Programmed death ligand 1 (PD-L1) PET imaging in patients with (Diffuse) Large B-cell lymphoma who are treated with CD19-directed CAR T-cell therapy: a pilot study.

Anti-CD19 Chimeric Antigen Receptor (CAR)-T cell therapy has changed the
treatment landscape of patients with (Diffuse) Large B-cell Lymphoma (LBCL) and
other types of Non-Hodgkin Lymphoma (NHL). Patients with LBCL who do not
respond to first-line therapy, have a relapse within 6 months (primary
refractory), or after second-line therapy, including high-dose chemotherapy and
autologous stem cell rescue, have a poor prognosis and only 6% of these
patients have a long-term survival. The recent results of 3 pivotal studies
with 3 different anti-CD19 CAR T-cell products administered to patients with
relapsed/refractory (R/R) LBCL resulted in high response rates and long-term
remissions in almost half of the patients. Unfortunately, some patients do not
respond to CAR T-cell therapy and their prognosis is extremely poor.
Possible mechanisms of non-responsiveness include loss of CD19 expression on
the tumor cells, upregulation of immune checkpoint proteins such as programmed
death-ligand 1 (PD-L1, CD274) or impaired T-cell function due to an
immunosuppressive microenvironment. However the role each of these mechanisms
play in the case of a diminished or non-response to CAR T-cell therapy is not
yet defined.
Engagement of the PD-1/PD-L1 pathway is known to result in the reduction of
T-cell activation, proliferation, and survival. Moreover, PD-L1 expression can
be altered by radiotherapy, used as bridging therapy in CAR T-cell therapy.
Hypothetically, patients with high or upregulated PD-L1 expression are more
likely to be non-responders to CAR T-cell therapy and these patients might
benefit from additional PD-1/PDL-1 blocking therapy. However, the exact role of
PD-L1 expression in CAR T-cell therapy is not yet defined.
Currently, predicting tumor PD-L1 expression is not optimal, because it
requires invasive sequential biopsies that are often subject to the errors and
limitations of invasive tissue collection. Recently, positron-emission
tomography computed topography (PET/CT) imaging with 89Zr-atezolizumab
(formerly known as 89Zr-MPDL3280A), a PET-labeled antibody against PD-L1, was
found to correlate better with response to immune checkpoint inhibition than
immunohistochemistry- or RNA-sequencing-based predictive biomarkers in
different solid tumors. By performing a 89Zr-atezolizumab-PET/CT scan prior to
CD19-directed CAR T-cell therapy PD-L1 expression could be defined in a
non-invasive manner.
Additionally, repeated 89Zr-atezolizumab-PET/CT scan in the case of a suspected
relapse or non-response might distinguish between lymphoma activity and a
treatment-related inflammatory reaction without the need to take invasive
biopsies. Fluor-18-deoxyglucose (18F-FDG)-PET/CT scans are currently used for
the diagnosis, staging, and evaluation of response in patients with NHL.
However, response assessment with 18F-FDG-PET/CT may regularly be
false-positive as a result of pseudo-progression or local immune activation
(histiocytic or sarcoid-like reactions). Most often these reactions are
mediated by macrophages/histiocytes which are known to express PD-L1 at high
levels on their cell surface compared to lower levels on malignant B-cells.
Therefore, a 89Zr-atezolizumab could be used to differentiate between a
relapse/non-response or a treatment-related inflammatory reaction.

This study has been transitioned to CTIS with ID 2024-518422-32-01 check the CTIS register for the current data.

Primary objectives:
The first primary objective is to study the expression of PD-L1 in normal
tissue and lymphoma lesions before CAR T-cell therapy in LBCL patients by
89Zr-atezolizumab PET/CT imaging and to correlate the pretreatment
89Zr-atezolizumab distribution to the response to CD19-directed CAR T-cell
therapy thereby identify clinically relevant PD-L1 expression.
The second primary objective is to study whether the amount of
89Zr-atezolizumab uptake, measured by the intensity of 89Zr-atezolizumab PET/CT
imaging (SUV), can be used to differentiate between lymphoma activity and a
treatment-related inflammatory reaction (histiocytic/sarcoid-like reaction) in
patients with an end-of-treatment 18F-FDG-positive PET/CT signal.

Secondary objectives:
a) To correlate the pretreatment 89Zr-atezolizumab distribution to CAR T-cell
peak expansion and persistence.
b) To correlate the pretreatment 89Zr-atezolizumab uptake to CAR T-cell therapy
related grade 1-5 adverse events (cytokine release syndrome (CRS) and immune
effector cell associated neurotoxicity (ICANS)).
c) To correlate tumor 89Zr-atezolizumab uptake with tumor and tumor
infiltrating cell PD-L1-expression as assessed by immunohistochemistry on a
fresh contemporaneous tumor biopsy.
d) To compare the 89Zr-atezolizumab distribution in irradiated versus
non-irradiated lymphoma lesions in patients who require radiotherapy as a
bridging strategy prior to CAR T-cell infusion. If possible, these results will
be compared to tumor and tumor infiltrating cell PD-L1 expression as assessed
by immunohistochemistry on a fresh contemporaneous tumor biopsy of an
irradiated lymphoma lesion.
e) To determine the incidence of a treatment-related inflammatory signal on
18F-FDG-PET/CT scan (histiocytic/sarcoid-like reaction) after CAR T-cell
therapy.

