Programmed death ligand (PD-L1) expression in tumors may predict response to checkpoint blockade therapy, but tissue samples are not always on hand to guide therapy. Imaging specialists have addressed this issue by developing and evaluating techniques for non-invasive imaging of PD-L1 expression in tumors.

“Non-invasive imaging of therapeutically effective PD-1 [programmed death 1] and PD-L1 antibodies is of high interest for preclinical and potentially also for the clinical development of these drugs, as it provides an elegant opportunity to obtain quantitative and kinetic information on the whole-body biodistribution of these antibodies, including parameters such as tumor accumulation and blood half-life,” explained Gabriele Niedermann, MD, PhD, of the German Cancer Research Center in Heidelburg, and colleagues, writing recently in Theranostics.

Niedermann’s group developed radiotracers, based on therapeutic checkpoint-blocking antibodies, that allowed for high-resolution PET imaging of both PD-1 and PD-L1 in immunocompetent mice. This “immunoPET” of naïve mice showed similar overall expression patterns for PD-1 and PD-L1 in secondary lymphoid organs (spleen and lymph nodes).

The research also found that PD-L1 tracer uptake was reduced in PD-L1 knockout tumors, and that monitoring the expression changes of PD-L1 in response to its main inducer, the effector T cell cytokine IFN-γ, revealed “robust upregulation in the lung.”

“This suggests that T cell responses in the lung, a vital organ continuously exposed to a variety of antigens, are strongly restrained by the PD-1 checkpoint. In turn, this could explain the association of PD-1 checkpoint inhibition with potentially fatal immune-mediated pneumonitis and partially also its efficacy in lung cancer,” Niedermann and colleagues wrote.

In another animal-model study, Samit Chatterjee, PhD, of Johns Hopkins University in Baltimore, and colleagues performed SPECT-CT imaging, biodistribution, and blocking studies in NSG (NOD scid gamma) mice bearing tumors with constitutive PD-L1 expression (CHO-PDL1) and in controls (CHO).

The preclinical evaluation of a humanized radiolabeled anti-PD-L1 antibody showed specific and increased uptake of radioligand in CHO tumors with stable PD-L1 expression compared with control CHO tumors. The results were confirmed in NSCLC xenografts with varying levels of PD-L1 expression, and in triple-negative breast cancer.

“Subcutaneous NSCLC xenografts showed specific uptake in H2444 tumors compared to H1155 tumors,” the researchers wrote.

They explained that the clinical utility of this antibody imaging agent and others would be to use the radiolabeled antibody accumulation in the tumors to guide therapeutic antibody dosing, and correlate that uptake with tumor response.

“This could be used to establish a relationship between tumor PD-L1 status and therapeutic response, which may have prognostic implications.”

Can these results be translated into humans? Yes, according to Jill Fredrickson, PhD, of Genentech in South San Francisco, and colleagues, who utilized FDG-PET-CT imaging to evaluate atezolizumab (Tecentriq) response among chemotherapy-naïve and previously treated stage IIIB/IV non-small cell lung cancer (NSCLC) patients.

Atezolizumab was developed by Roche, the owner of Genentech, and was grantedpriority review by the FDA in April 2016 for the treatment of locally advanced or metastatic NSCLC with PD-L1 expression.

Fredrickson’s group suggested that patients with NSCLC undergoing immunotherapy may benefit from FDG-PET imaging to assess their disease and predict treatment response, presenting the results of their multinational study at the 2016 Society of Nuclear Medicine and Molecular Imaging Annual Meeting.

Atezolizumab inhibits activity between the PD-1 receptor expressed on certain immune cells and PD-L1, leading to enhanced T-cell priming and re-invigoration of suppressed immune cells.

The primary endpoint of the phase II study was objective response rate on the basis of modified immune-related response criteria. Patients underwent single-time-point FDG-PET scanning — 60 minutes of radiotracer uptake prior to imaging — at baseline, at the time of first tumor assessment during week 6 of immunotherapy, and at disease progression.

Fredrickson and colleagues also wanted to determine if the PET modality and its FDG radiotracer could distinguish between radiographic pseudo progression — an increase in apparent tumor burden due to an anti-tumor T-cell response – from true disease progression.

The study enrolled 138 patients at 28 clinical sites in 5 countries, with 103 patients providing evaluable PET scans at baseline and a post-baseline time point. All patients received 1,200 mg of atezolizumab intravenously every 3 weeks. The scans were analyzed using European Organization for Research and Treatment of Cancer (EORTC) criteria.

Patients with metabolic response by EORTC criteria on scans at week 6 had a higher overall response rate (73.9%) than metabolic non-responders did (6.3%). A patient’s whole-body metabolic tumor volume at the FDG-PET baseline scan was found to be a significant negative prognostic maker for overall survival. A further increase of tumor volume at the 6-week scan was also a sign of decreased overall survival.

The researchers noted that response after apparent radiographic progression was seen in only two patients, so the utility of FDG-PET to distinguish pseudo from true progression could not be determined.

“The utility of FDG-PET in patients with NSCLC on immune blockade therapy appeared to be similar to what has been reported with conventional chemotherapeutic treatments, with early metabolic response predicting subsequent benefit,” the team concluded.

“This study is the first to prospectively evaluate FDG-PET imaging in a phase II trial of lung cancer patients receiving the novel immune checkpoint inhibitor atezolizumab,” Fredrickson said in a press statement. “These findings help define the potential role of FDG-PET as a prognostic and predictive biomarker in the treatment of lung cancer with such immunotherapeutics.”