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PSA: 178 ng/ml
(a) (b)
PSA: 3.5 ng/ml
Figure 2.11 (a) 68Ga-PSMA11-PET images of a 66-year-old patient with castration-resistant prostate cancer
pretreated with docetaxel, abiraterone, and six cycles of
223
Radium. Maximum intensity projection (MIP)
on the left side shows multiple bone and lymph node lesions. Patient was treated with three cycles of
177
Lu-PSMA-617 radioligand therapy with a cumulative activity of 13.5 GBq (reduced activity because of
single kidney). The MIP images on the right side show signicant reduction in prostate-specic membrane
antigen (PSMA)-positive lesions in correlation with a PSA decline of 99%. Source: Reproduced from Rahbar etal. 2018[27] under a Creative Commons License (https://creativecommons.org/licenses/by-nc/4.0).
(b) Fused images of
68
Ga-PSMA11-positron emission tomography/computed tomography (PET/CT). Images
in the upper row show a signicant reduction in PSMA-positive lesions. Low-dose CT images (lower row)
show a signicant volume reduction in soft tissue lesions (especially in the right pelvis). Source: Reproduced from Rahbar etal. 2018[27] under a Creative Commons License (https://creativecommons.org/
licenses/by-nc/4.0).
(mCRPC) is also being investigated. With a higher LET and multiple alpha particles in
their decay cascades, these isotopes have been successful in treating cancer with smaller
doses as compared to beta-emitting isotopes. For example,
excellent results in patients with mCRPC.
225
Ac-PSMA treatment has also been successful
in both chemotherapy-resistant and naïve patients, and where beta therapy with
225
Ac-PSMA-617 has shown
177
Lu-
PSMA failed[25, 31, 32].
TAT with
225
Ac-PSMA has also been employed in patients who have a contraindication
for beta-emitting therapy (e.g. diuse red marrow inltration) and patients showing
progression during or after treatment with
177
Lu-PSMA-617. Due to the transient nature
of radionuclides, and because each of the nuclides in the decay chain has dierent properties, it is likely that they free themselves from the chelating group attached to the
targeting moiety. When radiotherapeutics are bound to the cell surface, the dissociated
radionuclide can be rapidly circulated away from the targeted area, potentially decreasing
treatment ecacy and increasing toxicity. However, as PSMA-617 is internalized by the
PSMA expressing cell, the parent radionuclide and its daughters remain internalized in
the cancerous cell. Clinical studies have demonstrated positive results after two or three
cycles of
225
Ac-PSMA-617 therapy in a range of PC patients (Figure2.12)[31, 32].
Chapter 2: Concepts andIssues forTherapeutic Radiopharmaceuticals 35
1x 2x 3x
July 2017
PSA = 782 ng/ml
Sep 2017
PSA = 71 ng/ml
Nov 2017
PSA = 0.64 ng/ml
Jan 2018
PSA = 0.07 ng/ml
May 2018
PSA = 0.04 ng/ml
Figure 2.12 A treatment-naïve patient who presented with extensive bone metastasis at primary diag-
nosis achieved complete remission after three cycles of
225
Ac-PSMA-617 with de-escalating activities of
8/7/6 MBq. He also remained symptom-free on 11-month follow-up with his serum PSA remaining below
the detectable level and the follow-up
68
Ga-PSMA-11 PET/CT scan remaining negative for disease recurrence. Source: Reproduced from Sathekge etal. 2019[32] under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0).
2.3.5 Lymphoma andLeukemia
Immunotherapy and RIT strategies have been investigated for the treatment of leukemia
and lymphomas. These mAb-based therapies are compatible with malignancies in the
blood, bone marrow, and lymph nodes. As a large percentage of lymphomas are B-cell
derived, the targeting of the B-cell specic epitope CD20 led to advances in lymphoma
treatment. One such example is the use of
is a treatment using both the
131
I-labeled, CD20-specic antibody tositumomab as well
as the non-radioactive version. The non-radioactive antibody is administered rst with
the goal of saturating the CD20 epitope on non-malignant B-cells. This is also thought
to extend the time the radiolabeled antibody spends in circulation, allowing longer for
perfusion of the therapeutic into the tumor[4]. Currently, Bexxar is no longer used in the
clinic as GlaxoSmithKline stopped producing it in 2014.
