Molecular Imaging of Immunotherapy Targets in Cancer

Ehlerding, Emily B.; England, Christopher G.; McNeel, Douglas G.; Cai, Weibo

doi:10.2967/jnumed.116.177493

Cited by 76 publications

(91 citation statements)

References 43 publications

(50 reference statements)

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“…19 However, to date no studies have evaluated the in vivo expression of CD38 using molecular imaging techniques. 20 Correlations have been drawn between traditional positron emission tomography (PET) imaging agents (e.g., 18 F-fluordeoxyglucose) and single-photon emission computed tomography (SPECT) agents (e.g., 99m Tc-methoxyisobutylisonitrile) and CD38 levels as determined through ex vivo analysis, 21,22 but these studies still require invasive biopsy procedures.…”

Section: Introductionmentioning

confidence: 99%

CD38 as a PET Imaging Target in Lung Cancer

et al. 2017

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Daratumumab (Darzalex, Janssen Biotech) is a clinically approved antibody targeting CD38 for the treatment of multiple myeloma. However, CD38 is also expressed by other cancer cell types, including lung cancer, where its expression or absence may offer prognostic value. We therefore developed a PET tracer based upon daratumumab for tracking CD38 expression, utilizing murine models of non-small cell lung cancer to verify its specificity. Daratumumab was prepared for radiolabeling with 89Zr (t1/2 = 78.4 h) through conjugation with desferrioxamine (Df). Western blot, flow cytometry, and saturation binding assays were utilized to characterize CD38 expression and binding of daratumumab to three non-small cell lung cancer cell lines: A549, H460, and H358. Murine xenograft models of the cell lines were also generated for further in vivo studies. Longitudinal PET imaging was performed following injection of 89Zr-Df–daratumumab out to 120 h postinjection, and nonspecific uptake was also evaluated through the injection of a radiolabeled control IgG antibody in A549 mice, 89Zr-Df–IgG. Ex vivo biodistribution and histological analyses were also performed after the terminal imaging time point at 120 h postinjection. Through cellular studies, A549 cells were found to express higher levels of CD38 than the H460 or H358 cell lines. PET imaging and ex vivo biodistribution studies verified in vitro trends, with A549 tumor uptake peaking at 8.1 ± 1.2%ID/g at 120 h postinjection according to PET analysis, and H460 and H358 at lower levels at the same time point (6.7 ± 0.7%ID/g and 5.1 ± 0.4%ID/g, respectively; n = 3 or 4). Injection of a nonspecific radiolabeled IgG into A549 tumor-bearing mice also demonstrated lower tracer uptake of 4.4 ± 1.3%ID/g at 120 h. Immunofluorescent staining of tumor tissues showed higher staining levels present in A549 tissues over H460 and H358. Thus, 89Zr-Df–daratumumab is able to image CD38-expressing tissues in vivo using PET, as verified through the exploration of non-small cell lung cancer models in this study. This agent therefore holds potential to image CD38 in other malignancies and aid in patient stratification and elucidation of the biodistribution of CD38.

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Section: Introductionmentioning

confidence: 99%

CD38 as a PET Imaging Target in Lung Cancer

et al. 2017

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“…Currently, there have been few investigations into the molecular imaging of immunotherapy targets, especially CTLA-4 9 . Previously, Higashikawa et al .…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, CTLA-4 is constitutively expressed on the surface of more than 88% of human-derived cancer cell lines, and incubation of these cells with recombinant CD80 and CD86 has been found to result in caspase-3/caspase-8-mediated apoptosis 8 . This expression of CTLA-4 by tumor tissues lends itself to exploration with molecular imaging techniques, which are suitable for monitoring expression levels of receptors in a dynamic and noninvasive fashion 9, 10 . With the increase in immunotherapy treatments, researchers are investigating new imaging strategies to better investigate the complex interactions between tumors and the immune system.…”

