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Advances in immunotherapy for lymphomas and myelomas

Advances in immunotherapy for lymphomas and myelomas. Larry W. Kwak, M.D., Ph.D. Chairman, Department of Lymphoma/Myeloma Justin Distinguished Chair in Leukemia Research Co-Director, Center for Cancer Immunology Research MD Anderson Cancer Center. CME Disclosures.

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Advances in immunotherapy for lymphomas and myelomas

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  1. Advances in immunotherapy for lymphomas and myelomas Larry W. Kwak, M.D., Ph.D. Chairman, Department of Lymphoma/Myeloma Justin Distinguished Chair in Leukemia Research Co-Director, Center for Cancer Immunology Research MD Anderson Cancer Center

  2. CME Disclosures • Biovest International (consultant) • Xeme Biopharma, Inc. (equity) • Celgene (research support) • Celltrion (consultant) • OncoPep (consultant)

  3. Positive controlled Phase III cancer vaccine/immunotherapy clinical trials • Sipuleucel-T (prostate cancer) * NEJM July 2010 • Ipilimumab (melanoma) * NEJM August 2010 • gp100 peptide (melanoma) NEJM June 2011 • B-cell idiotype protein (lymphoma) J Clin Oncol July 2011 * FDA approved

  4. Bench-to-bedside development of a homegrown therapeutic agent from an academic laboratory Y Lymphoma Tumor • Phase I/II Clinical Trial (Nature Med 1999): • Vaccine induces molecular remissions Isolate antigen Preclinical • Addition of GM-CSF Adjuvant improves vaccine potency (Kwak et al. PNAS 1996) Package in Delivery system Tumor protein • Phase III Controlled Clinical Trial • (J Clin Oncol 2011) • Vaccine prolongs DFS in patients in a chemotherapy- induced remission (n=117, p=0.045) CD8+ cytokines CD4+

  5. Idiotype: A clonal marker and model tumor antigen * Mature B cells Lymphoma = malignant transformation * Idio-: Defn: Ancient Greek ἴδιος (“own, personal, distinct”)

  6. Personalized Human Vaccine Production Fusion and Id sequence determination Tumor biopsy Hybridoma scale-up (automated) Affinity purification Id protein matches each patient’s tumor

  7. Vaccine components • Idiotypeof the Igantigen of a B-cell lymphoma canbe used as a tumor-specific immunogen • Keyhole lympet hemocyanin (KLH) carrier serves as an immune stimulant • GM-CSF administered concurrently at site of injection as an adjuvant KLH GM-CSF

  8. Types of vaccines Therapeutic Secondary prevention Prevention (e.g. infectious diseases)

  9. NCI/Biovest Phase III Trial: 2-Stage Study Design (Id Vaccine) Chemo Stratify for IPI1, cycles of PACE2 2:1 Randomization LN Bx Assign CR (Control) 6 - 12 months 6 months 6 - 8 months ITT mITT • 2 prospective efficacy analyses • Primary endpoint: disease-free survival • 14 sites enrolled patients from 2000-2007 1low, low-intermediate or high-intermediate, high groups 2 < 8 or > 8 cycles

  10. Disease Free Survival from Randomization (mITT) • Median Follow-up • 56.6 mo (range 12.6 – 89.3) • Median DFS • Id vaccine = 44.2 mo • Control vaccine = 30.6 mo • Events • Id vaccine = 44 • Control vaccine = 29 • Cox PH Model • HR = 0.62; [95% CI: 0.39,0.99] (p=0.047) Id vaccine( n=76) Control vaccine (n=41) log-rank p=0.045 Schuster , Neelapu et al. (Kwak) J Clin Oncol 29:2787, 2011

  11. Disease Free Survival for Patients with IgM-isotype lymphomas: a potential predictive biomarker Median Follow-up 56.6 mo (range 12.6 – 89.3) N = 60 IgM-Id vaccine N = 35 Control N = 25 Median DFS IgM-Id vaccine = 52.9 mo [95% CI:40.2,NA] Control = 28.7 mo [95% CI:21.0,39.8] Events IgM-Id vaccine = 17 Control = 20 Schuster , Neelapu et al. (Kwak) J Clin Oncol 29:2787, 2011 52nd ASH Annual Meeting, Orlando, FL

  12. Positive Phase III trial: Potential challenges to “Delivery” • Patient accrual stopped early/treatment effect apparent only in modified ITT • requirement for biopsy and personalized manufacture (“high commercial risk”) • optimal treatment requires sustained complete remission

