Remodeling the Vascular Microenvironment of Glioblastoma with α-Particles

Behling, Katja; Maguire, William F.; Gialleonardo, Valentina Di; Heeb, Lukas E. M.; Hassan, Iman; Veach, Darren R.; Keshari, Kayvan R.; Gutin, Philip H.; Scheinberg, David A.; McDevitt, Michael R.

doi:10.2967/jnumed.116.173559

Cited by 27 publications

(28 citation statements)

References 40 publications

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“…These advantageous properties were explored for the treatment of acute myeloid leukemia in phase I/II clinical trials with a CD33-targeted 225 Ac-radioimmunoconjugate (HuM195; Lintuzumab), studies that underscored the potential of 225 Ac-radioimmunotherapy (RIT) for the treatment of systemic disease (4)(5)(6). In addition, recent studies highlighted the potential of 225 Ac-RIT for the treatment of bulky tumors such as glioblastoma by targeting the vascular endothelium of the tumor (7,8). The radionuclide has also been conjugated to targeting vectors with more rapid pharmacokinetic profiles, including small-molecule inhibitors of prostate-specific membrane antigen (PSMA).…”

Section: Introductionmentioning

confidence: 99%

Leveraging Bioorthogonal Click Chemistry to Improve 225Ac-Radioimmunotherapy of Pancreatic Ductal Adenocarcinoma

Poty

Carter

Mandleywala

et al. 2019

Clinical Cancer Research

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Purpose: Interest in targeted alpha-therapy has surged due to a-particles' high cytotoxicity. However, the widespread clinical use of this approach could be limited by on-/off-target toxicities. Here, we investigated the inverse electron-demand Diels-Alder ligation between an 225 Ac-labeled tetrazine radioligand and a trans-cyclooctene-bearing anti-CA19.9 antibody (5B1) for pretargeted a-radioimmunotherapy (PRIT) of pancreatic ductal adenocarcinoma (PDAC). This alternative strategy is expected to reduce nonspecific toxicities as compared with conventional radioimmunotherapy (RIT).Experimental Design: A side-by-side comparison of 225 Ac-PRIT and conventional RIT using a directly 225 Ac-radiolabeled immunoconjugate evaluates the therapeutic efficacy and toxicity of both methodologies in PDAC murine models.Results: A comparative biodistribution study of the PRIT versus RIT methodology underscored the improved pharmacokinetic properties (e.g., prolonged tumor uptake and increased tumor-to-tissue ratios) of the PRIT approach. Cerenkov imaging coupled to PRIT confirmed the in vivo biodistribution of 225 Ac-radioimmunoconjugate but-importantly-further allowed for the ex vivo monitoring of 225 Ac's radioactive daughters' redistribution. Human dosimetry was extrapolated from the mouse biodistribution and confirms the clinical translatability of 225 Ac-PRIT. Furthermore, longitudinal therapy studies performed in subcutaneous and orthotopic PDAC models confirm the therapeutic efficacy of 225 Ac-PRIT with the observation of prolonged median survival compared with control cohorts. Finally, a comparison with conventional RIT highlighted the potential of 225 Ac-PRIT to reduce hematotoxicity while maintaining therapeutic effectiveness.Conclusions: The ability of 225 Ac-PRIT to deliver a radiotherapeutic payload while simultaneously reducing the off-target toxicity normally associated with RIT suggests that the clinical translation of this approach will have a profound impact on PDAC therapy.

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Section: Introductionmentioning

confidence: 99%

Leveraging Bioorthogonal Click Chemistry to Improve 225Ac-Radioimmunotherapy of Pancreatic Ductal Adenocarcinoma

Poty

Carter

Mandleywala

et al. 2019

Clinical Cancer Research

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“…However, the cancer cells and TME may respond favorably to pharmacologic pressure applied from the targeted a particle therapy and a redirected host immune system. 21,23,27 We show that a novel a particle emitting C¢ dot that recognizes melanoma in vivo and delivers cytotoxic radiotherapy to disease also stimulates the infiltration and activation of several critical immune cell types. This information will be used to augment primary a therapy and potentially add durable immunological responses to the cytotoxic radiation event.…”

Section: Discussionmentioning

confidence: 92%

“…[17][18][19] High linear energy transfer a particles are lethal to cancer cells as a consequence of ineffective double-strand DNA repair. 20,21 Moreover, in internalizing systems, such as aMSH-PEG-Cy5-C¢ dot and Lintuzumab, each 225 Ac decay produces several daughters generating three additional a particles able to contribute to cytotoxicity. 13 Malignant melanoma is diagnosed in *90,000 individuals in the United States per year and is the most lethal form of skin cancer.…”

Section: Introductionmentioning

confidence: 99%

A Genomic Profile of Local Immunity in the Melanoma Microenvironment Following Treatment with α Particle-Emitting Ultrasmall Silica Nanoparticles