Section: Introductionmentioning

confidence: 99%

ImmunoPET Imaging of CTLA-4 Expression in Mouse Models of Non-small Cell Lung Cancer

et al. 2017

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Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is expressed on the surface of activated T cells and some tumor cells, and is the target of the clinically-approved monoclonal antibody ipilimumab. In this study, we investigate specific binding of radiolabeled ipilimumab to CTLA-4 expressed by human non-small cell lung cancer cells in vivo using positron emission tomography (PET). Ipilimumab was radiolabeled with 64Cu (t1/2 = 12.7 h) through the use of the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) to formulate 64Cu-DOTA-ipilimumab. CTLA-4 expression in three non-small cell lung cancer (NSCLC) cell lines (A549, H460, and H358) was verified and quantified by Western blot and enzyme-linked immunosorbent assays (ELISA). A receptor binding assay was utilized to monitor the binding and internalization of 64Cu-DOTA-ipilimumab in the NSCLC cell lines. Next, the biodistribution of 64Cu-DOTA-ipilimumab was mapped by longitudinal PET imaging up to 48 h after injection. Ex vivo biodistribution and histological studies were employed to verify PET results. By in vitro analysis, CTLA-4 was found to be expressed on all three NSCLC cell lines with A549 and H358 showing the highest and lowest level of expression, respectively. PET imaging and quantification verified these findings as the tracer accumulated highest in the A549 tumor model (9.80 ± 0.22 %ID/g at 48 h after injection; n=4), followed by H460 and H358 tumors with uptakes of 9.37 ± 0.26 %ID/g and 7.43 ± 0.05 %ID/g, respectively (n=4). The specificity of the tracer was verified by injecting excess ipilimumab in A549 tumor-bearing mice, which decreased tracer uptake to 6.90 ± 0.51 %ID/g at 48 after injection (n=4). Ex vivo analysis following the last imaging session also corroborated these findings. 64Cu-DOTA-ipilimumab showed enhanced and persistent accumulation in CTLA-4-expressing tissues, which will enable researchers further insight into CTLA-4 targeted therapies in the future.

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“…The potential of immune checkpoint inhibitor antibodies for tracking of activated T cells has been demonstrated in vivo [143], and this could be translated for imaging of lymphoma. For more information on molecular imaging of immunotherapy targets, readers are directed to our recent review of this topic [144]. …”

Section: Discussion and Future Perspectivesmentioning

confidence: 99%

Lymphoma: current status of clinical and preclinical imaging with radiolabeled antibodies

England

Cai

2016

Eur J Nucl Med Mol Imaging

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Lymphoma is a complex disease that arises from cells of the immune system with an intricate pathology. While lymphoma may be classified as Hodgkin or non-Hodgkin, each type of tumor is genetically and phenotypically different and highly invasive tissue biopsies are the only method to investigate these differences. Noninvasive imaging strategies, such as immunoPET, can provide a vital insight into disease staging, monitoring treatment response in patients, and dose planning in radioimmunotherapy. ImmunoPET imaging with radiolabeled antibody-based tracers may also assist physicians in optimizing treatment strategies and enhancing patient stratification. Currently, there are two common biomarkers for molecular imaging of lymphoma, CD20 and CD30, both of which have been considered for investigation in preclinical imaging studies. In this review, we examine the current status of both preclinical and clinical imaging of lymphoma using radiolabeled antibodies. Additionally, we briefly investigate the role of radiolabeled antibodies in lymphoma therapy. As radiolabeled antibodies play critical roles in both imaging and therapy of lymphoma, the development of novel antibodies and the discovery of new biomarkers may greatly affect lymphoma imaging and therapy in the future.

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Molecular Imaging of Immunotherapy Targets in Cancer

Cited by 76 publications

References 43 publications

CD38 as a PET Imaging Target in Lung Cancer

CD38 as a PET Imaging Target in Lung Cancer

ImmunoPET Imaging of CTLA-4 Expression in Mouse Models of Non-small Cell Lung Cancer

Lymphoma: current status of clinical and preclinical imaging with radiolabeled antibodies

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