Another CD20-targeting immunotherapy involving a two-part treatment regimen,
Zevalin was rst introduced as an alternative to Bexxar and boasted the use of yttrium-90
as an advantage.
90
Y has a half-life of 64 hours, or one-third that of
Also, as a pure beta emitter, the use of
for the patient compared to the use of
administered rst, followed by
with the
111
In-labeled antibody to conrm normal distribution[4] prior to commencing
90
Y-ibritumomab tiuxetan. The FDA still requires imaging
treatment. During treatment, the initial administration of the non-radioactive rituximab
is benecial in the saturation of peripheral B-cells[6].
Comparing Bexxar and Zevalin, the most obvious dierence is the radioisotope in use.
131
I has both beta and gamma emissions, with the advantage of simultaneously allowing
131
I-tositumomab, developed as Bexxar. Bexxar
131
I (t
=193 hours).
90
Y means a decrease in the whole-body dose
131
I. The non-radioactive antibody rituximab is
1/2
36 Handbook of Radiopharmaceuticals
for imaging and therapy. Conversely, the gamma emissions detectable outside of the
body give iodine a more complicated post-treatment protocol and a higher chance of
those around the patient receiving a small dose of radiation. Zevalin, with its use of
90
Y,
primarily has a beta emission, making post-treatment less complicated, but precautions
are still taken with patients’ interactions with family members or other people.
In the treatment of leukemia, CD33 has been identied as a myeloid leukemia cellspecic glycoprotein. Anti-CD33 antibodies such as M195 and lintuzumab carrying betaemitting isotopes (e.g.
131
I, 90Y) have previously shown promise in treating leukemia[33].
However, as beta particles have a lower LET (travel a further distance in tissue), such
treatments came with side eects. In eorts to improve the therapeutic strategy, alpha
therapeutics such as
213
Bi-lintuzumab have also been investigated.
213
Bi also emits a
photon during decay, enabling in vivo imaging of the distribution of the therapeutic. A
phase I/II clinical trial was completed with
213
Bi-lintuzumab, in conjunction with cytarabine
chemotherapy. The pretreatment was implemented as it was believed that the chemotherapeutic would lessen the tumor burden to a level where the
213
Bi alpha therapy would
have an increased eect on the tumors[7]. The proof of principle study demonstrated
that this treatment is tolerable, and clinical responses were seen in 6 out of the 25
patients involved in the trial.
Hematological cancers such as lymphoma and leukemia are also characterized by
an overexpression of CXC-chemokine receptor-4 (CXCR4). CXCR4 expression has been
found to be upregulated in a number of human tumor cells. In addition, the high expression of these cells has been found to be an indicator in the presence and prevalence of
distant metastases. This receptor and its only ligand, CXCL12, are key communicators
in the proliferation of malignant cells. The targeting of the CXCR4/CXCL12 pair has
resulted in the development of many treatment modalities, only one of which is FDA
approved: AMD3100 (Plerixafor/Mozobil). [
68
Ga]Pentixafor (Figure2.13) was a product
of eorts toward an imaging agent to better quantify patients’ CXCR4 levels and therefore aid in conrming eligibility for a CXCR4/CXCL12 therapeutic strategy. While other
PET drugs can be directly translated to therapy with the substitution of the radiometal
(e.g. DOTATATE), small changes to
68
Ga-Pentixafor caused large changes in its anity
for CXCR4[34]. To address this issue, the addition of iodine to the meta-position of
the tyrosine in the peptide backbone allowed the use of the beta-emitting radionuclide lutetium-177 while maintaining CXCR4 anity, resulting in
(Figure2.13).
177
Lu-Pentixather has been utilized in early clinical trials where preliminary
177
Lu-pentixather[34]
results treating patients with extramedullary relapsed multiple myelomas were highly
promising (Figure2.14)[35].
