For sharing this topic: * An advocate’s perspective:
Future value of Radioimmunotherapy
-- rationale for continued study
of protocols based on RIT given with curative intent for indolent
lymphoma, with shorter duration of treatment and costs http://bit.ly/1TSS9Df
ASCO Post: Limited Access to Radioimmunotherapy
in Community Setting
May Lead to Extinction of a Unique Lymphoma Treatment
In a review article "Speed Bumps on the Road to A
Chemotherapy-Free World for Lymphoma Patients"
Bruce D. Cheson, M.D.
“With the increasing number of targeted
agents for the treatment of patients with lymphoid malignancies
comes the promise of safe and effective chemotherapy free
treatment strategies. A number of single agents, such as
ibrutinib and idelalisib, have demonstrated impressive efficacy
with a favorable toxicity profile.
The observations that most responses are, however, partial and
treatment duration is indefinite, have stimulated interest in
combinations of these agents with chemotherapy as well as with
each other. Despite the promise of this approach, several recent
trials of combinations of agents have been terminated as the
result of life-threatening and fatal complications. Such
outcomes have generated a cautionary note of the potential for
unforeseen adverse effects that challenge drug development and
mitigate against the empiric combination of such drugs outside
of a clinical trial setting.”
While RIT was not discussed in this otherwise
excellent article, I expect that Dr. Cheson recognizes its
potential. Apparently, he does not believe that RIT can overcome the
access issue in the community setting – that oncologists will not
take the time to describe the risk/benefit profile of a treatment
that requires that they send their patients elsewhere to receive it
– particularly when there are often reasonable alternatives to be
given directly by the community oncologist.
My fear is this: continuing low usage of RIT could lead to its
discontinuation in the very near future. I cannot yet accept this as
fate due to its unique properties and proven efficacy. I believe Dr.
Cheson’s article on the challenges of testing targeted agents
strengthens the case for additional testing of RIT (not Rituxan)
doublets with the intent of curing more patients with indolent
lymphoma in the near future – this with less physical and financial
toxicity – and with substantially less cost, burden, and time on
“Most of the doctors who see and treat
patients with NHL are not allowed to inject Zevalin. And those who
are authorized to inject Zevalin, the nuclear medicine doctors, they
don't see patients with non-Hodgkin’s lymphoma.
The unique features of RIT:
- It takes about 1 week to give the entire
treatment, (minutes for each infusion) compared to many months of
- It's the only non-chemotherapy-based approach with a very high
rate of durable remissions.
Larson, Press: Radioimmunotherapy of human tumours - Europe PMC Article - Europe PMC
“Seven Phase II studies and two Phase III studies have tested
RIT in patients newly diagnosed with NHL who received front-line
therapy either alone or as consolidation following
These studies have all demonstrated efficacy with ORRs of
90–100% and CRs of 60–100% (Figure 3A). Also, the CRs induced by
this approach have been very durable, with median remission
durations exceeding six years in many studies.”
Review: 90 Y-ibritumomab tiuxetan (Zevalin
a nearly forgotten opportunity
Patrizia Mondello, Salvatore Cuzzocrea, [...], and Michael Mian
It's an important and unique choice for
- who must continue to work through or shortly after treatment
- who cannot tolerate chemotherapy, because of advanced age, or
- who may prefer to limit the on-treatment side effects specific to
chemotherapy such as nausea, neuropathy, hair loss, gastric, and
gastric and mucositis complications.
The future value of RIT could be far greater than we realize and
could well address the challenges and findings cited by Dr. Cheson
above – particularly if utilized early in the disease course.
We ought not let enthusiasm for targeted drugs obscure the proven
efficacy and potential value of radioimmunotherapy for the following
1) Antibody-based therapies have fewer
anticipated adverse drug-interactions
Unlike chemotherapy agents and targeted drugs,
antibodies are proteins that are normally produced by the body to
fight infection. Unlike most classes of drugs, antibodies do not
stress the primary organs that remove toxins: such as the liver and
kidneys. Like these (and like Rituxan), RIT can be combined with
other drugs with fewer anticipated adverse drug-to-drug
There are many promising RIT Doublets and Triplets to test.
Having as the goal to enhance RIT, the targeted agents may also be
given for shorter time periods – the study schedule based on the
Pharmacokinetic properties of RIT. Such schedules could reduce
the toxicity that comes with indefinite or long term use of targeted
agents including maintenance Rituxan.
- Pre-targeting antibodies to clear normal b-cells before RIT
seems a promising way to further increase the potency of RIT.
(non-competing c19 antibody instead of cd20, for example, so that
the radio-labeled cd20 does not have to compete with non-labeled
monoclonal antibody for the same receptor)
- Immune modulating agents, such as
seems a promising way to complement the
immunotherapy-based mechanisms of action of RIT.
Anti-CD20 Antibody May Trigger Long-Term Protective T Cell
Immunity in Follicular Lymphoma
- Drugs targeting cellular pathways, such as
ABT-199 / Venetoclax may enhance the direct killing effects of
the radiation delivered by antibodies.
- Epigenetic agents may be given with or prior to RIT
(priming the cells to be more sensitive to radiation) sequentially …
instead of with RIT to further improve the safety.
- Radio sensitizing agents combined with RIT such as Velcade.
As in this admittedly small study which reported an 85% CR rate for
Follicular in the relapse setting. See Phase 1 study of
radiosensitization using bortezomib relapsed lymphoma receiving
"Sixteen patients responded (64%), including 44%
complete responses (CRs), with 82% CR in patients with follicular
lymphoma (FL). At a median follow-up of 7 months, median
progression-free survival was 7 months, and seven of 11 patients
with FL remained in remission at a median of 22 months."
