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Monoclonal Antibodies in Cancer Treatment

Monoclonal Antibodies in Cancer Treatment. Monoclonal Antibody Therapy for Cancer. FDA approved:. Rituximab anti-CD20 lymphoma Herceptin anti-her2/neu breast cancer Myelotarg anti-CD33 AML Campath anti-CD52 CLL Zevalin 90 Y anti-CD20 lymphoma Bexxar 131 I anti-CD20 lymphoma.

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Monoclonal Antibodies in Cancer Treatment

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  1. Monoclonal Antibodies in Cancer Treatment

  2. Monoclonal Antibody Therapy for Cancer FDA approved: Rituximab anti-CD20 lymphoma Herceptin anti-her2/neu breast cancer Myelotarg anti-CD33 AML Campath anti-CD52 CLL Zevalin 90Y anti-CD20 lymphoma Bexxar 131I anti-CD20 lymphoma

  3. Monoclonal Antibody Therapy for Cancer Mechanism of action: Rituximab antibody Herceptin antibody Myelotarg antibody + toxin Campath antibody Zevalin antibody + radioactive isotope Bexxar antibody + radioactive isotope

  4. Production of Hybridomas Immunize Myeloma cell line, unable to grow in HAT Mouse spleen cells Mix and fuse cells Transfer to HAT medium Darnell, Lodish, Baltimore. Molecular Cell Biology , Scientific American Books, 1986

  5. Only fusion cells (mutant myeloma + spleen) will grow in HAT medium Surviving colonies are grown in individual wells Darnell, Lodish, Baltimore. Molecular Cell Biology , Scientific American Books, 1986

  6. Hybridoma clone producing desired antibody is isolated and expanded

  7. Progress in the Production of Human Monoclonal Antibodies Mouse monoclonals - Kohler & Milstein, 1975 Development of YACs - 1987 Isolation of YAC containing > 1 mb of human immunoglobulin genes - 1989 Transgenic mouse producing human immunoglobulin - 1993 Transgenic mouse producing only human immunoglobulins - 1995 8 8 8 8 8

  8. Rituximab Anti-CD20 Monoclonal Antibody Therapy for Follicular Lymphoma > 375 mg/m2 4 to 5 hour i.v. infusion weekly x 4 doses > Follicular and other low-grade non-Hodgkin’s lymphomas with relapse > Treated patients: 4.5 years median since diagnosis 10 months median since last therapy > Adverse events: fever 73% chills 38% nausea 19% Most reactions were during the first infusion only Maloney DG, Grillo-Lopez AJ, Levy R, et al. Blood 1997; 90:2188-2195

  9. Patient V. H. age 72 Follicular lymphoma diagnosed 10 years ago, treated with radiation for supraclavicular adenopathy 8 years later treated briefly with cytoxan Treated with Rituxan several months later with minimal tumor regression Treated 1 year later with Zevalin

  10. V. H. 2/18/02

  11. CT scan 3 months after Zevalin

  12. Rituximab Anti-CD20 Monoclonal Antibody Therapy for Follicular Lymphoma CD20 is expressed on the cell surface of about 90% of b-cell lymphomas Mechanisms of cell kill: complement antibody-dependent cell-mediated cytotoxicity apoptotic effect mediated by CD20 Maloney DG, Grillo-Lopez AJ, Levy R, et al. Blood 1997; 90:2188-2195

  13. Time to Progression for Patients Responding to IDEC-C2b8 Monoclonal Antibody Maloney DG, Grillo-Lopez AJ, Levy R, et al. Blood 1997; 90:2188-2195

  14. Rituximab Anti-CD20 Monoclonal Antibody Therapy for Follicular Lymphoma > 9% CR, 41% PR (37 patients treated) > 50 days median time to response > B-cell depletion lasting > 6 months > 25% had infection in first 60 days, all treated successfully with antibiotics > Normal immunoglobulin levels Maloney DG, Grillo-Lopez AJ, Levy R, et al. Blood 1997; 90:2188-2195

  15. Rituximab anti-CD20 monoclonal antibody as initial therapy for follicular lymphoma > 60 patients with untreated follicular or small cell NHL > Rituxan 375 mg/m2 i.v. weekly x 4, then repeated q 6 months x 4 > Response rate = 73%, 37% complete response > Median duration of progression-free survival = 34 months Hainsworth JD Litchy S, et al. J Clin Oncol 2002; 20:4261-7

  16. Rituximab anti-CD20 monoclonal antibody as initial therapy for follicular lymphoma Hainsworth JD Litchy S, et al. J Clin Oncol 2002; 20:4261-7

  17. Rituximab + Chemotherapy as initial therapy for follicular non-Hodgkin’s lymphoma 40 patients with untreated follicular NHL CHOP-R x 6 Cytoxan, hydroxydaunamycin (adriamycin), oncovin (vincristine), prednisone + Rituxan Response rate = 95%, complete response = 55% Median duration of response not reached at 29 months 8 8 8 8 Czuczman MS Grillo-Lopez AJ, et al. J Clin Oncol 1999; 17:268-276

