Natural killer (NK) cells, which were first identified as lymphoid cells with lytic activity against tumor cells, play a relevant role in their detection and elimination without prior immunization. Recent advances highlighted how NK are a promising alternative to conventional T-cell based immunotherapy, but diagnostic tools to predict and evaluate therapeutic outcomes are lacking. Imaging can offer several approaches to address this issue. We focalized our research for the validation of a new radiopharmaceutical based on monoclonal antibodies (mAb) that target NK cells, in particular based on F(ab')2 fragments to detect NK cell trafficking. Radiolabelled anti-CD56 mAbs have favourable characteristics and showed to be an excellent choice for these aims as demonstrated in our pre-clinical studies. However, the main drawback in the use of whole mAbs is due to the response caused by production of human anti-murine antibodies (HAMAs). To overcome this limitation, the Fc region of the mAb can be cleaved to produce two Fab fragments bound together in a divalent structure referred to as the F(ab')2 fragment. Also, the shorter half-life of the F(ab')2 allows the use of radioisotopes with shorter half-life life (e.g. 68Ga) suitable for immune-PET that provides a better resolution and feasibility to human translation. The radiolabelled F(ab')2 fragment from anti-CD56 mAb could be an important diagnostic tool, both to predict and monitor the response to cancer immunotherapy.
Molecular imaging can help to select patients that could benefit from immunotherapy. Moreover, it can allow us to elucidate which immune cells and specific subpopulations are present before and during immunotherapy [8]. Currently, there is no gold standard to image NK cells in vivo and the development of an appropriate diagnostic tool for this purpose is vitally needed. Despite some reports with ex-vivo labelled NK cells using 111In-oxine or 18F-FDG, this approach showed many limitations
Our preliminary results with radiolabelled anti-CD56 mAb demonstrated that in vivo labelling of NK cells is feasible and can be accomplished with radiolabelled mAbs or peptides [7]. However, the use of the whole murine antibody involves the risk of developing HAMAs, limiting its use in clinics. Therefore, the production of a F(ab)2 fragment would overcome this issue and its radiolabelling would allow a safe NK visualization in vivo. Indeed, the radiolabelled F(ab)2 fragment would have other several advantages if compared to the intact anti-CD56 mAb, including short half-life and lower plasmatic background that allows us to radiolabel the F(ab)2 with short-lived isotopes.
Finally, the development of this radiopharmaceutical could be an important diagnostic tool, both to predict and monitor the response to cancer immunotherapy based on NK cells.
REFERENCES
1- Wang M, Zhao J, Zhang L, Wei F, Lian Y, Wu Y, et al. Role of tumor microenvironment in tumorigenesis. J Cancer 2017; 8: 761-773.
2- Sounni NE, Noel A. Targeting the Tumor Microenvironment for Cancer Therapy. Clin Chem 2013; 59: 85-93.
3- Ansell SM, Vonderheide RH. Cellular Composition of the Tumor Microenvironment. ASCO Educ Book 2013; e91-97.
4- Van der Veen EL, Bensch F, Glaudemans AWJM, Lub-de Hooge M, de Vries EGE. Molecular imaging to enlighten cancer immunotherapies and underlying involved processes. Cancer Treatment Rev 2018; 70: 232-244.
5- Davis ZB, Felices M, Verneris MR, Miller JS. Natural Killer Cell Adoptive Transfer Therapy: Exploiting the First Line of Defense Against Cancer. Cancer J. 2015. 21: 486¿491
6- Galli F, Histed S, Aras O. NK cell imaging by in vitro and in vivo labelling approaches. Q J Nucl Med Mol Imaging 2014; 58:276-83.
7- Galli F, Rapisarda AS, Stabile H, Malviya G, Manni I, Bonanno E, Piaggio G, Gismondi A, Santoni A, Signore A. In Vivo Imaging of Natural Killer Cell Trafficking in Tumors. J Nucl Med 2015; 56:1575-80.
8- Marciscano AE, Thorek DLJ. Role of noninvasive molecular imaging in determining response. Adv Radiat Oncol. 2018. 3: 534¿547.