Urbanska

Khanin

Alidori

et al. 2020

Cancer Biotherapy and Radiopharmaceuticals

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An a particle-emitting nanodrug that is a potent and specific antitumor agent and also prompts significant remodeling of local immunity in the tumor microenvironment (TME) has been developed and may impact the treatment of melanoma. Biocompatible ultrasmall fluorescent core-shell silica nanoparticles (C¢ dots, diameter *6.0 nm) have been engineered to target the melanocortin-1 receptor expressed on melanoma through a melanocyte-stimulating hormone peptides attached to the C¢ dot surface. Actinium-225 is also bound to the nanoparticle to deliver a densely ionizing dose of high-energy a particles to cancer. Nanodrug pharmacokinetic properties are optimal for targeted radionuclide therapy as they exhibit rapid blood clearance, tumor-specific accumulation, minimal off-target localization, and renal elimination. Potent and specific tumor control, arising from the a particles, was observed in a syngeneic animal model of melanoma. Surprisingly, the C¢ dot component of this drug initiates a favorable pseudopathogenic response in the TME generating distinct changes in the fractions of naive and activated CD8 T cells, Th1 and regulatory T cells, immature dendritic cells, monocytes, MF and M1 macrophages, and activated natural killer cells. Concomitant upregulation of the inflammatory cytokine genome and adaptive immune pathways each describes a macrophage-initiated pseudoresponse to a viral-shaped pathogen. This study suggests that therapeutic a-particle irradiation of melanoma using ultrasmall functionalized core-shell silica nanoparticles potently kills tumor cells, and at the same time initiates a distinct immune response in the TME.

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“…2). Because of the particle range, this cross-fire effect is thought to be higher with b-emitters, but recent studies showing a-particles to have a significant therapeutic effect on large tumors question this concept (6)(7)(8). In addition to direct effects, indirect radiation effects have been observed.…”

Section: α-Emitting Isotope Radiochemistrymentioning

confidence: 98%

α-Emitters for Radiotherapy: From Basic Radiochemistry to Clinical Studies—Part 1

et al. 2018

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Learning Objectives: On successful completion of this activity, participants should be able to (1) cite α-emitter families available for therapeutic use and understand their current production limit; (2) consider radiation safety concerns when handling α-emitters; and (3) overcome radiolabeling and daughter redistribution hurdles with the approaches described in this educational review. CME Credit: SNMMI is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing education for physicians. SNMMI designates each JNM continuing education article for a maximum of 2.0 AMA PRA Category 1 Credits. Physicians should claim only credit commensurate with the extent of their participation in the activity. For CE credit, SAM, and other credit types, participants can access this activity through the SNMMI website (http://www.snmmilearningcenter.org) through June 2021.With a short particle range and high linear energy transfer, α-emitting radionuclides demonstrate high cell-killing efficiencies. Even with the existence of numerous radionuclides that decay by α-particle emission, only a few of these can reasonably be exploited for therapeutic purposes. Factors including radioisotope availability and physical characteristics (e.g., half-life) can limit their widespread dissemination. The first part of this review will explore the diversity, basic radiochemistry, restrictions, and hurdles of α-emitters. Radi onuclide strategies for curative therapy, disease control, or palliation are positioned to constitute a major portion of nuclear medicine. The range of available therapeutic radioisotopes, including a, b, or Auger electron emission, has considerably expanded over the last century (1). Matching the particle decay pathway, effective range, and relative biological effectiveness to tumor mass, size, radiosensitivity, and heterogeneity is the primary consideration for maximizing therapeutic efficacy. b-emitting radioisotopes have the longest particle pathlength (#12 mm) and lowest linear energy transfer (LET) (;0.2 keV/mm), supporting their effectiveness in medium to large tumors (Fig. 1). Although the long b-particle range is advantageous in evenly distributing radiation dose in heterogeneous tumors, it can also result in the irradiation of healthy tissue surrounding the tumor site. Conversely, Auger electrons have high LET (4-26 keV/mm) but a limited pathlength of 2-500 nm that restricts their efficacy to single cells, thus requiring the radionuclide to cross the cell membrane and reach the nucleus. Finally, a-particles have a moderate pathlength (50-100 mm) and high LET (80 keV/mm) that render them especially suitable for small neoplasms or micrometastases. A recent clinical study highlighted the ability of a-radiotherapy to overcome treatment resistance to b-particle therapy, prompting a paradigm shift in the approach toward radionuclide therapy (2).For optimized therapeutic efficacy, the a-cytotoxic payload is expected to accumulate selectively in diseased tissue and deliver a suf...

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Remodeling the Vascular Microenvironment of Glioblastoma with α-Particles

Cited by 27 publications

References 40 publications

Leveraging Bioorthogonal Click Chemistry to Improve 225Ac-Radioimmunotherapy of Pancreatic Ductal Adenocarcinoma

Leveraging Bioorthogonal Click Chemistry to Improve 225Ac-Radioimmunotherapy of Pancreatic Ductal Adenocarcinoma

A Genomic Profile of Local Immunity in the Melanoma Microenvironment Following Treatment with α Particle-Emitting Ultrasmall Silica Nanoparticles

α-Emitters for Radiotherapy: From Basic Radiochemistry to Clinical Studies—Part 1

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