Other agents may come into the pipeline:
See for example: Preclinical evaluation of a prodrug for
radiosensitization in mouse and human tissues.
Poly(ADP-ribose) polymerase inhibitors (PARP inhibitors) such as
ABT-888 combined with external beam and
radioimmunotherapy to treat aggressive lymphoma
3) Enhancing RIT’s immune-mediated activity
One way that RIT is thought to work is by activating
the immune system to attack tumor cells. Because of the very short
duration of RIT treatment and because its activity is focused on
b-cells expressing cd20, the negative impact on effector cells
(other types of immune cells) seems limited compared to repeated use
of chemotherapy over many months. RIT’s negative impact on the
b-cell compartment of the immune system is less than Rituxan due to
the short duration of treatment (2 days), -- compared to Rituxan
which is typically given every 3 months for 2 years. 2 years of
maintenance leading to long term b-cell depletion … and not
infrequently to a higher incidence of infections that can require IV
infusions of Immunoglobulins (naturally occurring antibodies
produced by mature b-cells).
Related article, 2016: Radiotherapy
combination opportunities leveraging immunity for the next oncology
practice - Herrera - 2016 - CA: A Cancer Journal for Clinicians -
Wiley Online Library
4) The targeted delivery of radiation by RIT offers
a better potential to address tumor heterogeneity.
Lymphoma cells are known to be sensitive to
radiation a mechanism of action that is not pathway-specific.
So-called precision medicine by targeted drugs is limited by tumor
heterogeneity – that is the tumor cells have varying types of
genetic changes and abnormal pathways that are active within the
cells. Tumor heterogeneity exists within the same patient and in
different patients with the same diagnosis. This limits the scope
and efficacy of single drugs that target specific genetic changes.
5) How do the risks of RIT compare to
The most serious risks of RIT are equivalent to
While the radiation part of RIT adds risk (such as for MDS), this
risk appears to be no greater than for standard chemotherapy
(Kaminski) and this risk is very low in the first-line setting.
Czuczman, et al, Treatment-Related Myelodysplastic Syndrome and
Acute Myelogenous Leukemia in Patients Treated With Ibritumomab
6) The potential vaccine-like effects of RIT -
inducing an immune response appears to be a key to achieving the
most durable remissions
When tumor cells are killed by radiation, this may
lead to a vaccine-like effect activating the immune system to attack
tumor cells. This effect has been observed for local radiation where
tumors in other parts of the body regress. (The abscopal effect).
A vaccine effect for RIT is also suggested by the delayed time to
optimal response to Bexxar RIT reported by Kaminski - well beyond
the half life of the drug in the body.
"When given as initial
treatment: "Responses were observed in
72 of the 76 patients, most of whom reported
regression of palpable tumor within two weeks. Complete responses
were observed in 57 of 76 patients (Table 1), with a median time
to an evaluated complete response of 202 days (range, 55 to
Also see Radiation therapy and cancer vaccines: Timing is everything
“In situ” vaccination for systemic effects in follicular lymphoma -
Europe PMC Article - Europe PMC
6) Financial toxicity and sustainability challenges
-- RIT based therapy can substantially reduce on-treatment time and
related risks and costs
Decreasing on-treatment time is an important
objective for clinical research … for the patient and for the health
care system overall. When feasible, patients will be better served
by a single course of treatment that achieves very high rates of
durable remissions and cures. Being free of the disease and of
treatment seems the ideal objective of clinical research … where
this outcome is feasible. RIT doublets and triplets (given
concurrently and/or in sequence) within weeks appear to have a
unique potential to achieve this ideal for indolent lymphoma and
deserves testing by the NCTN (NCI cooperative groups).
~ Perspective by Karl Schwartz,
Research advocate, President of PAL
With no financial conflict of interest to report
See also our letter
educating our Senators about the impact of a burdensome training
requirements for the administration of RIT on patient access to
RIT in the community setting.
When your body detects something that does not belong, such as
bacteria (pathogen), one way it eliminates the threat is to produce antibodies
that bind to the protein shapes that are specific to the
RIT agents are man-made antibodies with different radiation components
attached. These antibodies are designed to bind to a protein
shape called CD20, which sticks out of mature B lymphocytes (immune
cells), both malignant and nonmalignant (cancerous and normal).
... Importantly, the cd20 shape (or antigen / receptor) is not found on precursor B cells
- immature b-cells which can later mature to replenish the supply of
normal mature b-cells.
RIT is considered a targeted therapy, because the antibodies that
deliver the radiation are specific to one type of cell. RIT is more potent
than unlabeled antibody therapy, such as Rituxan, but it also has
unique potential risks.
is given in therapeutic steps
The initial antibody dose ("cold" or "naked"
antibody) clears the body of normal b-cells so that subsequent
doses will be more focused on tumor cells.
The second "warm" dose has anti-tumor effects, but
also helps calculate the optimal final dose based on uptake of the drug
and individual clearance rates as determined by imaging of the gamma radioactive
(3) The final "hot"
dose has has the most potent anti-tumor effects, and is focused on
tumor cells, because prior doses have cleared the body of normal
mechanisms of action
When radio-labeled antibody binds to tumor cells it can cause tumor
Apoptosis - programmed cell death triggered by the
Complement-dependent cytotoxicity (CDC) - where antibody fixes
complement that kills the tumor cells
Antibody-dependent cellular cytotoxicity (ADCC) - where effector
cells (immune cells) kill the tumor cells
Ionizing radiation from the radioisotope damages the tumor cells,
leading to cell death
Vaccine-like effect - leading to adaptive immunity against cells
that may survive initial treatment