  13. Future directions • Excisional biopsies serve as a rich source of residual tumor on all patients for genomic profiling/biomarkers • Additional clinical trials combining this vaccine with anti-CD20 mAb (rituximab)-containing chemotherapy regimens • Making further improvements in the vaccine product (e.g. 2nd generation DNA fusion vaccines)

  14. 2nd generation DNA Vaccine Strategy • Maintain or improve efficacy • Reduce Manufacturing Time • For Protein Vaccines: 3-6 months • For DNA Vaccines: 4-5 weeks

  15. Next generation vaccine development: genetic fusions Antigen Presenting Cell (APC) Receptor Targeting Biragyn et al. [Kwak] Nature Biotech 1999 and Science 2002

  16. Phase I Study of an Active Immunotherapy for Asymptomatic Phase Lymphoplasmacytic Lymphoma with DNA Vaccines Encoding Antigen-Chemokine Fusion (RAC # 1007-1050 Sept. 2010) • Formulation and Administration: • 0.5ml intramuscular injection rotated between thighs • Dosing Cohorts: • Cohort 1: 500 g • Cohort 2: 2500 g • Schedule of Administration: Wk 0 Wk 4 Wk 8

  17. Artificial APC: Bead Anti-CD3 Anti-CD28 TcR/CD4 CD28 CTLA4 Signal 1 Signal 2 Growth Activated T Cell Production with Artificial APCs Cellular and Vaccine Production Facility CVPF J Immunol 1997; 159: 5921 Science 1997; 276: 273 Immunol. Rev. 1997; 160: 43 Mol. Ther. 2004; 9; 902 Exp. Opin. Biol. Ther. 2008; 8: 475

  18. Activated T Cell Production Ex Vivo 1. Leukapheresis, enrich, deplete, or isolate cells of interest Reinfuse cells 5. Quality Control 4. Remove beads, wash and concentrate cells 3. Large scale cell expansion 2. Stimulate cells with aAPC

  19. Combining Active and Passive Immunotherapy Cancer Vaccine T cell expansion ex vivo 100 10 1 0.1 0.01 Hypothesis “Threshold for cure” % Tumor specific T cells in vivo

  20. Central Hypothesis • Idiotype (Id-KLH) vaccine + the vaccine-primed adoptive T cell transfer will result in a robust Id-specific humoral and cellular response, compared to a control vaccine (KLH only)

  21. Objectives • Primary • Whether infusions of Id-KLH primed CD3/CD28 activated autologous lymphocytes mediate a more intense Id-specific immunity than KLH-primed CD3/CD28 activated autologous lymphocytes • Secondary • To demonstrate that Id-KLH primed CD3/CD28 autologous lymphocytes can be infused safely and effectively in more than 80% of eligible patients • To determine whether Id-KLH primed CD3/CD28 activated autologous lymphocytes are as safe and as well tolerated as the KLH-primed primed CD3/CD28 activated autologous lymphocytes • To determine if the presence of Id-specific immunity correlates with disease response

  22. Overview of the Clinical Trial Multiple Myeloma SPORE, Project 1 (Qazilbash/Kwak)

  23. Conclusions • Lymphoma vaccination improves disease-free survival following chemotherapy in patients already in complete remission at time of vaccination (secondary prevention) • The clinical effect of the vaccine is validated by the subgroup analysis of patients expressing the IgMisotype • Long-term clinical experience with the vaccine demonstrates low toxicity, making it ideal for consolidation or maintenance therapy (standard of care) • Future cancer vaccine strategies should feature combinations with adoptive T-cell therapy or immunologic checkpoint blockade

  24. Acknowledgements Center for Cancer Kwak LaboratoryImmunology Research • Soung-chul Cha SapnaParshottam • Hong Qin SattvaNeelapu • SheetalRaoSheeba Thomas • Daniel PaickDept. of SCTCT • IppeiSakamaki Richard Champlin • FlavioBaioMuzaffarQazilbash • James WengEJShpall/Ian McNiece • BeataLerman • Guowei Wei • Kunhwa Kim • Sung Doo Kim • Grant support • Leukemia & Lymphoma Society SCOR (7262-08) • Myeloma SPORE (NCI P50 CA142509) • DoD CDMRP (W81XWH-07-1-0345) • CPRIT (RP100457)

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