Targeting Malignant Brain Tumors with Antibodies

Razpotnik, Rok; Novak, Neža; Šerbec, Vladka Čurin; Rajčević, Uroš

doi:10.3389/fimmu.2017.01181

Cited by 66 publications

(46 citation statements)

References 148 publications

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“…Glioblastoma multiforme (GBM) remains an incurable malignancy, with a median survival of ∼14 months from initial presentation (1). There are several issues with developing new effective GBM therapeutics; e.g., the blood brain barrier often prevents the full therapeutic dose of many drugs reaching a brain-localized tumor; the brain is also an immunologically privileged environment that results both in a lack of checkpoint immunotherapy efficacy but also in an environment that contains activated brain associated macrophages, the microglia, which promote the growth, invasion, and survival of GBM cells (2)(3)(4)(5)(6). In the specific instance of brain tumors, whether metastatic disease or GBMs, activated microglia have a symbiotic relationship with tumor cells, each producing growth factors and cytokines that reinforces the malignant phenotype of the tumor cells (7,8).…”

Section: Introductionmentioning

confidence: 99%

Fingolimod Augments Monomethylfumarate Killing of GBM Cells

et al. 2020

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Previously we demonstrated that the multiple sclerosis drug dimethyl fumarate (DMF) and its plasma breakdown product MMF could interact with chemotherapeutic agents to kill both GBM cells and activated microglia. The trial NCT02337426 demonstrated the safety of DMF in newly diagnosed GBM patients when combined with the standard of care Stupp protocol. We hypothesized that another multiple sclerosis drug, fingolimod (FTY720) would synergize with MMF to kill GBM cells. MMF and fingolimod interacted in a greater than additive fashion to kill PDX GBM isolates. MMF and fingolimod radiosensitized glioma cells and enhanced the lethality of temozolomide. Exposure to [MMF + fingolimod] activated an ATM-dependent toxic autophagy pathway, enhanced protective endoplasmic reticulum stress signaling, and inactivated protective PI3K, STAT, and YAP function. The drug combination reduced the expression of protective c-FLIP-s, MCL-1, BCL-XL, and in parallel caused cell-surface clustering of the death receptor CD95. Knock down of CD95 or over-expression of c-FLIP-s or BCL-XL suppressed killing. Fingolimod and MMF interacted in a greater than additive fashion to rapidly enhance reactive oxygen species production and over-expression of either thioredoxin or super-oxide dismutase two significantly reduced the drug-induced phosphorylation of ATM, autophagosome formation and [MMF + fingolimod] lethality. In contrast, the production of ROS was only marginally reduced in cells lacking ATM, CD95, or Beclin1. Collectively, our data demonstrate that the primary generation of ROS by [MMF + fingolimod] plays a key role, via the induction of toxic autophagy and death receptor signaling, in the killing of GBM cells.

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Section: Introductionmentioning

confidence: 99%

Fingolimod Augments Monomethylfumarate Killing of GBM Cells

et al. 2020

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“…At this regard, it would be intriguing to assess whether the conjugation of the PDGFRβ aptamer with a fragment smaller than the entire antibody, such as a Fab lacking the Fc region, preserves the aptamer's ability to deliver the antibody cargo through the BBB. In such a case the construct could exert therapeutic bene t on brain tumors or brain metastases of breast cancer, while avoiding the side effects previously seen with antibodies entering the brain [79], thanks to the lower dose of the antibody dispensed in a conjugated form.…”

Section: Discussionmentioning

confidence: 99%

Aptamer targeted therapy potentiates immune checkpoint blockade in triple-negative breast cancer

