PARP Targeted Alpha-Particle Therapy Enhances Response to PD-1 Immune-Checkpoint Blockade in a Syngeneic Mouse Model of Glioblastoma

Dabagian, Hannah; Taghvaee, Tahereh; Martorano, Paul; Martı́nez, Daniel; Samanta, Minu; Watkins, Carolyn M; Chai, Richard; Mansfield, Adam; Graham, Thomas J. A.; Maris, John M.; Pryma, Daniel A.; Mach, Robert H.; Makvandi, Mehran

doi:10.1021/acsptsci.0c00206

Cited by 27 publications

(28 citation statements)

References 17 publications

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“…In addition to inhibiting PARP, it is also feasible to inhibit other tumor escape pathways. One such method is the blocking of the PD-1 immune-checkpoint, which is normally used by the tumor cells to evade the tumor surveillance mechanism of the body [ 100 ]. In order to enhance the immune-checkpoint blockade, the α-emitter [ 211 At]MM4 was tested in mono- and combination therapy on mice bearing GL26 glioblastoma tumor cells ( Figure 5 D) [ 100 ].…”

Section: Current Status Of Parp-targeted Radiotherapymentioning

confidence: 99%

“…One such method is the blocking of the PD-1 immune-checkpoint, which is normally used by the tumor cells to evade the tumor surveillance mechanism of the body [ 100 ]. In order to enhance the immune-checkpoint blockade, the α-emitter [ 211 At]MM4 was tested in mono- and combination therapy on mice bearing GL26 glioblastoma tumor cells ( Figure 5 D) [ 100 ]. Hereby, average tumor response was the greatest (100%) for the combination treatment compared to the mono treatments with either 200 µg anti-PD-1 (83.6%) or 36 MBq/kg [ 211 At]MM4 (58.2 %) [ 100 ].…”

Section: Current Status Of Parp-targeted Radiotherapymentioning

confidence: 99%

“…In order to enhance the immune-checkpoint blockade, the α-emitter [ 211 At]MM4 was tested in mono- and combination therapy on mice bearing GL26 glioblastoma tumor cells ( Figure 5 D) [ 100 ]. Hereby, average tumor response was the greatest (100%) for the combination treatment compared to the mono treatments with either 200 µg anti-PD-1 (83.6%) or 36 MBq/kg [ 211 At]MM4 (58.2 %) [ 100 ]. Similar results were observed for the average progression free intervals (65, 36.4 and 23.2 days, respectively) and for the percentages of disease-free mice at the end of the study (100%, 60% and 0%, respectively), suggesting [ 211 At]MM4 to be a potential candidate for combinatorial therapy of glioblastoma with PD-1 immune-checkpoint blockade [ 100 ].…”

Section: Current Status Of Parp-targeted Radiotherapymentioning

confidence: 99%

“…( D ) Treatment of syngeneic glioblastoma (GL26) with a single i.v. dose of ~720 kBq [ 211 At]MM4 and in combination with anti-PD-1 checkpoint inhibitor [ 100 ] Stars indicate signifant differences (Anova, *, p < 0.05). Copyright notice: (A) Reprinted with permission from [ 96 ].…”

Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

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DNA Repair Enzyme Poly(ADP-Ribose) Polymerase 1/2 (PARP1/2)-Targeted Nuclear Imaging and Radiotherapy

Nguyen

Pacelli

Nader

et al. 2022

Cancers

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Since it was discovered that many tumor types are vulnerable to inhibition of the DNA repair machinery, research towards efficient and selective inhibitors has accelerated. Amongst other enzymes, poly(ADP-ribose)-polymerase 1 (PARP1) was identified as a key player in this process, which resulted in the development of selective PARP inhibitors (PARPi) as anti-cancer drugs. Most small molecule PARPi’s exhibit high affinity for both PARP1 and PARP2. PARPi are under clinical investigation for mono- and combination therapy in several cancer types and five PARPi are now clinically approved. In parallel, radiolabeled PARPi have emerged for non-invasive imaging of PARP1 expression. PARP imaging agents have been suggested as companion diagnostics, patient selection, and treatment monitoring tools to improve the outcome of PARPi therapy, but also as stand-alone diagnostics. We give a comprehensive overview over the preclinical development of PARP imaging agents, which are mostly based on the PARPi olaparib, rucaparib, and recently also talazoparib. We also report on the current status of clinical translation, which involves a growing number of early phase trials. Additionally, this work provides an insight into promising approaches of PARP-targeted radiotherapy based on Auger and α-emitting isotopes. Furthermore, the review covers synthetic strategies for PARP-targeted imaging and therapy agents that are compatible with large scale production and clinical translation.

