Malignant tumours usually display intratumoral heterogeneity as well as phenotypic
and genotypic heterogeneity among patients. Consequently, there is the need to develop
treatments appropriate to each patient [1]. Screening of tumour phenotypes requires
biopsy, a procedure that is invasive and limited to accessible tumour sites. Moreover,
it is difficult to obtain repeated biopsies from the same lesions to explore changes
in properties and heterogeneity during therapy. There is therefore the need for new
noninvasive diagnostic technologies such as molecular imaging to assess whole-body
tumour phenotypes to allow more specific therapeutic strategies to be developed.
There has been a considerable increase in the use of targeted therapies, including
monoclonal antibodies (mAbs), in cancer management. A recent review found that there
are more than 50 mAbs in advanced clinical development in oncology, including several
antibody–drug conjugates and radiolabelled mAbs for radioimmunotherapy (RIT) [2].
Until now, only immunohistochemistry (IHC) analysis and quantitative polymerase chain
reaction analysis of tumour biopsies have been able to identify patients with the
highest chance of response to antibody-based therapy. However, these approaches do
not allow whole-body mapping of tumour cell biomarker expression and do not assess
biomarker accessibility.
mAbs can be labelled with radionuclides and are promising probes for theranostic approaches,
offering a noninvasive solution to quantitatively assess in vivo target expression,
to select patients for expensive and potentially toxic therapies and to monitor responses
[3]. mAbs were initially labelled with single-photon emitters, such as 131I or 111In,
and were subsequently used in planar imaging or SPECT imaging procedures to improve
RIT using dosimetry procedures. Accurate quantitative information can be obtained
more readily using PET. The good spatial resolution of PET allows better delineation
of tumours and organs than with SPECT. Additionally, key factors for the superiority
of PET over SPECT and planar imaging include exact attenuation correction, precise
scatter correction and high sensitivity, combined with the possibility of performing
true whole-body imaging in a reasonable time. Marrying mAbs and PET emitters requires
an appropriate match between the biological half-life of the protein and the physical
half-life of the isotope [4]. The use of 18F or 68Ga with a short half-life is limited
to small molecules such as antibody fragments that distribute rapidly in the body,
whereas 89Zr and 124I are well suited to the labelling of larger molecules such as
intact immunoglobulins. 64Cu with an intermediate half-life of 12.7 h can be used
for labelling a large number of molecules of different sizes.
In the present issue of EJNMMI, Sun et al. report the use of an anti-CD146 mAb labelled
with 64Cu for quantitative immunoPET imaging of CD146 antigen expression in lung cancer
models [5]. This antigen induces epithelial-to-mesenchymal transition, has a favourable
receptor density expression (125,000 receptors per cell) and may be associated with
the metastatic potential of cells and their resistance to apoptosis. Moreover, it
has low expression levels in normal tissues. Therefore, a mAb specific for this antigen
(YY146) has good potential for therapeutic application. In a preclinical study the
authors assessed six human lung cancer cell lines with different expression levels
of CD146 and showed a strong correlation between tumour uptake of 64Cu-NOTA-YY146
and relative expression of CD146 in the tumour cell lines. This radioimmunoconjugate
is consequently appropriate for immunoPET for quantitative evaluation of CD146 expression
in lung cancers before therapy using coupled or uncoupled YY146 antibody.
The first clinical proof that immunoPET is a powerful molecular diagnostic tool was
reported by Divgi et al. The mAb girentuximab binds carbonic anhydrase IX, a cell-surface
antigen highly and homogeneously expressed in more than 95 % of clear-cell renal cell
carcinomas (ccRCC). In 26 presurgical patients with renal masses, immunoPET using
124I-girentuximab demonstrated a sensitivity of 94 % and a specificity of 100 %, with
a negative predictive value of 90 % and a positive predictive value of 100 % [6].
These impressive results were corroborated in a phase III study, showing that 124I-girentuximab
immunoPET discriminates the presence or absence of ccRCC with an accuracy at least
comparable to that of biopsy analysis, suggesting that this invasive procedure with
its inherent risks could be avoided [7].
Treatment strategies for individual patients could be tailored by using immunoPET.
