Author:

Chris Bull, Sr. Scientific Advisor, Imaging

Date:

October 24, 2017

Immunotherapy agents (IO) are increasingly being used to treat solid tumors due to their dramatic effects on tumor response. However, the assessment of tumor response is not always straightforward given their unique mechanisms of action which include enhancing immune cell infiltration and activation in tumors. Current standard imaging techniques such as fluorinated deoxy-glucose (18F-FDG) PET cannot differentiate between cancer and immune cells. These tumor immune responses can lead to radiographic pseudo-progression whereby there can be an initial “worsening” of radiographic lesions. While IO therapies can be incredibly successful, understanding when a given treatment is successful or if the regimen needs to be augmented, is paramount.1 This confounding, radiographic evidence can lead to patients continuing therapy when no benefit is present or removal of therapy prematurely due to a delay in response time.

Labeling cells with 111In, iron oxide or 19F nanoparticles can allow for tracking of cell homing to tumors in-situ; however, these methodologies require the exogenous manipulation of cells and are limited in their duration of detection. Currently, there are multiple methodologies under development to explore the presence and activity of endogenous immune cells. Engineered antibody fragments have been used to detect the presence of CD4+ and CD8+ T-cells.2 These antibody fragments incorporate properties specifically optimized for imaging such as an accelerated clearance rate that allows for same day imaging, but retains the specificity and affinity of the parent antibody.

Fig. 1: Regulation of T-cell Activity:

Figure 1: Regulation of T-cell Activity

While these methods may inform you of the presence of specific immune cells that could potentially be activated by checkpoint inhibitors, it still does not indicate whether those immune cells are attacking the cancer cells. Determining the success of the treatment still requires a wait and see approach. The presence or absence of CD8+ T-cells alone does not appear to determine treatment success or failure with IO therapies and therefore may not be a robust biomarker of treatment efficacy.3 Technologies like flow cytometry can utilize up to 14 markers or more to create a holistic view of the tumor’s immune cell populations and elucidate the complex interplay between immune cell types wherein the presence of suppressor cells can inhibit the actions of killer cells (figure 1). Additionally, use of histology and immunohistochemistry endpoints on the tumor and surrounding tissue can provide added value of where the immune cells reside within the tumor and the tumor microenvironment. Thus, an imaging biomarker may need to be used in combination with another endpoint to increase its predictive value.

While a holistic view of the tumor microenvironment may not be possible using in vivo imaging, visualizing active immune cells may be possible. 18F-labeled guanosine analog 2’-deoxy-2’fluoro-9-b-D-arabinofuranosylguanine (F-AraG) allows for the detection of activated T cells due to increased mitochondrial activity relative to cancer cells.4 Labeled antibodies to granzyme B may also prove to be a diagnostic for detection of functionally active immune cells.5 Release of granzyme B can be attributed primarily to activated T cells and NK cells.6 These methods to monitor the immune system’s function in greater detail open a new and potentially informative approach to assist in the assessment of IO therapies.

1Sheng J et al.  Clinical Pharmacology Considerationsfor the Development of Immune Checkpoint Inhibitors. J of Clin Pharm 2017, 57(S10) S26–S42.

2Tarvare R et al. An effective immuno-PET imaging method to monitor CD8-dependent responses to immunotherapy. Cancer Res.  2016, 76(1): 73-82.

3Whiteside T. The role of regulatory T cells in cancer immunology. Immunotargets Ther. 2015, 4:159-171.

4Namaravari M et al. Synthesis of 2′-deoxy-2′-[18F]fluoro-9-β-D-arabinofuranosylguanine: a novel agent for imaging T-cell activation with PET. Mol Imaging Biol. 2011, 13(5):812-8.

5Larimer B. Granzyme B PET Imaging as a Predictive Biomarker of Immunotherapy Response.  Cancer Res. 2017, 77(9):2318-2327.

6Tumeh et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014, 27;515(7528):568-71.