2.3.6 Treatment ofViral, Fungal, andInfectious
Diseases withRadiotherapy
While most radiotherapy is targeted at cancer, it is also being evaluated in the treatment
of viral, fungal, and bacterial infectious diseases. In this context, radiotherapy is appealing
for some of the same reasons it is an attractive strategy for cancer treatment: using
Chapter 2: Concepts andIssues forTherapeutic Radiopharmaceuticals 37
Therapeutic: R = I, M =
(Pentixather)
O
O
Figure 2.13 Pen-
(a) (b) (c)
tixafor and
Pentixather.
R
OH
O
O
NH
N
NH
O
HN
H
N
O
Diagnostic: R = H, M = 68Ga
HN
HN
O
O
O
N
NH
N
M
N
HO
N
O
O
O
NH
NH
2
3+
(Pentixafor)
177Lu3+
[18F]FDG [68Ga]Pentixafor [68Ga]Pentixafor[
Before
177
[
Lu]Pentixather
Figure 2.14 Example of partial response to CXCR4-directed treatment with [
intensity projection (MIP) of [
68
therapy, indicating high CXCR4-expression in multiple intramedullary [
177
Lu]Pentixather
7 d after
177
[
Lu]Pentixather
8 wk after
177
[
Lu]Pentixather
177
Lu]Pentixather. (a) Maximum
Ga]Pentixafor- and [18F]FDG-PET/CT of patient #4 prior to Pentixather
18
F]FDG-negative myeloma lesions.
Source: Reproduced from Lapa etal. 2017[35] under a Creative Commons License (https://creativecommons.org/licenses/by-nc/4.0). (b) Scintigraphic images of patient #4 7 days after administration of 7.8 GBq
177
[
Lu]Pentixather, conrming the long-lasting binding to the CXCR4-target after treatment. The patient
is seen from ventral (left) and dorsal (right). Source: From Lapa etal. 2017[35] under a Creative Commons
License (https://creativecommons.org/licenses/by-nc/4.0). (c) MIP of [
177
after [
Lu]Pentixather therapy, displaying partial response with the disappearance of most of the mye-
68
Ga]Pentixafor-PET/CT eight weeks
loma manifestations. In concordance, serological response was assessed as stable disease. Source:
Reproduced from Lapa etal. 2017[35] under a Creative Commons License (https://creativecommons.org/
licenses/by-nc/4.0).
38 Handbook of Radiopharmaceuticals
targeted molecules or antibodies leads to fewer o-target eects. In addition, radiotherapy is desirable for the treatment of infectious diseases because viral, fungal, and
bacterial infections have become increasingly resistant to current standards of care. Many
patients who experience these infections are already immunocompromised due to chemotherapy, HIV infections, or adjusting to organ transplants. Radiotherapy has already been
shown to be tolerable in patients that t these categories, most of all those with a history
of chemotherapy treatments[36, 37]. In vitro and in vivo studies in mice of various antibodies labeled with alpha- and beta-emitting radioisotopes have shown the eectiveness
of this therapy on infections such as Streptococcus pneu monia or biolms[38, 39]. However,
applications of these treatments in a clinical setting have yet to be disclosed.
2.4 SUMMARY ANDFUTURE OUTLOOK
Targeted radiotherapy is an exciting area of growth in the radiopharmaceutical sciences
and nuclear medicine that is showing remarkable results primarily in the treatment of a
variety of tumors and associated metastases, but also in other emerging areas such as
treatment of infection. The therapeutics described in this chapter are in various states
of investigation and regulatory approval, with a recent increase in the interest and use
of alpha-emitting radionuclides such as
225
is advancing quickly thanks to many studies demonstrating an increase in response
rates, there is still urgency around a reliable pipeline of both therapeutic radionuclides
and formulated radiotherapeutics. For example, while
be very eective in the attenuation of this disease, the current supply chain of
not sucient to provide the necessary therapy to the current population living with
mCRPC[41]. Reecting this, there is signicant research being done to establish reliable
methods for the production of
225
Ac, which is essential to support the anticipated growth
in alpha therapy use in the coming years.
Ac and
211
At[40]. While targeted radiotherapy
225
Ac-PSMA-617 has shown to
225
Ac is
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42 Handbook of Radiopharmaceuticals
PART II
Production of
Radionuclides
