EJNMMI: A strong combination of low-dose radionuclides and PD-L1/CTLA-4 dual targeted immunosuppressant KN046 improves immunotherapy response rate

Recently, the latest result of Professor Song Shaoli, director of the Department of Nuclear Medicine of Fudan University Cancer Hospital, "Enhanced Antitumor Immune Responses via a New Agent [131I]-labeled Dual-target Immunosuppressant" was selected by the European Journal of Nuclear Medicine and Molecular Imaging, EJNMMI).

This study innovatively explores the value of
low-dose radionuclide ¹³¹I sensitizing PD-L1/CTLA-4 dual-targeted immunosuppressants in anti-tumor immune responses.

Since the entry into the clinic of immune checkpoint inhibitor drugs represented by PD-1/PD-L1 and CTLA-4, they have brought great changes to tumor treatment, especially the combination therapy of immune checkpoint inhibitors has shown encouraging effects
in the treatment of many malignant tumors.
However, at the same time, immunocombination therapy can significantly increase the toxicity of treatment and its tolerance to drugs, thus limiting its further application
.
As a PD-L1/CTLA-4 Fc fusion bispecific antibody, KN046 has significant advantages in anti-tumor efficacy, but it is still limited by the limitations of the narrow beneficiary population and low objective immune response rate, so how to improve the response rate in immunotherapy is a key problem
to be solved in the development of immunotherapy.

Studies have reported that low-dose ionizing radiation stimulation can be used for immune enhancement
by inducing the release of tumor immunogenicity-associated antigens.
¹³¹ I is the most commonly used therapeutic nuclide that decays and releases 99% of β rays and 1% of γ rays
.
β rays are used for treatment, while γ rays are used for SPECT/CT imaging
.
Therefore, we constructed 131 I-KN046 using 131 I and KN046, and the results showed that 131 I-KN046 had high affinity and specificity for PD-L1/CTLA-4 immune dual targets, which could accurately screen the subpopulation benefiting KN046 antibody immunotherapy, and ¹³¹I-KN046 had a high tumor retention rate.
Showed significant anti-tumor effect
.
More importantly, due to the high targeting of KN046, the enrichment of low-dose ¹³¹I at the tumor site can upregulate the expression of immunogenicity-related antigens in the tumor microenvironment, increase the activation degree of T cells and the number of invasive T cells in the tumor, thereby significantly improving the anti-tumor efficacy
of KN046.

This study demonstrates that the combination of low-dose ¹³¹I and KN046 has a synergistic effect on anti-tumor immune response, providing an optimized strategy
for improving anti-tumor immunotherapy.
This golden combination will expand the application field of tumor nuclear medicine in immunotherapy, and the use of low-dose radionuclide sensitization immunotherapy is expected to become a new direction of anti-tumor immunotherapy, with broad application prospects
.
Dr.
Jiang Chunjuan from Fudan University Cancer Hospital is the first author of the paper, and Professor Song Shaoli from Fudan University Cancer Hospital is the corresponding author
.

It is reported that with the continuous strengthening of the talent team of the Department of Nuclear Medicine in the Cancer Hospital of Fudan University, the competitiveness of young people in the department has been continuously improved, and a group of outstanding young medical talents who have won the excellent technical leaders of Shanghai, the "Pujiang Talent Program" of Shanghai, the "New Star of the Medical Garden" of Shanghai, the "Yangfan Program" and the "Young Eagle Program" of Shanghai have stood out
。 The department has won 12 national-level projects and 12 provincial-level projects, and the cumulative scientific research funds have exceeded 10 million yuan; He has published more than 60 SCI papers, and many research results have been published in Advanced Science, Journal of Nuclear Medicine, European Journal of Nuclear Medicine and Molecular Imaging, Theranostics, Clinical Cancer Research, ACS Nano, and Journal of Hematology and Oncology and other international authoritative journals
.