Radioimmunotherapy

RADIOIMMUNOTHERAPY
MECHANISM
APPROVED AGENTS

1. RADIOIMMUNOTHERAPY PRESENTER: Dr.M.RAVIKRISHNA MODERATOR: Dr.SWAPNA DEPT. OF RADIOTHERAPY SVIMS 02-03-2018 RAVIKRISHNA 1

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. 02-03-2018 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 02-03-2018 3

4. 02-03-2018 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. 02-03-2018 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

6. Crossfire Enhances Efficacy Unlabeled “Cold” Antibody Radiolabeled Antibody Courtesy of Andrew D. Zelenetz, MD, PhD. 02-03-2018 RAVIKRISHNA 6

7. 02-03-2018 RAVIKRISHNA 7 BYSTANDER

8. 02-03-2018 RAVIKRISHNA 8 BYSTANDER

9. 02-03-2018 RAVIKRISHNA 9 BYSTANDER

10. 02-03-2018 RAVIKRISHNA 10 Inverse Dose Rate Effect

11. 02-03-2018 RAVIKRISHNA 11 TARGETS( TUMOR ANTIGENS) CARRIERS( ANTIBODIES) RADIONUCLIDES RADIOCHEMISTRY

12. 02-03-2018 12 TARGETS( TUMOR ASSOCIATED ANTIGENS) RAVIKRISHNA

13. 02-03-2018 13 Ideal target overexpressed on cancer cells , U niformly 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 ≥10 5 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

14. 02-03-2018 14 Carrier IDEAL MORE TUMOR UPTAKE LESS TIME TO ACCRETION AND FASTER CLEARANCE RAVIKRISHNA

15. 02-03-2018 15 RADIONUCLIDES RAVIKRISHNA

16. 02-03-2018 16 RADIONUCLIDES RAVIKRISHNA

17. 02-03-2018 17 RADIOCHEMISTRY METALLIC RADIONUCLIDES – BIFUNCTIONAL CHELATING AGENT ( Tixuetan ) RADIOHALOGEN I 131------HALOGENATION REACTION RAVIKRISHNA

18. 02-03-2018 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

19. 02-03-2018 19 1.Bispecific mono clonal antibody RAVIKRISHNA

20. 02-03-2018 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. 02-03-2018 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 infusion RAVIKRISHNA

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 02-03-2018 RAVIKRISHNA 22

23. 02-03-2018 RAVIKRISHNA 23

24. 02-03-2018 RAVIKRISHNA 24 RELAPSE SETTING

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. 02-03-2018 RAVIKRISHNA 25

26. 02-03-2018 RAVIKRISHNA 26 FRONTLINE THERAPY

27. RIT consolidation: FIT 90 Y-ibritumomab (n = 207) Rituximab 250 mg/m 2 days −7, 0 90 Y-ibritumomab (0.4 mCi/kg) [max 32 mCi] day 0 CONSOLIDATION No further treatment (n = 202) CONTROL RANDOMIZATION 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 02-03-2018 RAVIKRISHNA 27

28. The 5-year overall PFS was 29% in the control arm compared with 47% in the 90 Y-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 12 24 36 48 60 Proportion Progression Free PFS From Time of Randomization (months) 90 Y-ibritumomab Control 207 174 117 133 83 113 67 98 65 80 46 At risk: 202 90 Y-ibritumomab: n = 207 Median PFS: 49 mo Control: n = 202 Median PFS: 15 mo N F Control 202 144 90 Y-ibritumomab 207 108 RIT consolidation: FIT 02-03-2018 RAVIKRISHNA 28

29. The 5-year OS was 89% in the control arm compared with 93% in the 90 Y-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 90 Y-ibritumomab Control At risk: 207 202 202 194 195 192 185 182 172 171 146 135 25 50 75 100 12 24 36 48 60 Proportion Alive OS From Time of Randomization (months) 90 Y-ibritumomab Control 207 202 18 22 N F 90 Y-ibritumomab: n = 207 Median PFS: > 98 mo Control: n = 202 Median PFS: > 101 mo RIT consolidation: FIT 02-03-2018 RAVIKRISHNA 29

30. FIT Trial: Conclusions… 90 Y-Ibritumomab consolidation resulted in: High conversion rates from PR to CR/CRu: 78% High overall CR rate: 87% Significantly prolonged median PFS 90 Y-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: 90 Y-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. J Clin Oncol . 2008;26:5156-5164 02-03-2018 RAVIKRISHNA 30

31. RIT consolidation: SWOG 0016 Untreated follicular lymphoma PS 0-2 Stage III-IV RANDOMIZE CHOP21 x 6 CHOP21 x 6 + R x 6 (4 pre, 2 post) CHOP21 x 6 + 131I tositumomab post 02-03-2018 RAVIKRISHNA 31

32. RIT consolidation: SWOG 0016 Untreated follicular lymphoma PS 0-2 Stage III-IV RANDOMIZE 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 02-03-2018 RAVIKRISHNA 32

33. RIT consolidation: SWOG 0016 (PFS) 0% 20% 40% 60% 80% 100% 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 02-03-2018 RAVIKRISHNA 33

34. Overall Survival: S0016 0% 20% 40% 60% 80% 100% 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 02-03-2018 RAVIKRISHNA 34

35. 02-03-2018 RAVIKRISHNA 35 SOLID TUMORS

36. 131 I-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) 131 I-METUXIMAB( LICARTIN) The Chinese State Food and Drug Administration has approved Licartin as adjuvant therapy after OLT for HCC in 2005 02-03-2018 RAVIKRISHNA 36

37. 02-03-2018 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. 02-03-2018 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. 02-03-2018 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. 02-03-2018 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

41. 02-03-2018 RAVIKRISHNA 41 THANK YOU