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Journal of Nuclear Medicine

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OtherBasic Science (Animal or Phantoms)

Addition of Peptide Receptor Radiotherapy to Immune Checkpoint Inhibition Therapy Improves Outcomes in Neuroendocrine Tumors

Shadi A. Esfahani, Carolina De Aguiar Ferreira, Priska Summer, Umar Mahmood and Pedram Heidari
Journal of Nuclear Medicine April 2023, jnumed.123.265391; DOI: https://doi.org/10.2967/jnumed.123.265391
Shadi A. Esfahani
Athinoula A. Martinos Center for Biomedical Imaging, Radiology dept, Massachusetts General Hospital, United States
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Carolina De Aguiar Ferreira
Athinoula A. Martinos Center for Biomedical Imaging, Radiology dept, Massachusetts General Hospital, United States
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Priska Summer
Athinoula A. Martinos Center for Biomedical Imaging, Radiology dept, Massachusetts General Hospital, United States
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Umar Mahmood
Athinoula A. Martinos Center for Biomedical Imaging, Radiology dept, Massachusetts General Hospital, United States
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Pedram Heidari
Athinoula A. Martinos Center for Biomedical Imaging, Radiology dept, Massachusetts General Hospital, United States
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Abstract

Neuroendocrine tumors (NETs) are often diagnosed in advanced stages. Despite the advances in treatment approaches, including somatostatin analogs and peptide receptor radionuclide therapy (PRRT), these patients have no curative treatment option. Moreover, immunotherapy often yields modest results in NETs. We investigated whether combining PRRT using [177Lu]DOTATATE and immune checkpoint inhibition therapy improves treatment response in NETs. Methods: A gastroenteropancreatic NET model was generated by subcutaneous implantation of human QGP-1 cells in immunereconstituted NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice engrafted with human peripheral blood mononuclear cells (n = 96). Mice were randomly assigned to receive pembrolizumab (anti-PD1), [177Lu]DOTATATE (PRRT), simultaneous anti-PD1 and PRRT (S-PRRT), anti-PD1 on day 0 followed by PRRT on day 3 (delayed PRRT [D-PRRT]), PRRT on day 0 followed by anti-PD1 (early PRRT [E-PRRT]), or vehicle as control (n = 12/group). Human granzyme-B–specific [68Ga]NOTAhGZP PET/MRI was performed before and 6 d after treatment initiation, as an indicator of T-cell activation. Response to treatment was based on tumor growth over 21 d and on histologic analyses of extracted tissues on flow cytometry for T cells, hematoxylin and eosin staining, and immunohistochemical staining. Results: [68Ga]NOTAhGZP PET/MRI showed significantly increased uptake in tumors treated with E-PRRT, S-PRRT, and anti-PD1 on day 6 compared with baseline (SUVmax: 3.36 ± 0.42 vs. 0.73 ± 0.23; 2.36 ± 0.45 vs. 0.76 ± 0.30; 2.20 ± 0.20 vs. 0.72 ± 0.28, respectively; P < 0.001), whereas no significant change was seen in PET parameters in the D-PRRT, PRRT, or vehicle groups (P > 0.05). Ex vivo analyses confirmed the PET results showing the highest granzyme-B levels and T cells (specifically CD8-positive effector T cells) in the E-PRRT group, followed by the S-PRRT and anti-PD1 groups. Tumor growth follow-up showed the most significant tumor size reduction in the E-PRRT group (baseline to day 21, 205.00 ± 30.70 mm3 vs. 78.00 ± 11.75 mm3; P > 0.0074). Tumors showed less growth reduction in the PRRT, D-PRRT, and S-PRRT groups than in the E-PRRT group (P < 0.0001). The vehicle- and anti-PD-1–treated tumors showed continued growth. Conclusion: Combination of PRRT and anti-PD1 shows the most robust inflammatory response to NETs and a better overall outcome than immune checkpoint inhibition or PRRT alone. The most effective regimen is PRRT preceding anti-PD1 administration by several days.

  • Animal Imaging
  • Molecular Imaging
  • Neuroendocrine
  • PET
  • Radionuclide Therapy
  • Radiopharmaceuticals
  • Granzyme B
  • Immunotherapy
  • Neuroendocrine Tumor
  • PET
  • Peptide Receptor Radiotherapy
  • Copyright © 2023 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
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Journal of Nuclear Medicine: 66 (5)
Journal of Nuclear Medicine
Vol. 66, Issue 5
May 1, 2025
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Addition of Peptide Receptor Radiotherapy to Immune Checkpoint Inhibition Therapy Improves Outcomes in Neuroendocrine Tumors
Shadi A. Esfahani, Carolina De Aguiar Ferreira, Priska Summer, Umar Mahmood, Pedram Heidari
Journal of Nuclear Medicine Apr 2023, jnumed.123.265391; DOI: 10.2967/jnumed.123.265391

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Addition of Peptide Receptor Radiotherapy to Immune Checkpoint Inhibition Therapy Improves Outcomes in Neuroendocrine Tumors
Shadi A. Esfahani, Carolina De Aguiar Ferreira, Priska Summer, Umar Mahmood, Pedram Heidari
Journal of Nuclear Medicine Apr 2023, jnumed.123.265391; DOI: 10.2967/jnumed.123.265391
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Keywords

  • Animal Imaging
  • Molecular imaging
  • neuroendocrine
  • PET
  • radionuclide therapy
  • radiopharmaceuticals
  • granzyme B
  • immunotherapy
  • neuroendocrine tumor
  • peptide receptor radiotherapy
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