This document discusses radioimmunotherapy (RIT), which involves targeting tumor cells with radiolabeled antibodies or other constructs. It covers the basics of immunology and tumor immunology as they relate to identifying tumor antigens. The ideal properties of tumor targets and carriers for RIT are described. Challenges with RIT for solid tumors are outlined, as are strategies to improve effectiveness like pretargeting techniques and using different types of radiation. Key radionuclides used in RIT and factors in radiochemistry like chelators are also summarized.
Hypofractionation in early breast cancer is no more a research scholars topic. Multiple studies with robust data have proven its utility. It may hold an important role in many countries with constrained resources. This is a short presentation incorporating important completed and ongoing trials. Feel free to use this.
Hypofractionation in early breast cancer is no more a research scholars topic. Multiple studies with robust data have proven its utility. It may hold an important role in many countries with constrained resources. This is a short presentation incorporating important completed and ongoing trials. Feel free to use this.
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
Acute scrotum is a general term referring to an emergency condition affecting the contents or the wall of the scrotum.
There are a number of conditions that present acutely, predominantly with pain and/or swelling
A careful and detailed history and examination, and in some cases, investigations allow differentiation between these diagnoses. A prompt diagnosis is essential as the patient may require urgent surgical intervention
Testicular torsion refers to twisting of the spermatic cord, causing ischaemia of the testicle.
Testicular torsion results from inadequate fixation of the testis to the tunica vaginalis producing ischemia from reduced arterial inflow and venous outflow obstruction.
The prevalence of testicular torsion in adult patients hospitalized with acute scrotal pain is approximately 25 to 50 percent
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
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2. Introduction
• Magic bullet or targeted therapy
• Paul Ehrlich in 1898
• Successful targeting of tumor cells
• High affinity
• Targeted radionuclide therapy – appropriate
term
3. Immunology
• Innate and adaptive immunity
• Innate – immediate – neutrophils, macrophages and
NK cells, complement system, cytokines
• Adaptive – develops over time – late 1-7 days
• More effective with subsequent exposure of antigen
• Remember and responds quickly to same antigen
• Lymphocytes and secreted antibodies
• Humoral immunity – B lymphocytes
• cell mediated immunity – helper T cells, cytotoxic T
lymphocytes
4. • Somatic mutations
• Deregulation of tumor suppressor genes / oncogenes
• Expression of tumor antigens
• TA are recognized by T cells and NK cells
• Cancer immune surveillance
• Transplant patients – SCC, BCC, kaposi, Melanoma,
Lymphoma
• Discontinuing immunosuppressive drugs – tumor
regression
• Immunocompromised & immunocompetent
• Majority in immunocompetent
7. Targets of RIT
• TAA (Tumor Associated Antigens
• Expressed on the surface of tumor cells
• Abnormal extracellular matrix
• >2000 TAAs
• SEREX
– Methodology to identify TAAs
– Serologic Analysis of recombinant cDNA Libraies
– Prepared from various malignancies or testes tissue
– This cDNA library is transduced in E.Coli to produce protein library
– Various proteins are tested againts serum of cancer patients
– Clones that react to IgG antibodies – TAA
• Cancer immunome
8. • SErEX defined
– Mutational antigens
– Amplified or over expressed antigens
– Differentiation antigens
– Cancer/Testes antigens
• Only few TAAs have been used as targets of
RIT
9. MUC1 Breast & Ovary
Prostate
TAG72 Breast & Ovary
Prostate , Lung
Colorectal
PSMA Prostate
EGFR H&N
CEA Colorectal, Breast, lung, MTC
Melanin Melanoma
NCAM NB
Ganglioside GD2 Medulloblastoma
10. Ideal target
• One that is overexpressed on cancer cells
– Overexpression is necessary because typical targeting constructs require antigen densities
≥105 receptors on each cell for adequate targeting.
• Uniformly expressed
– Nonuniform activity distributions will significantly lower the effectiveness of RIT by
subsequently resulting in nonuniform or heterogeneous dose distributions.