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Section: Current Status Of Parp-targeted Radiotherapymentioning

confidence: 99%

Section: Current Status Of Parp-targeted Radiotherapymentioning

confidence: 99%

Section: Current Status Of Parp-targeted Radiotherapymentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

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DNA Repair Enzyme Poly(ADP-Ribose) Polymerase 1/2 (PARP1/2)-Targeted Nuclear Imaging and Radiotherapy

Nguyen

Pacelli

Nader

et al. 2022

Cancers

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Alpha‐emitters and targeted alpha therapy in cancer treatment

Zhang,

Qin,

Yang

et al. 2023

iRADIOLOGY

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Alpha emitters are radionuclides with good pharmacological characteristics for the treatment of cancer because they decay by emitting high linear energy transfer particles. Recent advancements in isotope production and purification and the generation of novel techniques for optimum targeting have led to the development of targeted alpha therapy (TAT). The great cytotoxic potential of α‐particle emissions combined with monoclonal antibodies, peptides, small compounds, or nanoparticles has led to investigations of TAT in the pre‐clinical context and more recently, in oncology clinical trials. Numerous studies have shown that TAT is effective both in vitro and in vivo. The first α‐emitter to obtain FDA approval for the treatment of prostate cancer with metastatic bone lesions was radium‐223 dichloride. Many clinical trials are being conducted to evaluate the efficiency and safety of several radionuclides in cancer treatment, including radium‐223, astatine‐211, actinium‐225, bismuth‐213, lead‐212, and thorium‐227. This review provides an overview of the therapeutic use of these radionuclides and a summary of the studies that lay the groundwork for future clinical advancement.

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New insights into immune cells in cancer immunotherapy: from epigenetic modification, metabolic modulation to cell communication

Qin,

Xie,

Wang

et al. 2024

MedComm

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Cancer is one of the leading causes of death worldwide, and more effective ways of attacking cancer are being sought. Cancer immunotherapy is a new and effective therapeutic method after surgery, radiotherapy, chemotherapy, and targeted therapy. Cancer immunotherapy aims to kill tumor cells by stimulating or rebuilding the body's immune system, with specific efficiency and high safety. However, only few tumor patients respond to immunotherapy and due to the complex and variable characters of cancer immune escape, the behavior and regulatory mechanisms of immune cells need to be deeply explored from more dimensions. Epigenetic modifications, metabolic modulation, and cell‐to‐cell communication are key factors in immune cell adaptation and response to the complex tumor microenvironment. They collectively determine the state and function of immune cells through modulating gene expression, changing in energy and nutrient demands. In addition, immune cells engage in complex communication networks with other immune components, which are mediated by exosomes, cytokines, and chemokines, and are pivotal in shaping the tumor progression and therapeutic response. Understanding the interactions and combined effects of such multidimensions mechanisms in immune cell modulation is important for revealing the mechanisms of immunotherapy failure and developing new therapeutic targets and strategies.

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PARP Targeted Alpha-Particle Therapy Enhances Response to PD-1 Immune-Checkpoint Blockade in a Syngeneic Mouse Model of Glioblastoma

Cited by 27 publications

References 17 publications

DNA Repair Enzyme Poly(ADP-Ribose) Polymerase 1/2 (PARP1/2)-Targeted Nuclear Imaging and Radiotherapy

DNA Repair Enzyme Poly(ADP-Ribose) Polymerase 1/2 (PARP1/2)-Targeted Nuclear Imaging and Radiotherapy

Alpha‐emitters and targeted alpha therapy in cancer treatment

New insights into immune cells in cancer immunotherapy: from epigenetic modification, metabolic modulation to cell communication

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