Camorani

Passariello

Agnello

et al. 2020

Preprint

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Background: Triple-negative breast cancer (TNBC) is a uniquely aggressive cancer with high rates of relapse due to resistance to chemotherapy. TNBC expresses higher levels of programmed cell death-ligand 1 (PD-L1) compared to other breast cancers, providing the rationale for the recently approved immunotherapy with anti-PD-L1 monoclonal antibodies (mAbs). A huge effort is dedicated to identify actionable biomarkers allowing for combination therapies with immune-checkpoint blockade. Platelet-derived growth factor receptor β (PDGFRβ) is highly expressed in invasive TNBC, both on tumor cells and tumor microenvironment. We recently proved that tumor growth and lung metastases are impaired in mouse models of human TNBC by a high efficacious PDGFRβ aptamer. Hence, we aimed at investigating the effectiveness of a novel combination treatment with the PDGFRβ aptamer and anti-PD-L1 mAbs in TNBC.Methods: The targeting ability of the anti-human PDGFRβ aptamer toward the murine receptor was verified by streptavidin-biotin assays and confocal microscopy, and its inhibitory function by transwell migration assays. The anti-proliferative effects of the PDGFRβ aptamer/anti-PD-L1 mAbs combination was assessed in human MDA-MB-231 and murine 4T1 TNBC cells, both grown as monolayer or co-cultured with lymphocytes. Tumor cell lysis and cytokines secretion by lymphocytes were analyzed by LDH quantification and ELISA, respectively. Orthotopic 4T1 xenografts in syngeneic mice were used for dissecting the effect of aptamer/mAb combination on tumor growth, metastasis and lymphocytes infiltration. Ex vivo analyses through immunohistochemistry, RT-qPCR and immunoblotting were performed. Results: We show that the PDGFRβ aptamer potentiates the anti-proliferative activity of anti-PD-L1 mAbs on both human and murine TNBC cells, according to its human/mouse cross-reactivity. Further, by binding to activated human and mouse lymphocytes, the aptamer enhances the anti-PD-L1 mAb-induced cytotoxicity of lymphocytes against tumor cells. Importantly, the aptamer heightens the antibody efficacy in inhibiting tumor growth and lung metastases in mice. It acts on both tumor cells, inhibiting Akt and ERK1/2 signaling pathways, and immune populations, increasing intratumoral CD8+T cells and reducing FOXP3+Treg cells. Conclusion: Co-treatment of PDGFRβ aptamer with anti-PD-L1 mAbs is a viable strategy, thus providing for the first an evidence of the efficacy of PDGFRβ/PD-L1 co-targeting combination therapy in TNBC.

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“…Smaller peptides less than 50 residues (which can cross cell membranes) have been shown to circumvent the bloodbrain barrier via receptor-mediated transcytosis. 150 Antihuman epidermal growth factor (HER2) antibodies conjugated with cell-penetrating peptides were able to cross the blood-brain barrier and prolong overall survival in BT-474 mice with brain tumors. 151 It has also been demonstrated that CAR T cells can bypass the blood-brain barrier, particularly when conjugated to cell-penetrating peptides less than 40 residues that can undergo transcytosis.…”

Section: -Neurotoxicitymentioning

confidence: 99%

<p>Immunotherapy for Medulloblastoma: Current Perspectives</p>

Kabir¹,

Kunos²,

Villanó³

et al. 2020

ITT

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Background: Immune-mediated therapies have transformed the treatment of metastatic melanoma and renal, bladder, and both small and non-small cell lung carcinomas. However, immunotherapy is yet to demonstrate dramatic results in brain tumors like medulloblastoma for a variety of reasons. Recent pre-clinical and early phase human trials provide encouraging results that may overcome the challenges of central nervous system (CNS) tumors, which include the intrinsic immunosuppressive properties of these cancers, a lack of antigen targets, antigenic variability, and the immune-restrictive site of the CNS. These studies highlight the growing potential of immunotherapy to treat patients with medulloblastoma, a disease that is a frequent cause of morbidity and mortality to children and young adults. Methods: We conducted an inclusive review of the PubMed-indexed literature and studies listed in clinicaltrials.gov using combinations of the keywords medulloblastoma, immunotherapy, CNS tumors, brain tumors, vaccines, oncolytic virus, natural killer, and CAR T to identify trials evaluating immunotherapy in preclinical experiments or in patients with medulloblastoma. Given a limited number of investigations using immunotherapy to treat patients with medulloblastoma, 24 studies were selected for final analysis and manuscript citation. Results: This review presents results from pre-clinical studies in medulloblastoma cell lines, animal models, and the limited trials involving human patients. Conclusion: From our review, we suggest that cancer vaccines, oncolytic viral therapy, natural killer cells, and CAR T therapy hold promise against the innate immunosuppressive properties of medulloblastoma in order to prolong survival. There is an unmet need for immunotherapy regimens that target overexpressed antigens in medulloblastoma tumors. We advocate for more combination treatment clinical trials using conventional surgical and radiochemotherapy approaches in the near-term clinical development.

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Targeting Malignant Brain Tumors with Antibodies

Cited by 66 publications

References 148 publications

Fingolimod Augments Monomethylfumarate Killing of GBM Cells

Fingolimod Augments Monomethylfumarate Killing of GBM Cells

Aptamer targeted therapy potentiates immune checkpoint blockade in triple-negative breast cancer

<p>Immunotherapy for Medulloblastoma: Current Perspectives</p>

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