– Radionuclides with short path lengths of the emitted particles (i.e., Auger and α-particle
emitters).
• Not found to any significant level in normal tissue
• Not shed into the circulation
– the targeting construct may bind and “complex” with the antigen
– result in a more rapid clearance of the RIT agent and a much less effective treatment
• Exhibits an important role in tumor growth and progression.
– add to the cytotoxicity of the radionuclide because of the blockade or promotion of
intracellular signaling
– disruption of growth pathways important for tumor growth.
11. Carriers (targeting constructs)
• Antibodies
• Antibody fragments
• Peptides
• Affibodies
• Aptamers
• nanostructures (i.e., liposomes, nanoparticles, microparticles, nanoshells, and
minicells).
• Intact monoclonal antibodies (mAbs) have dominated the field of RIT as targeting
constructs
• In humans, there are five classes or isotypes of antibodies
– (IgA, IgD, IgE, IgG, and IgM)
– IgG is the most commonly used mAb for RIT because it is the most prevalent antibody in
serum and has the longest serum half-life, typically measured in weeks (~23 days).
– IgG is further divided into four subtypes, IgG1–4.
– IgG antibodies are large glycoprotein macromolecules, with an atomic mass of approximately
150,000 dalton (Da) or 150 kDa. The “y-shaped structure” consists of two Fab fragments
(antigen-binding fragment; ~50,000 Da each) and an Fc fragment (crystallizable fragment;
~50,000 Da).
12.
13. • Hybridoma technique
• Murine mAbs – NHL
– Ibritumomab & tositumomab
– Concerns of HAGAs/HAMAs (human antiglobulin
antibodies)
– Decreasing targeting capabilities and adverse effects
• Two main strategies to overcome immunogenicity
– the production of antibody chimeras derived from
both murine and human DNA
– the production of humanized or fully human
antibodies
14. • RIT has been less successful for treating solid tumors than
hematologic malignancies.
– lack of radiosensitivity of epithelial tumors (compared to
hematologic malignancies)
– poor penetration of mAbs into large tumors.
– The decreased penetration of 150-kDa antibodies into large
tumors is a direct result of increased tumor interstitial pressure,
an aberrant tumor vasculature, and an abnormal tumor
extracellular matrix.
• When radiolabeled, a long serum half-life of the targeting
construct will increase exposure of the bone marrow to
radiation
– hematologic toxicity and limits the amount of antibody and
radionuclide that can be given.
15. • Somatostatin is one of the most common peptides
• Overexpressed in a multitude of malignancies
– breast cancer, small cell lung cancer, medullary thyroid cancer, and
neuroendocrine tumors (NETs).
– Somatostatin is rapidly degraded- octreotide, is very stable.
– Octreoscan (indium-111 diethylenetriamine penta-acetic acid [111In-DTPA])
has been shown to be highly diagnostic for NETs.
• Aptamers are single-stranded DND or RNA oligonucleotides
– Library by a process termed SELEX (systemic evolution of ligands by
exponential enrichment).
– Attractive alternative to larger mAbs because they are chemically synthesized ,
have a low cost of production, exhibit high affinities, have a small size, are
rapidly cleared from the circulation, have an unlimited shelf life, exhibit rapid
tissue penetration, and are nonimmunogenic.
– The major detriment of using aptamers as targeting constructs for RIT is their
short serum half-life (measured in minutes) secondary to nuclease
degradation.
16. THE PHYSICS AND RADIOBIOLOGY OF
RIT
• Delivers radiation to the target tissue in a continuous,
although declining, low–dose rate (LDR) fashion
• 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.
• This can be compared to the high–dose rate (HDR)
delivery of radiation by external beam radiation
therapy (EBRT).
• EBRT typically will deliver radiation at a dose rate of
100 to 500 cGy per minute.
17. • In RIT, the dose rate is 1,000-fold lower
– Quadratic portion of the curve will have a much lower impact on
survival
– Sublethal damage will be repaired during the more lengthy delivery of
LDR radiation.