  18. Rituximab + Chemotherapy as initial therapy for follicular non-Hodgkin’s lymphoma 8 8 of 18 patients had lymphoma cells expressing bcl-2 by PCR 7/8 had negative PCR after therapy Abstract at ASH 2001 reports median duration of remission > 5.5 years 8 8 Czuczman MS Grillo-Lopez AJ, et al. J Clin Oncol 1999; 17:268-276

  19. Rituximab + Chemotherapy as initial therapy for follicular non-Hodgkin’s lymphoma Czuczman MS Grillo-Lopez AJ, et al. J Clin Oncol 1999; 17:268-276

  20. Rituximab + CHOP for large cell non-Hodgkin’s lymphoma 8 399 patients between 60 and 80 randomized Diffuse large cell b-cell lymphoma No prior treatment CHOP x 8 cycles vs (CHOP + R) x 8 cycles 8 8 8 Coiffier B, Lepage E, et al. NEJM 2002; 346:235-42

  21. Rituximab + CHOP for large cell non-Hodgkin’s lymphoma Coiffier B, Lepage E, et al. NEJM 2002; 346:235-42

  22. Rituximab + CHOP for large cell non-Hodgkin’s lymphoma Coiffier B, Lepage E, et al. NEJM 2002; 346:235-42

  23. Rituximab + CHOP for large cell non-Hodgkin’s lymphoma Coiffier B, ASCO 2003

  24. Radioimmunopharmaceuticals 90Yttrium conjugated anti-CD20 antibody 131I iodinated anti-CD20 antibody

  25. Zevalin Murine anti-CD20 Path length = 5.5 mm 90Y half life = 64 hr Bexxar Murine anti-CD20 Path length = 0.8 mm 131I half life = 8 days

  26. Treatment with isotope-conjugated antibody Contraindicated if > 25% bone marrow involvement with lymphoma Imaging dose given for dosimetry calculations “Cold” antibody given first to saturate b-cells in circulation

  27. Treatment with isotope-conjugated antibody Given as a single treatment Myelosuppression 4 to 6 weeks after treatment

  28. Rituxan vs Zevalin for Non-Hodgkins for Lymphoma Relapsed or refractory follicular or transformed NHL 147 patients randomized to Rituxan or Zevalin Witzig TE, Gordon LI, et al. J Clin Oncol 2002; 20:2453-63

  29. Rituxan vs Zevalin for Non-Hodgkins for Lymphoma Time to progression for patients with follicular NHL Time to progression for patients with CR Witzig TE, Gordon LI, et al. J Clin Oncol 2002; 20:2453-63

  30. Rituxan vs Zevalin for non-Hodgkins for lymphoma Myelosuppression after treatment with Zevalin Time to progression for patients with CR Witzig TE, Gordon LI, et al. J Clin Oncol 2002; 20:2453-63

  31. Rituxan vs Zevalin for non-Hodgkin’s for lymphoma Circulating b-cells after treatment Witzig TE, Gordon LI, et al. J Clin Oncol 2002; 20:2453-63

  32. Bexxar for follicular NHL Relapsed or refractory follicular or transformed NHL Median of 4 previous treatments 60 patients treated with a single course of 131I anti-CD20 antibody Kaminski MS, Press OW, Vose JM, et al. J Clin Oncol 2001; 19:3918-28

  33. Bexxar for follicular NHL Kaminski MS, Press OW, Vose JM, et al. J Clin Oncol 2001; 19:3918-28

  34. Bexxar + Chemotherapy for follicular NHL 90 patients with advanced, untreated follicular NHL (SWOG S0016) Age 23 to 84 CHOP x 6 Bexxar 4 to 8 weeks after last course of chemotherapy Press OW, Maloney DG, et al. Blood 2003; 102:1606-12

  35. Bexxar + chemotherapy for follicular NHL PR + CR = 90% CR = 67% Restaged after CHOP and after Bexxar 57% had improvement in best response following Bexxar Press OW, Maloney DG, et al. Blood 2003; 102:1606-12

  36. Bexxar + chemotherapy for follicular NHL Press OW, Maloney DG, et al. Blood 2003; 102:1606-12

  37. Bexxar + chemotherapy for follicular NHL Press OW, Maloney DG, et al. Blood 2003; 102:1606-12

  38. Potential Problems with Monoclonal Antibody Therapy Allergic reaction to foreign protein Inadequate exposure of tumor cells to antibody Blocking effect of soluble antigen Inadequate host effector response Antigenic variation of tumor cells 4 4 4 4 4

  39. Further developments for monoclonal antibody therapy Replacement of hybridoma technique with “repertoire cloning” Continued development of antibodies as diagnostic reagents Clinical trials with monoclonals targeting other tumor-relevant antigens: Vascular endothelial growth factor (VEGF), epithelial growth factor, integrins, numerous other cell surface antigens (>200 trials open) 4 4 4

  40. Monoclonal antibodies for treatment of non-Hodgkin’s lymphoma Rituxan, Zevalin, Bexxar generally not adequate as single agent treatment for large cell lymphoma Rituxan is becoming accepted as standard treatment when used with CHOP as initial therapy 8 8

  41. Monoclonal antibodies for treatment of non-Hodgkin’s lymphoma Rituxan, Zevalin, Bexxar have useful activity for treatment of follicular lymphoma relapsed or refractory to chemotherapy Possible use as single agent for initial therapy Most effective use may be with chemotherapy as initial therapy 8 8 8

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