Giving peptide receptor radionuclide therapy (PRRT) before the immunotherapy drug pembrolizumab produced the strongest anti-tumor immune response and most significant tumor shrinkage in a neuroendocrine tumor mouse model.
62% Tumor ReductionPRRT followed by pembrolizumab shrank neuroendocrine tumors from 205 to 78 mm³ in 21 days — with the highest T-cell activation of any treatment sequence
What the researchers found
In 96 humanized mice with gastroenteropancreatic NETs, the early PRRT group (PRRT on day 0 followed by anti-PD1 on day 3) showed the most significant tumor reduction: 205 mm³ to 78 mm³ over 21 days (p=0.0074). PET/MRI imaging confirmed the strongest T-cell activation in this group, with SUVmax increasing from 0.73 to 3.36 (p<0.05) for granzyme-B uptake — indicating robust cytotoxic T-cell activation. The simultaneous and anti-PD1-first groups showed less tumor growth reduction, and PRRT or anti-PD1 alone were least effective.
Why it matters
Neuroendocrine tumors have limited treatment options and often resist immunotherapy. This study reveals that PRRT can 'prime' the immune system — the radiation delivered by the peptide carrier triggers an inflammatory response that makes immunotherapy much more effective. The finding that sequence matters (PRRT first works best) provides a practical framework for designing combination clinical trials.
How the study worked
Researchers implanted human QGP-1 neuroendocrine tumor cells into immunodeficient mice engrafted with human immune cells (96 mice total, 12 per group). Six groups received: pembrolizumab alone, [177Lu]DOTATATE PRRT alone, simultaneous treatment, delayed PRRT (anti-PD1 first), early PRRT (PRRT first then anti-PD1), or vehicle control. Granzyme-B-specific PET/MRI tracked T-cell activation before and 6 days after treatment. Response was measured by tumor growth over 21 days and histological analysis.
What this study cannot tell us
This is a preclinical study using humanized mice, which do not fully replicate the human immune system or tumor microenvironment. The human immune reconstitution model has inherent limitations, including potential graft-versus-host effects. The 21-day follow-up is short and doesn't capture long-term outcomes or potential toxicity. The gastroenteropancreatic NET model may not represent all NET subtypes.
How to read the evidence
This is a well-designed preclinical study with appropriate controls, multiple treatment arms, and both imaging and histological validation. However, humanized mouse models have significant limitations compared to human immune systems, and clinical trials are needed to confirm these findings.
When this study was published
Published in 2023, this study provides timely preclinical rationale for ongoing and planned clinical trials combining PRRT with immune checkpoint inhibitors for neuroendocrine tumors.
The bigger picture
PRRT using [177Lu]DOTATATE is already FDA-approved for neuroendocrine tumors, and immunotherapy with pembrolizumab is widely used in oncology. This study provides preclinical evidence that combining these two approved treatment modalities — in the right sequence — could dramatically improve outcomes for NET patients. The concept of using radiation to prime the immune response is gaining traction across oncology and could extend to other tumor types.
Questions still open
- Will the PRRT-before-immunotherapy sequence show the same superiority in human clinical trials?
- What is the optimal timing gap between PRRT and immunotherapy initiation — is 3 days ideal?
- Could this combination approach extend to other somatostatin receptor-expressing tumor types beyond NETs?
Common questions
What is peptide receptor radionuclide therapy (PRRT)?
Why does giving PRRT before immunotherapy work better than the reverse?
Read the original research
Addition of Peptide Receptor Radiotherapy to Immune Checkpoint Inhibition Therapy Improves Outcomes in Neuroendocrine Tumors.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 64(7), 1056-1061
Citation
Esfahani, Shadi A; De Aguiar Ferreira, Carolina; Summer, Priska; Mahmood, Umar; Heidari, Pedram. (2023). Addition of Peptide Receptor Radiotherapy to Immune Checkpoint Inhibition Therapy Improves Outcomes in Neuroendocrine Tumors.. Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 64(7), 1056-1061. https://doi.org/10.2967/jnumed.123.265391