2. • Radioimmunotherapy involves the coupling of
a radionuclide with monoclonal antibodies
(mAbs) that are targeted against tumor-
associated antigens or antigens expressed by
cells of the tumor microenvironment.
01-03-2018 2
Definition
RAVIKRISHNA
3. Radioimmunotherapy (RIT)
What Are We Talking About?
Targeting and destroying cancer cells with radionuclide,
without damaging surrounding healthy cells.
Cancer cells express a
specific antigen
The chelator links
the antibody to the
isotope
The isotope
destroys
the cancer cell
The antibody
recognizes and
targets the cancer
cell’s antigen
RAVIKRISHNA
01-03-2018 3
4. 01-03-2018 4
RADIOBIOLOGY
Typical dose rates for RIT are in the range of 10 to 20 cGy per
hour.
The total dose delivered by RIT is low, in the range of 1,500 to
2,000 cGy, with an effective half-life of 24 to 72 hours.
It should be noted that these total dose ranges for RIT occur
despite overall very low percent injected doses (0.1% to
10.0%) that ultimately localize in target tissue.
EBRT typically will deliver radiation at a dose rate of 100 to
500 cGy per minute.
RAVIKRISHNA
5. 01-03-2018 5
RADIOBIOLOGY
Considering dose rate, RIT is approximately 20% less effective
than HDR EBRT.
RIT, however, does appear to be relatively effective.
This phenomenon can be attributed to many radiobiologic
processes that appear to cause greater than predicted rates
of apoptosis.
These processes include low-dose/dose rate apoptosis,
lowdose hyperradiosensitivity , inverse dose rate effect (G2
synchronization), radiation-induced biologic bystander effect,
and the crossfire effect.
RAVIKRISHNA
13. 01-03-2018 13
Ideal target
overexpressed on cancer cells,
Uniformly expressed,
Not found to any significant
level in normal tissue,
Not shed into the circulation,
Exhibits an important role in
tumor growth and progression.
antigen densities ≥105 receptors on each cell
for adequate targeting
Nonuniform activity distributions
↓effectiveness of RIT , heterogeneous dose
distributions
Ab binds to Ag in circulation,
Rapid clearance , less effectve treatment
disruption of growth pathways important
for tumor growth
RAVIKRISHNA
18. 01-03-2018 18
RADIOCHEMISTRY
ideal delivery would manifest the targeting properties of
an intact mAb but exhibit the blood clearance pattern of a
small molecular weight construct.
Because no known such construct exists, pretargeting
strategies have been developed.
1.Bispecific mono clonal antibody
2. Streptavidin – Biotin system
RAVIKRISHNA
20. 01-03-2018 20
2.Streptavidin – Biotin system
In the streptavidin-biotin system, streptavidin is conjugated to the
initial pretargeting macromolecule, and biotin is conjugated to the
radionuclide.
Streptavidin and biotin have a very high affinity for each other .
The tumor/blood ratios of the targeting agent are significantly
increased
RAVIKRISHNA
21. 01-03-2018 21
APPROVED THERAPEUTIC AGENTS
These 3 scans are used to confirm the
safety of the biodistribution pattern (no
evidence of dangerous radioisotope
pooling or large-scale dehalogenation)
and to establish a predictive bioclearance
curve for the subsequent high-dose
therapeutic infusionRAVIKRISHNA
22. Regulatory Status of Anti-CD20 Radioimmunotherapy
• Y-90 ibritumomab tiuxetan
– 2002 FDA approval: relapsed or refractory, low grade or
follicular NHL
– 2009 FDA approval: treatment of previously untreated
follicular NHL in patients who achieve a partial or complete
response to first-line chemotherapy
• I-131 tositumomab
– 2003 FDA approval: treatment of patients with CD20 antigen-
expressing relapsed/refractory, low grade, follicular, or
transformed NHL, including rituximab-refractory NHL
• Not indicated for first-line treatment of CD20+ NHL
01-03-2018 RAVIKRISHNA 22
25. Efficacy of RIT in Patients with Relapsed/Refractory CD20+ B-cell NHL
Reference n
Patient Characteristics
Median
Number of
Prior
Therapies
Response Rate
ORR CR
Disease Control
Median
Duration of
Response
Y-90 ibritumomab tiuxetan
Witzig TE, et al. J
Clin Oncol
1999;17:3793-803
51 Relapsed or refractory
low-grade or follicular
NHL or intermediate-
grade or mantle-cell NHL
2 67% 26% Median TTP:
12.9+ months
11.7+ months
Witzig TE, et al. J
Clin Oncol
2002;20:2453-63
143 Relapsed or refractory
low-grade, follicular, or
transformed NHL
2 80% CR 30%;
CRu 4%
Rand Trial of Zevalin
vs. Rituximab
Median TTP:
11.2 months
14.2 months
Wiseman GA, et al.