This is a single-center, single-arm pilot study designed to evaluate the
expression of PD-L1 in patients with LBCL and its role in non-responsiveness to
CAR T-cell therapy in a non-invasive manner. Moreover, we aim to study the
possibility of PD-L1 PET/CT imaging to distinguish between lymphoma activity
and a treatment-related inflammatory signal (histiocytic/sarcoid-like reaction)
in case of a relapse or non-response after CAR T-cell therapy.

In this imaging trial, the purpose is to explore the feasibility of anti-PD-L1
PET/CT imaging in patients to gain insights into clinically relevant PD-L1
expression in the setting of CD19-directed CAR T-cell therapy. A
89Zr-atezolizumab PET/CT scan will be performed prior to CAR T-cell therapy.
Moreover, in case of a suspicion of relapse or non-response after CAR T-cell
therapy, a second 89Zr-atezolizumab PET/CT scan will be performed to
investigate if this scan can be used to distuingish between lymphoma activity
and a treatment-related inflammatory reaction (histiocytic/sarcoid-like
reaction) Patients with R/R LBCL will receive standard of care CD19-directed
CAR T-cell therapy according to the eligibility criteria as formed by the Dutch
National CAR-T tumor board.

For this imaging study, patients have to make a maximum of 6 extra visits to
the clinic for screening, 89Zr-atezolizumab injection, a PET/CT-scan visit and
a biopsy taken within 7 days of the PET-scan visit when feasible. In case of an
end-of-treatment positive 18F-FDG PET/CT signal two visits are needed for the
second 89Zr-atezolizumab injection and the PET/CT-scan. The biopsy taken
afterwards is part of standard procedure of care, but will only be performed
when feasible.
In case of bridging with radiotherapy and depending on the accessibility of the
tumor lesions, patients will be asked if they are willing to undergo an extra
biopsy. In practice, most procedures will be combined with visits to the
hospital in the context of clinical care, to minimize patient burden.
The intravenous tracer injection 89Zr-atezolizumab is between day -19 to day
-10 of the CAR T-cell infusion (depending on time needed for bridging
strategy). All patients will be observed for at least 30 minutes after
89Zr-atezolizumab injection to monitor for possible acute infusion related
adverse events. The subsequent 89Zr-atezolizumab PET/CT imaging scan is 7 days
(day -15 to day -6) after tracer infusion. The PET/CT-imaging is followed by a
biopsy within 7 days, but the biopsy will always take place before day -5 when
biopsy is considered safe. Optimal time point for the
89Zr-atezolizumab-PET/CT-scan is determined in the first 3 patients, as they
received a 89Zr-atezolizumab-PET/CT-scan on day 4 and 7.
In case of an end-of-treatment 18F-FDG-positive PET/CT signal another
89Zr-atezolizumab injection will be given followed by a 89Zr-atezolizumab
PET/CT imaging and a biopsy within 7 days (standard procedure).
The radiation burden following administration of 37 MBq of 89Zr-atezolizumab is
18.1 mSv, in addition to 1.0 mSv per low-dose attenuation correction CT-scan.
Thus, patients will receive 37 or 74 MBq doses of 89Zr-atezolizumab and undergo
to 1 or 2 low-dose CT-scans. The radiation exposure will be 19.1 mSv per
imaging round. Besides PET/CT imaging, patients will be asked to provide 12
blood samples (108 mL), which are taken in combination with standard clinical
and outpatient care. The easiest and safest accessible tumor lesion will be
biopsied within 7 days of the 89Zr-atezolizumab PET/CT scans when considered
feasible. Based on a literature review, the risk of tumor biopsies is
considered low with a small risk of significant or major complications or
death. The risk associated with the 89Zr-atezolizumab is considered acceptable
based on extensive preclinical testing of separate components and clinical
safety data from the first-in-human 89Zr-atezolizumab-study where only one
low-grade adverse event (pruritus, grade 1) has been reported. Although
patients do not directly benefit from this study, results from this study will
be valuable for our understanding of the tumor immune response and will guide
further prospective research and hopefully, treatment decisions. After
participation within the imaging trial, eligible patients will proceed with
CD19-directed CAR T-cell treatment, provided they continue to meet the
eligibility criteria to receive CD19-directed CAR T-cells.