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Immune Checkpoint Inhibitor-Mediated Cancer Theranostics with Radiolabeled Anti-Granzyme B Peptide
Carolina de Aguiar Ferreira1, Pedram Heidari1, Bahar Ataeinia1
1Department of Radiology, Massachusetts General Hospital, Boston, MA 02114, USA.
Abstract:
Although immune checkpoint inhibitors (ICI) have revolutionized cancer management, patient response can be heterogeneous, and the development of ICI resistance is increasingly reported. Novel treatment strategies are necessary not only to expand the use of ICI to previously unresponsive tumor types but also to overcome resistance. Targeted radionuclide therapy may synergize well with ICIs since it can promote a pro-inflammatory tumor microenvironment. We investigated the use of a granzyme B targeted peptide (GZP) as a cancer theranostic agent, radiolabeled with 68Ga (68Ga-GZP) as a PET imaging agent and radiolabeled with 90Y (90Y-GZP) as a targeted radionuclide therapy agent for combinational therapy with ICI in murine models of colon cancer. Our results demonstrate that GZP increasingly accumulates in tumor tissue after ICI and that the combination of ICI with 90Y-GZP promotes a dose-dependent response, achieving curative response in some settings and increased overall survival.
Insights
Combining immune checkpoint inhibitors (ICI) with targeted radionuclide therapy using 90Y-labeled granzyme B peptide (90Y-GZP) shows promise. This combination enhances tumor inflammation and improves survival in colon cancer models, offering a new strategy against ICI resistance.
Area of Science:
- Oncology
- Nuclear Medicine
- Immunotherapy
Background:
- Immune checkpoint inhibitors (ICIs) have transformed cancer treatment but face challenges with patient response heterogeneity and resistance.
- Targeted radionuclide therapy (TRT) presents a potential synergistic approach with ICIs by modulating the tumor microenvironment.
- Developing novel theranostic agents is crucial for overcoming ICI resistance and expanding treatment efficacy.
Purpose of the Study:
- To evaluate the efficacy of a granzyme B targeted peptide (GZP) as a theranostic agent for PET imaging (68Ga-GZP) and targeted radionuclide therapy (90Y-GZP).
- To investigate the combination therapy of ICI with 90Y-GZP in murine colon cancer models.
- To assess the impact of this combination on tumor inflammation and therapeutic outcomes.
Main Methods:
- Development of a granzyme B targeted peptide (GZP) radiolabeled with Gallium-68 (68Ga) for PET imaging and Yttrium-90 (90Y) for therapy.
- Administration of GZP theranostic agents in combination with immune checkpoint inhibitors (ICIs) in murine colon cancer models.
- Assessment of GZP tumor accumulation post-ICI treatment and evaluation of dose-dependent therapeutic responses.
Main Results:
- Granzyme B targeted peptide (GZP) demonstrated increased accumulation in tumor tissues following ICI treatment.
- The combination of ICI with 90Y-GZP resulted in a dose-dependent therapeutic response.
- Curative responses and significantly increased overall survival were observed in some settings with the combination therapy.
Conclusions:
- The combination of immune checkpoint inhibitors (ICIs) with 90Y-GZP represents a promising strategy for enhancing anti-tumor immunity and overcoming ICI resistance.
- Granzyme B targeted peptide theranostics offer a novel approach for both imaging and treating cancers in conjunction with immunotherapy.
- This combinational therapy approach holds potential for improving patient outcomes in difficult-to-treat cancers.
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