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Precision screening tool for immunotherapy: Molecular immunoPET imaging technology
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Screening tool for immunotherapy: Molecular immunoPET imaging technology. Immunotherapy can be said to be one of the most exciting areas of cancer research.
In the past decade, immunotherapy has brought revolutionary changes to cancer treatment.
However, still only some cancer patients respond to immunotherapy, and even patients in remission may develop resistance after a period of time.
Therefore, researchers are making continuous efforts to screen the most suitable patients for immunotherapy and to expand the scope of immunotherapy.
PD-L1 expression is recommended for many indications currently approved by the FDA. The heterogeneity of tumor PD-L1 expression may limit the predictive power of current detection methods¹.
Currently, only immunohistochemistry is available for the detection of PD-L1 antigen clinically approved. The latest molecular immuno-PET imaging technology can help find the most suitable patients for immunotherapy.
Deficiencies of traditional immunohistochemistry
Immunohistochemistry requires invasive methods (such as puncture, surgical resection) to obtain tumor tissue, but many patients cannot obtain tumor tissue for various reasons, which is not conducive to screening suitable medication patients.
The difference in the expression of PD-L1 in tissue space and time. For example, due to metastasis and other reasons, PD-L1 positive tumors may appear in multiple tissues of the patient, and there are differences in expression in different tissues.
The same tumor is being treated There will be differences in PD-L1 expression before and after treatment.
Invasive detection methods are difficult to collect materials from multiple locations throughout the body and then perform pathological detection, and the expression differences of different tissues require accurate quantitative methods.
McLaughlin. JAMA Onc. 2016:2;46.²
According to statistics, the interchange analysis of various detection methods and different positive judgment standards will also cause 37% of patients to be “misclassified” in PD-L1 status.
In addition, studies have shown that among patients with negative PD-L1 expression under the immunohistochemical test standards, about 10% of patients still have a good response to anti-PD-1/PD-L1 treatment.
Therefore, a non-invasive, highly sensitive, high-resolution, and standardized PD-1/PD-L1 systemic examination method is needed clinically to screen suitable patients for medication.
Molecular immunoPET imaging
In a narrow sense, Molecular ImmunoPET (ImmunoPET) is a tool that uses antibody molecules as imaging agents. The PET tag emits positrons.
When the positrons collide with the electrons in the body, a pair of gamma-ray particles will be generated, and they will leave each other at high speed in opposite directions.
As long as the pair of particles are detected at the same time, the position and abundance of the target in the body can be displayed.
PET imaging can quantitatively and non-invasively detect the pharmacokinetics of radiopharmaceuticals in vivo, with high sensitivity and high spatial resolution, so it can play an important role in tumor immune imaging.
Molecular immunoPET has obvious advantages over traditional immunohistochemistry.
Clinical study of PD-L1 molecular immuno-PET imaging
At present, most clinical immuno-PET imaging studies use ⁸⁹Zr-labeled monoclonal antibodies, which combine the sensitivity of PET with the specificity of antibodies, making whole-body PET imaging sensitive and quantitative.
The research team at the University of Groningen in the Netherlands used ⁸⁹Zr-labeled atezolizumab to predict the response of patients to PD-L1 antigen, and performed PD-L1 PET imaging on 22 patients with locally advanced or metastatic bladder cancer, non-small cell lung cancer, or triple-negative breast cancer Clinical research.
The results show that the development of PD-L1 expression before treatment with PD-L1 inhibitors can better predict the clinical response of patients to PD-L1 inhibitors, and its correlation is significantly higher than that of biomarkers based on immunohistochemistry or RNA sequencing ⁵.
Compared with immunohistochemistry, molecular imaging has the ability to predict curative effect
Clinical study of CD8 molecular immunoPET imaging
Molecular immunoPET imaging is an open technology. In addition to being used for PD-L1, it can also be extended to more immunotherapy fields.
The visualization of tumor-infiltrating lymphocytes is another research hotspot of molecular immunoPET imaging.
