Advances in immunotherapy for lymphomas and myeloma


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  • Other affected firms
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  • RL introduced me to ….
  • We evaluated an autologous lymphoma vaccine following chemotherapy for treatment of follicular lymphoma.The structure of this vaccine, called BiovaxID, is shown.BiovaxID is composed of tumor-derived Ig containing tumor specific idiotypic and isotypic determinants used to induce a specific immune response against idiotype or Id-bearing tumor cells.This Ig is covalently linked to KLH, which serves as a carrier protein and an immune stimulant.BiovaxID is subcutaneously injected with GM-CSF which serves as an immunologic adjuvant.
  • Modeled after the NCI Phase II trial
  • Standard ITT: NS44.2mo vs. 30.6mo = 50% increase
  • #1 & 2: Practical limitations#3: FL heterogeneous#4: No curative therapy
  • From academic standpoint#1: i.e. CR patients; Excisional biopsies available for genomic profiling/biomarkers#2: PBL IR assays pending (focus on T cell responses)#4: Combinations with novel agents (checkpoint blockade)
  • Goal of the planned study is to translate the knowledge gained in follicular lymphoma to treat patients with LPL.Simplified
  • #1: scientifically, a positive clinical experiment#2: 50% increase vs. 20% projected; c/w Dendreon (3 mo improvement)
  • Advances in immunotherapy for lymphomas and myeloma

    1. 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. 2. CME Disclosures • Biovest International (consultant) • Xeme Biopharma, Inc. (equity) • Celgene (research support) • Celltrion (consultant) • OncoPep (consultant)
    3. 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. 4. Bench-to-bedside development of a homegrown therapeutic agent from an academic laboratory CD4+ • Addition of GM-CSF Adjuvant improves vaccine potency CD8+ cytokines Lymphoma Tumor Y (Kwak et al. PNAS 1996) Phase I/II Clinical Trial (Nature Med 1999): •Vaccine induces molecular remissions • 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) Preclinical Isolate antigen Package in Delivery system
    5. 5. Idiotype: A clonal marker and model tumor antigen Mature B cells Lymphoma* = malignant transformation * Idio-: Defn: Ancient Greek ἴδιος (“own, personal, distinct”)
    6. 6. Personalized Human Vaccine Production Tumor biopsy Fusion and Id sequence determination Hybridoma scale-up Affinity purification Id protein matches each patient’s tumor (automated)
    7. 7. Vaccine components • Idiotype of the Ig antigen of a B- cell lymphoma can be 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 KLHGM-CSF
    8. 8. Types of vaccines • Therapeutic • Secondary prevention • Prevention (e.g. infectious diseases)
    9. 9. NCI/Biovest Phase III Trial: 2-Stage Study Design LN Bx Assign CR Stratify for IPI1, cycles of PACE2 2:1 Randomization Chemo • 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 6 - 12 months 6 months6 - 8 months (Id Vaccine) (Control) ITT mITT
    10. 10. Disease Free Survival from Randomization (mITT) log-rank p=0.045 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) Control vaccine (n=41) Id vaccine( n=76) Schuster , Neelapu et al. (Kwak) J Clin Oncol 29:2787, 2011
    11. 11. 52nd ASH Annual Meeting, Orlando, FL 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
    12. 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. 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. 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. 15. Biragyn et al. [Kwak] Nature Biotech 1999 and Science 2002 Next generation vaccine development: genetic fusions Antigen Presenting Cell (APC) Receptor Targeting
    16. 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 4 Wk 8Wk 0 RP100457, Cancer Prevention & Research Institute of Texas (CPRIT; Kwak) Multiple Myeloma SPORE, Project 2 (Thomas/Neelapu)
    17. 17. 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 Anti-CD3 Anti-CD28 Artificial APC: Bead Signal 1 Growth CD28 CTLA4TcR/CD4 Signal 2 Activated T Cell Production with Artificial APCs Cellular and Vaccine Production Facility CVPF
    18. 18. Activated T Cell Production Ex Vivo 1. Leukapheresis, enrich, deplete, or isolate cells of interest 3. Large scale cell expansion Reinfuse cells 4. Remove beads, wash and concentrate cells 2. Stimulate cells with aAPC 5. Quality Control
    19. 19. 100 10 1 0.1 0.01 T cell expansion ex vivo Cancer Vaccine “Threshold for cure”% Tumor specific T cells in vivo Hypothesis Combining Active and Passive Immunotherapy
    20. 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. 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. 22. Overview of the Clinical Trial Figure D1. Schematic overview of the clinical protocol. Immunoassessment R Id-KLH/GM-CSF Priming vs Placebo vaccine Id-KLH/GM-CSF Booster Vaccines / Placebo T cell Transfer Lymphodepletion Chemotherapy Day 0 Day 2Day -14 Apheresis T cell expansion B A Plasma- pheresis Eligibility TumorRestaging Multiple Myeloma SPORE, Project 1 (Qazilbash/Kwak)
    23. 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 IgM isotype • 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. 24. Acknowledgements Center for Cancer Kwak Laboratory Immunology Research • Soung-chul Cha Sapna Parshottam • Hong Qin Sattva Neelapu • Sheetal Rao Sheeba Thomas • Daniel Paick Dept. of SCTCT • Ippei Sakamaki Richard Champlin • Flavio Baio Muzaffar Qazilbash • James Weng EJ Shpall/Ian McNiece • Beata Lerman • 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)