. A single session of sequential magnetic resonance image guided chemo‐immunotherapy effecti vely activates T cell infiltration, insisting tumor specific adaptive immunity and tumor rejection superior to systemic aPD‐L1 treatment after Cbz of the same dose. AbstractHerein, ferumoxytol (Fer) capped antiprogrammed cell death ‐ligand 1 (PD‐L1) antibodies (aPD‐L1) loaded...
Source: Small - Category: Nanotechnology Authors: Tags: Full Paper Source Type: research
Gold nanospheres can be functionalized with interleukin ‐12 (IL12), a potent anticancer and immunostimulatory cytokine, and a cyclic peptide containing the isoDGR motif (Iso1) that, after coupling to albumin (Iso1‐HSA), recognizes the αvβ3 integrin overexpressed in tumor vessels and on different tumor cell types. Bifunctional nanospheres (Iso1/Au/I L12) increase the infiltration of immune cells and inhibit tumor growth in preclinical tumor models. AbstractThe clinical use of interleukin ‐12 (IL12), a cytokine endowed with potent immunotherapeutic anticancer activity, is limited by systemic toxicity. The hy...
Source: Small - Category: Nanotechnology Authors: Tags: Full Paper Source Type: research
Abstract Skeletal metastases are common in genitourinary malignancies-including prostate cancer, renal cell carcinoma, and urothelial cancer-and portend significant morbidity and poor prognosis. The presence of skeletal metastases can result in decreased quality of life and increased morbidity. Strategies can be employed to prevent bone-related complications including lifestyle modifications and dietary supplementation. Additionally, pharmacologic agents exist to prevent bone loss and may be appropriate for patients at high risk of fragility-related or skeletal complications, such as pathologic fracture related to...
Source: Urologic Oncology - Category: Urology & Nephrology Authors: Tags: Urol Oncol Source Type: research
ConclusionsBET Bromodomain inhibition can mediate changes in expression at a genome wide level in prostate cancer cells, resulting in an increased susceptibility to CD8 T cell targeting. These data suggest that combining BET bromodomain inhibition with immune checkpoint blockade may have clinical activity in prostate cancer patients.
Source: Journal for Immunotherapy of Cancer - Category: Cancer & Oncology Source Type: research
Authors: Schepisi G, Brighi N, Cursano MC, Gurioli G, Ravaglia G, Altavilla A, Burgio SL, Testoni S, Menna C, Farolfi A, Casadei C, Tonini G, Santini D, De Giorgi U Abstract Immunotherapy represents the new era of cancer treatment because of its promising results in various cancer types. In urological tumors, the use of the immune-checkpoint inhibitors (ICIs) is increasingly spreading. Although not all patients and not all diseases respond equally well to immunotherapy, there is an increasing need to find predictive markers of response to ICIs. Patient- and tumor-related factors may be involved in primary and secon...
Source: Journal of Oncology - Category: Cancer & Oncology Tags: J Oncol Source Type: research
In this study we review the principles that have guided the engineering of CAR-T cells and the specific prostatic antigens identified as possible targets for immunological and non-immunological therapies. We also provide a state-of-the-art overview of CAR-T cell therapy in PCa, defining the key obstacles to its development and underlining the mechanisms used to overcome these barriers. At present, although there are still many unanswered questions regarding CAR-T cell therapy, there is no doubt that it has the potential to become an important treatment option for urological malignancies.
Source: Journal for Immunotherapy of Cancer - Category: Cancer & Oncology Source Type: research
ConclusionsThese findings suggest that IDO expression is a mechanism of immune evasion used by prostate cancer and that future clinical trials using T-cell-based immune strategies might best include IDO inhibition.
Source: Cancer Immunology, Immunotherapy - Category: Cancer & Oncology Source Type: research
ConclusionsImmunotherapy with primary DC subsets induced functional antigen-specific T cells. The presence of functional antigen-specific T cells correlated with longer rPFS.Clinical trial identificationNCT02692976.Legal entity responsible for the studyJolanda de Vries and Winald Gerritsen.FundingThis work was supported by Stichting Afweer Tegen Kanker, Dr. Paul A.J. Speth Stichting and H2020 EU grant PROCROP (grant No 635122). Carl G. Figdor received ERC Adv Grant PATHFINDER (269019) and the NWO Spinoza grant. I. Jolanda M. de Vries received NWO-Vici grant (918.14.655).DisclosureAll authors have declared no conflicts of interest.
Source: Annals of Oncology - Category: Cancer & Oncology Source Type: research
AbstractBackgroundThere are currently no good indicators of which patients with cancer will respond or not to immunotherapy. Novel computational analysis of computed tomography scans (CT) (i.e. radiomics) provides information about the tumour-infiltrating CD8 and predict response to immunotherapy. We aim to validate in an external cohort the VHIO CT-radiomics signature and to develop a combined radiomics-clinical signature that predicts the response to immune checkpoint inhibitors in patients with advanced solid tumours.MethodsThe VHIO CT-radiomics signature was developed in a population of 115 consecutive patients treated...
Source: Annals of Oncology - Category: Cancer & Oncology Source Type: research
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