Almost all current cancer immunotherapies are aimed at increasing the presence and activity of cytotoxic CD8+ T cells. Therefore, accurate tracking and quantification of CD8+ T cells in patients helps researchers to capture the immune response in patients, so as to more effectively detect drugs. Efficacy.
ImaginAb, its mini-antibody 89Zr-Df-IAB22M2C for CD8 molecular immunoPET imaging, has completed a clinical phase 1 dose escalation study, determined its safety, effective dose and optimal PET imaging protocol, and proved that molecular immuno PET The concept of imaging technology as a clinical tool for detecting and imaging CD8 T cells in patients.
Cooperated with many major international tumor immunotherapy companies including Eli Lilly, Merck, Roche, AZ, Pfizer and Takeda, and carried out a number of evaluations of the utility and value of CD8 molecular immunoPET imaging technology in the development of immuno-oncology drugs the study.
Selection of molecular immunological PET imaging probes
The ideal molecular immuno PET imaging agent should provide high uptake rate and low background signal in a short time.
Molecular immuno-PET uses antibodies to recognize target cells, but it is not easy to design immuno-PET imaging probes.
Factors such as the choice of radiotracer, antibody design, and imaging kinetics all require careful consideration.
Monoclonal antibodies have a relatively large molecular weight and a long blood circulation retention time.
They need to be labeled with nuclides with a longer half-life, and the imaging time is longer.
Generally, imaging can only be performed after 72 hours of injection of the imaging agent, which is difficult for clinical application.
Researchers are also working on molecules with smaller molecular weights and better pharmacokinetics.
Ideally, single-domain antibodies are only 1/10 the weight of full-length antibodies.
Its tissue penetrating power is consistent with that of small molecule peptides, while maintaining the same ability as antibodies to specifically bind to antigens.
Free antibodies can be rapidly metabolized by the kidneys, and high-contrast imaging can be obtained within 1-2 hours.
Nanobody-based molecular imaging probes for molecular immunoPET imaging
It is reported that the domestic radiopharmaceutical company Intellectual Biosciences has cooperated with Jiangsu Provincial Key Laboratory of Molecular Nuclear Medicine and many other scientific research institutions to publish important research results in the top nuclear medicine journal “journal of nuclear medcine”⁶. The new molecular immunological PET imaging agent [⁶⁸Ga]Ga-SNA002 based on the single-domain antibody technology of the mouse, it only takes 1 hour to obtain high-resolution imaging of PD-1/PD-L1 on PET, which may be able to Become a new PD-1/PD-L1 non-invasive detection method to better screen patients suitable for tumor immunotherapy and predict the efficacy.
Intellectual Biosciences and its partners have also published related research content on CD8+ T cell immuno-PET imaging tracer developed based on its single domain antibody technology⁷. [⁶⁸Ga]Ga-SNA006 is a new type of nanotracer targeting human CD8 antigen with high radiochemical purity and affinity.
Compared with other drug candidates, [⁶⁸Ga]Ga-SNA006 has the advantages of long tumor retention time, stability, and low background. It can accurately track human CD8+ T cells in animal models, and shows great in immunotherapy monitoring and efficacy evaluation. potential.
The promise of immune checkpoint inhibitor treatment strategies lies in our ability to transform our increasing understanding of the human immune response in the tumor microenvironment into more effective treatments.
The use of immunohistochemistry to assess the tumor microenvironment on tumor biopsy is unlikely to play a greater role in this regard in the future.
Molecular immunoPET imaging can be extended to more immunotherapy fields. Such as the uptake of ADC drugs, biodistribution, accompanying diagnosis of various antibody drugs, imaging of immune cells, effector molecules, such as CD8+T cell imaging, effector molecule granzyme B imaging, etc., imaging of TILs in vivo distribution, etc.
The image of PD-1 treatment on CD8+T effector cells and MDSCs suppressor cells⁸
In the future, more large-scale clinical trials are needed to promote targeted molecular immune PET imaging, to provide a more scientific basis for tumor immunotherapy and evaluation, and to achieve the accuracy, individualization and optimization of tumor immunity.
Precision screening tool for immunotherapy: Molecular immunoPET imaging technology
(source:internet, reference only)