– “small” or absent observable shoulder and flattening of the cell
survival curve.
– RIT, α alone will define the radiosensitivity of the tumor (blue line
– RIT is approximately 20% less effective than HDR EBRT.
– RIT does appear to be effective.
• low-dose/dose rate apoptosis
• low-dose hyperradiosensitivity-increased radioresistance
• inverse dose rate effect (G2 synchronization)
• radiation-induced biologic bystander effect
• crossfire effect
18.
19. Radionuclides
• Three basic categories depending on the type of emitted particulate
radiation.
• β-emitters - Radionuclides that emit high-energy electrons
– electrons have maximum path lengths in tissue from 0.6 to 12.0 mm.
– range of approximately 60 to 1,100 cell diameters.
– The most commonly used β-emitters - yttrium 90 [90Y], iodine 131 [131I], and
lutetium 177 [177Lu].
• α-emitters - 211At and 225Ac.
– An α-particle is a helium nucleus that has a maximum range in tissue of 55 to
100 μm (5 to 10 cell diameters).
– Although it has a short range, the α-particle is very destructive and has a high
linear energy transfer (LET).
• Low-energy electron emitters also emit radiation that is high LET
– path lengths between 2 and 500 nm
– Auger emitters, such as 111In or 125I, are most effective if delivered to the
nucleus of a cell or incorporated into the DNA.
20. Half life MeV
Yttrium 90 2.7 d 2.19
Iodine 131 8.0 d 0.28
Astatine-211 7.2 h 5.87
Actinium-225 9.92 d 5.83
Iodine 125 60.1 d 0.030
Iodine 123 0.55 d 0.030
Indium 111 2.80 d 0.026
Technetium 99m 6.01 h 0.018
Gallium 67 3.26 d 0.009
21. Radiochemistry
• Labeling the targeting construct with the appropriate
radionuclide is exceedingly important and equally
complex.
• Radionuclides are attached to targeting constructs
– using a “linker” molecule, termed a bifunctional chelating agent
(BCA)
– a chemical reaction that forms a covalent bond between the
radionuclide and the targeting construct.
• Three basic scientific fields converged to make
radiochemistry a reality:
– coordination chemistry
– directed biologic targeting
– medical application of radiopharmaceuticals
22. • Metallic radionuclides will require a BCA for labeling
– 90Y (metallic radionuclide)
• Radiohalogens will require a chemical reaction (halogenation)
– 131I (radiohalogen)
• One of the most commonly used BCAs is DTPA
– A polyaminopolycarboxylate straight chain ligand.
• Tiuxetan
– Modified DTPA molecule
– Used as a linker molecule to chelate 90Y to ibritumomab (90Y
ibritumomab tiuxetan; Zevalin).
• The halogenation reaction that bonds 131I to a protein-targeting
construct (131I tositumomab; Bexxar, GlaxoSmithKline,
Philadelphia, PA; discontinued 2013) is called iodination.
23. • RIT is much less effective for soild tumours
• Strategies to potentially increase the
effectiveness
– Pre targetting techniques
– Extracorporeal delivery
– Combined modality therapy
– ffractionation
– Radionuclide cocktail
– Different types of LET radiation
– Increasing antibody mass
24. Antibody based RIT
• Radiolabelled mAbs take 2-3 days to localize or accrete
into tumors
• Prolonged exposure to bone marrow
• Bone marrow as the dose-limiting normal tissue
• Smaller targetting constructs ((antibody fragments,
peptides, aptamers) can be used
• Rapid clearance from blood
• Lower tumor accretion and retention of smaller
constructs – rapid clearance is offset
• Auger radionuclides are only toxic if internalised to
cells
25. Pretargeting Strategies
• The basic premise of pretargeting is to
separate the delivery of a large,
macromolecule-targeting construct
(prolonged circulation time) from the delivery
of a much smaller cytotoxic radioconjugate
(more rapid circulation time).