For example, anti-HER2 therapeutic agents are only effective in patients who have
HER2-positive breast cancer as determined by IHC. It has been proven that mAbs labelled
with 68Ga, 64Cu or 89Zr can noninvasively identify HER2-positive lesions and a few
clinical studies have shown that immunoPET with 89Zr-mAbs is able to predict response
to anti-HER2 antibody-based therapy [8–11]. In the ZEPHIR study, pretreatment PET
using 89Zr-trastuzumab was assessed in 56 patients with IHC 3+ or FISH ≥2.2 HER2-positive
metastatic breast cancer scheduled for treatment with trastuzumab emtansine (T-DM1)
[12]. 18F-FDG PET was performed at baseline and before cycle 2 of T-DM1. The study
showed 29 % negative HER2 PET/CT. Based on RECIST1.1. criteria, immunoPET showed a
positive predictive value of 72 % and a negative predictive value of 88 %, and FDG
PET a positive predictive value of 96 % and a negative predictive value of 83 %. The
two imaging techniques combined gave a predictive value of 100 % and enabled patients
with time to treatment failure of 2.8 months to be discriminated from those with time
to treatment failure of 15 months.
In another study, the use of 89Zr-bevacizumab PET imaging for predicting response
to combination therapy with carboplatin, paclitaxel and bevacizumab was assessed in
seven patients with non-small-cell lung cancer. A positive but nonsignificant trend
for a correlation between tumour uptake and progression-free and overall survival
after treatment was found [13]. The same encouraging trend was found in ten patients
with K-RAS advanced colorectal cancer who received 89Zr-cetuximab followed by treatment
with cetuximab [14]. In other clinical applications such as 89Zr-bevacizumab followed
by everolimus therapy in patients with neuroendocrine tumours [15], and 89Zr-fresolimumab
followed by fresolimumab therapy in patients with high-grade glioma [16], no correlation
was found between tumour uptake and clinical response. Based on these promising preliminary
clinical results, it appears that immunoPET has a realistic potential for predicting
responses to antibody-based therapy assuming that the biodistribution of the radioimmunoconjugate
in immunoPET is the same as the biodistribution of the mAbs used for therapy. One
serious drawback would be a negative immunoPET result predicting nonresponse to subsequent
therapy in a patient who could have responded to the therapy, as has been shown in
a few patients [14]. Randomized multicentre studies in stratified patients with different
relevant indications are needed to demonstrate that immunoPET can be considered a
true diagnostic companion.
Moreover, molecular in vivo imaging plays an increasing role in the development of
new drugs by pharmaceutical companies. In vivo imaging is an effective solution for
the rapid assessment of drug candidates, which may be radiolabelled to monitor their
pharmacokinetics and biodistribution during preclinical and early clinical phases.
Indeed, immunoPET is a powerful innovation to improve knowledge about the in vivo
behaviour of mAbs, and provides information regarding the quantitative variation in
molecular targets during treatments. ImmunoPET could provide information about tumour
targeting, pharmacokinetics and accumulation in critical normal organs to determine
optimal dosing and the impact of preloading with unlabelled antibody for RIT [17].
Consideration of the cost and safety of immunoPET is also important. A cost approaching
several thousand euros per patient would be acceptable if the benefit in patient selection
for expensive therapies and in drug development could be confirmed. Regarding dosimetry,
the internal radiation doses estimated for immunoPET are comparable to those from
conventional imaging and are acceptable. Due to a shorter physical half-life, the
dose delivered with 64Cu is lower than that with 89Zr. Indeed, the internal radiation
dose from 64Cu-trastuzumab absorbed by the patient has been estimated to be 4.5 mSv,
compared with 18 mSv from 89Zr-trastuzumab [10]. Using activities ranging from 370
to 740 MBq, the radiation dose absorbed from 18F-FDG PET has been estimated to be
7 to 14 mSv.
In conclusion, we consider that immunoPET is a promising tool for personalized medicine,
allowing better patient selection for antibody-based therapies and accelerating and
improving drug development. Whilst this innovative technology is currently associated
with a significant cost, this cost could become acceptable if the benefit in stratifying
patients before expensive targeted therapies can be clearly demonstrated in large
multicentre randomized clinical trials.