Blood
2002;99:4336-42
30 Relapsed or refractory
low-grade, follicular, or
transformed CD20+ NHL
and mild
thrombocytopenia
2 83% CR: 37%;
CRu: 6.7%
Median TTP: 9.4
months (12.6
months in
responders)
11.7 months
Witzig, et al. J Clin
Oncol
2002;20:3262-9
54 Rituximab-refractory
follicular B-cell NHL
4 74% 15% Median TTP: 6.8
months (8.7
months in
responders)
6.4 months
Gordon LI, et al.
Blood
2004;103:4429-31
51 Relapsed or refractory
low-grade or follicular B-
cell NHL
2 73% CR: 29%;
CRu: 22%
Median TTP: 9.3
months (12.6
months in
responders)
11.7 months
Witzig TE, et al. Leukemia Lymphoma. 2011;52:1188-99.
01-03-2018 RAVIKRISHNA 25
27. RIT consolidation: FIT
90Y-ibritumomab
(n = 207)
Rituximab 250 mg/m2 days −7, 0
90Y-ibritumomab (0.4 mCi/kg)
[max 32 mCi] day 0
CONSOLIDATION
No further treatment
(n = 202)
CONTROL
R
A
N
D
O
M
IZ
A
TI
O
N
Start of study
6-12 weeks after last
dose of induction
CVP = cyclophosphamide, vincristine, prednisone; CHOP = cyclophosphamide, doxorubicin,
vincristine, prednisone; CR = complete response; CR/u = unconfirmed CR; PR = partial response; NR
= no response; PD = progressive disease.
Morschhauser et al. J Clin Oncol. 2008;26:5156-5164.
INDUCTION
Patients with previously
untreated FL
First-line therapy with CVP,
CHOP, CHOP-like, chlorambucil,
fludarabine combination, or
rituximab combination
NR
PD
CR/CRu
or PR
Not Eligible
Response
01-03-2018 RAVIKRISHNA 27
28. The 5-year overall PFS was 29% in the control arm compared with 47% in the 90Y-
ibritumomab arm: HR = 1.95 (95% CI: 1.52 – 2.50); P < 0.001
Hagenbeek, et al. Blood (ASH Annual Meeting Abstracts), Nov 2010; 116: 594
25
50
75
100
0 12 24 36 48 60
ProportionProgressionFree
PFS From Time of Randomization (months)
90Y-ibritumomab
Control
207 174
117
133
83
113
67
98
65
80
46
At risk:
202
90Y-ibritumomab: n = 207
Median PFS: 49 mo
Control: n = 202
Median PFS: 15 mo
0
N F
Control 202 144
90Y-ibritumomab 207 108
RIT consolidation: FIT
01-03-2018 RAVIKRISHNA 28
29. The 5-year OS was 89% in the control arm compared with 93% in the 90Y-ibritumomab
arm: HR = 1.26 (95% CI: 0.68 – 2.35); P = 0.465
Hagenbeek, et al. Blood (ASH Annual Meeting Abstracts), Nov 2010; 116: 594
90Y-ibritumomab
Control
At risk:
207
202
202
194
195
192
185
182
172
171
146
135
0
25
50
75
100
0 12 24 36 48 60
ProportionAlive
OS From Time of Randomization (months)
90Y-ibritumomab
Control
207
202
18
22
N F
90Y-ibritumomab: n = 207
Median PFS: > 98 mo
Control: n = 202
Median PFS: > 101 mo
RIT consolidation: FIT
01-03-2018 RAVIKRISHNA 29
30. FIT Trial: Conclusions…
• 90Y-Ibritumomab consolidation resulted in:
– High conversion rates from PR toCR/CRu: 78%
– High overall CR rate: 87%
• Significantly prolonged median PFS
• 90Y-Ibritumomab consolidation was well-tolerated with manageable
hematologic adverse events
• Confers a durable PFS benefit for patients with advanced FL
• No unexpected toxicities emerging
• For patients who relapse:
– 90Y-Ibritumomab consolidation does not (appear to) rule out any
second-line treatment approach, including ASCT
• At current follow-up: no significant difference in OS between Rx arms
Morschhauser et al. JClin Oncol. 2008;26:5156-516401-03-2018 RAVIKRISHNA 30
31. RIT consolidation: SWOG 0016
• Untreated
follicular
lymphoma
• PS 0-2
• Stage III-IV
R
A
N
D
O
M
I
Z
E
CHOP21 x 6
CHOP21 x 6 +
R x 6 (4 pre, 2 post)
CHOP21 x 6 +
131I tositumomab post
01-03-2018 RAVIKRISHNA 31
32. RIT consolidation: SWOG 0016
• Untreated
follicular
lymphoma
• PS 0-2
• Stage III-IV
R
A
N
D
O
M
I
Z
E
CHOP21 x 6
CHOP21 x 6 +
R x 6 (4 pre, 2 post)
CHOP21 x 6 +
131I tositumomab post
N=27
N=279
N=276
01-03-2018 RAVIKRISHNA 32
33. RIT consolidation: SWOG 0016 (PFS)
0%
20%
40%
60%
80%
100%
0 2 4 6 8 10
Years from Registration
CHOP I-131
CHOP-R
At Risk
265
267
Relapse
or Death
86
106
2-Year
Estimate
80%
76%
2-sided, multivariate p = .11
S0016
CHOP-RIT
CHOP-R
Median FU 4.9y
01-03-2018 RAVIKRISHNA 33
34. Overall Survival: S0016
0%
20%
40%
60%
80%
100%
0 2 4 6 8 10
CHOP I-131
CHOP-R
At Risk
265
267
Deaths
40
26
2-Year
Estimate
93%
97%
2-sided, multivariate p = .08
Years from Registration
CHOP-R
CHOP-RIT
Median FU 4.9y
01-03-2018 RAVIKRISHNA 34
36. 131I-chTNT
• was approved by the Chinese State Food and Drug
Administration to treat refractory bronchogenic carcinoma.
• As a result, 131I-chTNT became the first solid tumor TRIT
agent in the world approved for therapy
• progressive and recurrent glioblastoma multiforme (PHASE 1
TRAIL)
131I-METUXIMAB( LICARTIN)
• The Chinese State Food and Drug Administration has
approved Licartin as adjuvant therapy after OLT for HCC in
2005
01-03-2018 RAVIKRISHNA 36
37. 01-03-2018 RAVIKRISHNA 37
there was no survival benefit for 90Y-HMFG1 IP instillation as consolidation treatment
for EOC, an improved control of IP disease was found, which appeared to be offset by
increased extraperitoneal recurrences
38. 01-03-2018 RAVIKRISHNA 38
RIT TOXICITY
minor allergic responses to the protein components of the cold
antibody
asthenia and nausea
Posttreatment hypothyroidism occurs in approximately 10% to
20% of patients treated with 131I-tositumomab despite
physiologic thyroidblocking maneuvers
Neutropenia and thrombocytopenia
Second Malignancies After RIT( MDS)
39. 01-03-2018 RAVIKRISHNA 39
90Y-Zevalin is a pure beta emitter
• to administer y-90 plexiglass(1cm) shielded syringe is
needed
• Radiation exposure for patient family and for the treatment
team is minimal.
RIT safety precautions Y-90
40. 01-03-2018 RAVIKRISHNA 40
the penetrating gamma emissions and longer half-life of 131I-
Bexxar mandate more extensive shielding for the patient’s family
and for the health care team.
lead bricks or custom shielding infusion syringe or infusion
pump,
isolated or shielded location for the treatment
more stringent posttreatment safety instructions must be given
to the patient and the patient’s family
RIT safety precautions I -131