• Two main approaches have been employed
– Bispecific monoclonal antibody (bsmAb) system
– Streptavidin–biotin system
26. bsmAb system
– Portion of the antibody has affinity for the tumor (antitumor), and
another portion has affinity for the radionuclide carrier ligand or
hapten–peptide (antihapten)
– Step 1
• A large “saturation” dose of the unlabeled bsmAb is administered, and the
antibody localizes in the tumor over several days. Occasionally, a clearing
step is used to facilitate the clearance of the bsmAb from the circulation
– Step 2
• A radionuclide conjugated to a hapten–peptide is administered that has
high affinity for the antihapten portion of the bsmAb.
• This step results in a rapid distribution of the radionuclide in the tumor
owing to the high affinity of the hapten–peptide for the bsmAb.
• The hapten–peptide has a small molecular weight, it will clear rapidly from
the body
• low–bone marrow exposure to radiation
27. Streptavidin–biotin system
• Streptavidin is conjugated to the initial pretargeting
macromolecule
• Biotin is conjugated to the radionuclide
• Streptavidin and biotin have a very high affinity for each other
• There may be some advantages to the bsmAB system
28. CONJUGATED THERAPY
• The basic premise - delivery of targeted cytotoxic
radiotherapy
• Low dose, LDR, sparsely ionizing and delivered in
a single fraction. Initially, this reality seemed to
be a natural “fit” for hematologic malignancies
that were sensitive to most types of radiation.
• Currently, Zevalin is greatly underutilized because
it has not shown a survival benefit for its
respective indications.
29. Hematologic Trials and Approved
Therapeutic Agents
• NCCN – RIT follicular lymphoma clinical situations
– first-line therapy for the elderly or infirm (Category 2B)
– first-line consolidation (Category 2B)
– Second-line (relapse/refractory) and subsequent therapy (Category 1).
– Zevalin continues to show very promising results for follicular
lymphoma first-line monotherapy, diffuse large B-cell lymphoma and
mantle cell lymphoma consolidation and second-line therapy, and
transplantation studies.
– Zevalin has the only U.S. FDA approval for first-line consolidation and
second-line therapy.
• 131I tositumomab is a mixed β-/γ-emitter. The gamma spikes at 364
keV, and the beta emission has energy of 0.6 MeV. The maximum
range in tissue of the β-particle is 2.3 mm (R90 = 0.7 mm)
• This agent can be imaged on gamma camera to calculate total body
clearance.
30. Drug Targeting
construct
Target Radionuclide Disease
Zevalin
(Ibritumomab
Tiuxetan)
IgG1
(Murine)
CD20 90Y NHL (low-grade
follicular)
Bexxar
(Tositumomab)
IgG2a
(Murine)
CD20 131I NHL (low grade
follicular)
31. • The treatment is delivered over 1 to 2 weeks
• On day 1, both protocols deliver an infusion of
nonradioactive (cold) anti-CD20 antibody (Zevalin employs
rituximab; Bexxar employed tositumomab) designed to
saturate the CD20 antigen sink (depletion of peripheral B
cells and the binding of nonspecific sites in the liver and
spleen) and provide antibody mass, which improves
biodistribution and tumor targeting.
• The administered activity for Zevalin is based on weight
– 0.4 mCi/kg for a platelet count ≥150,000
– 0.3 mCi/kg for a platelet count of 100,000 to 149,000
– maximum of 32 mCi
32. • A single gamma scan (111In ibritumomab tiuxetan) is used to
confirm a normal biodistribution on days 3 to 4.
• Based upon the analysis of five trials, which revealed an altered
biodistribution scan in only about 1% of patients, the FDA removed
the requirement of the biodistribution scan.
• The administered activity for Bexxar was based on a calculated total
body clearance (three scans over 1 week) that delivers a total-body
(red bone marrow) dose of 75 cGy.
• This calculation is reduced to a total-body dose of 65 cGy for a
platelet count <150,000.
• Eligible patients for Zevalin are also required to have an absolute
neutrophil count (ANC) ≥1,500 and a bone marrow biopsy that
reveals <25% lymphoma involvement.
33. Relapse Setting
• Zevalin or Bexxar appear to suggest an overall response
rate (ORR) of 60% to 80% and a CR rate of 20% to 50%.
• A phase III study comparing Zevalin versus rituximab for
patients with relapsed or refractory low-grade follicular B-
cell NHL or transformed NHL
– Patients were randomized to either a single intravenous (IV)
dose of Zevalin 0.4 mCi/kg (n = 73) or IV rituximab 375 mg/m2
weekly for four doses (n = 70).
– The RIT group was pretreated with two rituximab doses (250
mg/m2) to improve biodistribution and tumor targeting.
– After the first rituximab dose on day 1, 111In ibritumomab
tiuxetan was administered to assess biodistribution and to aide
in dosimetry.
34. – No patients received the therapeutic dose of 90Y ibritumomab tiuxetan
(Zevalin) if >20 or 3 Gy was calculated to any nontumor organ or the red
marrow, respectively.
– Zevalin was administered after the second rituximab dose approximately 1
week (days 7 to 9) after the first dose of rituximab and (111)In ibritumomab
tiuxetan.
– The administered activity of Zevalin was capped at 32 mCi.
– Patients in both arms of the study received two prior chemotherapy regimens.
– The ORR was 80% for Zevalin and 56% for rituximab (P = .002). The CR rates
were 30% and 16% (P = .04), respectively, in the Zevalin and rituximab group.
– Durable responses ≥6 months were 64% versus 47% (P = .030) for Zevalin
versus rituximab.
– The conclusion of the study was that RIT with Zevalin was well tolerated and
resulted in statistically significant and clinically significant higher ORRs and CRs
than rituximab alone.
35. Frontline Therapy
• Concerns about RIT for treating large bulky tumors
– Tumor penetration
– overall required dose,
– Nonuniform dose distributions
• Bringing RIT into a frontline therapeutic setting after induction chemotherapy and
maximum cytoreduction would be the next logical direction.
• Patients with CD20+ stage III/IV follicular B-cell NHL who achieved a PR or CR to
induction chemotherapy
• Randomized to Zevalin (n = 208) or to the control arm, representing no further
treatment (n = 206).
• Prior to chemotherapy, patients had documented <25% bone marrow
involvement.
• After induction chemotherapy, blood counts had to recover such that the ANC was
≥1.5, platelets were ≥150,000, and hemoglobin was ≥9.
• Patients in the Zevalin arm were treated with an activity of 0.4 mCi/kg; A
MAXIMUM ACTIVITY OF 32 MCI
• Although two doses of rituximab (250 mg/m2) were used, an 111In biodistribution
scan was not required.
36. • The data were analyzed with a median follow-up of 3.5 years.
Zevalin consolidation resulted in a median progression-free survival
(PFS) advantage of 36.5 versus 13.3 months in the control arm (P <
.0001).
• The PFS benefit was maintained in the Zevalin arm regardless if
patients achieved a PR (29.3 vs. 6.2 months; P < .0001) or CR (53.9
vs. 29.5 months; P = .0154).
• This resulted in a final CR rate of 87% in the treatment arm, and this
result compares well with established data. In the treatment arm,
90% of patients who were Bcl-2 positive converted to a negative
status (90% molecular CR).
• The FIT trial has been updated and with a median follow-up of 7.3
years 90Y-ibritumomab consolidation results in a 3-year benefit in
median PFS (41% vs. 22%; P < .001) and improves time to next
treatment by 5.1 years (P <.001).
37. SOLID TUMOR TRIALS AND APPROVED
THERAPEUTICS
• Peptide receptor radionuclide therapy (PRRT) used for greater than
a decade to treat advanced NETs expressing somatostatin receptors.
• The most common PRRT agents are
– 177Lu–DOTATATE
– 90Y–DOTATOC
• 177Lu–DOTATATE was administered at an activity of 7.4 GBq (200
mCi) per infusion, every 8 weeks for a total of 4 doses.
• The 177Lu–DOTATATE group exhibited a significant progression-free
survival (P < .001) and overall survival (P = .004).
• Lutathera gained US FDA approval for somatostain receptor positive
gastroenteropancreatic neuroendocrine tumors on 1/26/2018.
38. Advanced lung cancer
• Iodine-131–chimeric tumor necrosis treatment (131I-chTNT)
• IV administrations were delivered at an activity 0.8 mCi/kg
• Intratumoral injections were delivered at an activity of 0.8 mCi/cm3 of
tumor size.
• IV 131I-chTNT, the ORR was 35.5% (3.2% CR; 32.2% PR)
• Intratumoral injection of 131I-chTNT, the ORR was 33.3% (5% CR; 20.9%
PR)
• Median survival was 11.7 months, and the 1-year survival rate was 41.4%.
• The average absorbed doses
• Tumor and normal lung were 8.45 and 2.35 Gy for patients receiving
systemic 131I-chTNT and 30.0 and 2.65 Gy for patients receiving
intratumoral 131I-chTNT
• The major toxicity was hematologic and reversible
• In 2003, 131I-chTNT was approved by the Chinese State Food and Drug
Administration to treat refractory bronchogenic carcinoma
39. HCC
• 131I antiferritin antibody
• There was, however, no significant difference in
the initial “intent-to-treat” treatment arms based
on response rate and survival
• Licartin is an antibody fragment, F(ab’)2, that
targets HAb18G/CD147, a HCC TAA.
• Licartin (131I metuximab)
– The Chinese State Food and Drug Administration has
approved Licartin as adjuvant therapy after OLT for
HCC in 2005. To my knowledge, this trial has not been
updated.
40. CNS malignancies
• Antigen targets
– Epidermal growth factor receptor (EGFR)
– Tenascin
– Neural cell adhesion molecule (NCAM)
– Placental alkaline phosphatase (PLAP)
– Phosphatidyl inositide
• The RIT agent
– 125I-anti–EGFR antibody intravenously in three
weekly doses (50 mCi) beginning during week 4 of the
EBRT
41. • Most of the CNS RIT trials to date are of “dose searching pilot” or
phase I design.
• The evolution of the trials has seen the delivery route move from
systemic (intra-arterial or IV) to local instillation of the RIT agent
into a surgically created resection cavity (SCRC).
• Blood–brain barrier (BBB) is often disrupted by a rapidly growing
CNS malignancy
• 150-kDa antibodies would still not likely cross to a significant
degree
• EBRT in conjunction with TRT
• EBRT will cause an increase in the permeability of the BBB and
increase vascular leakage.
• Only 0.001% to 0.01% of the systemically delivered antibody will
penetrate each gram of solid tumor
42. • Direct instillation of the TRT agent into the SCRC is an attractive
alternative to the systemic approach
• The local approach is accomplished by injecting or instilling the RIT
agent directly into the SCRC via an Ommaya or Rickham catheter.
• Murine, chimeric, or humanized mAbs attached
– 131I
– 90Y
– 188Re
– 211At
• Fractionation, pretargeting, and a combined modality approach
using EBRT and chemotherapy.
• Binding site barrier phenomena, interstitial tumor pressure,
aberrant tumor vasculature, and a recusant extracellular tumor
matrix will significantly impede antibody penetration
43. • 131I or 90Y-ERIC-1 (anti-NCAM antibody)
• 131I-81C6 (antitenascin mAB)
– 80 mCi for leptomeningeal disease (intrathecal
delivery)
– 100 mCi for heavily pretreated and recurrent glioma
(into SCRC)
– 120 mCi for de novo glioma (into SCRC)
• 211At-ch81C6
• 131I-antitenascin antibody (Neuradiab)
• 131I-chTNT-1/B mAb