Advances in immunotherapy for lymphomas and myelomas Larry
- Slides: 25
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 • • • Biovest International (consultant) Xeme Biopharma, Inc. (equity) Celgene (research support) Celltrion (consultant) Onco. Pep (consultant)
Positive controlled Phase III cancer vaccine/immunotherapy clinical trials • Sipuleucel-T (prostate cancer) * NEJM July 2010 • Ipilimumab (melanoma) * NEJM August 2010 • gp 100 peptide (melanoma) NEJM June 2011 • B-cell idiotype protein (lymphoma) J Clin Oncol July 2011 * FDA approved
Bench-to-bedside development of a homegrown therapeutic agent from an academic laboratory Y Isolate antigen Phase I/II Clinical Trial (Nature Med 1999): Lymphoma Tumor • Vaccine induces molecular remissions 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 chemotherapyinduced remission (n=117, p=0. 045) CD 4+ CD 8+ cytokines
Idiotype: A clonal marker and model tumor antigen Mature B cells * Lymphoma * Idio-: Defn: Ancient Greek ἴδιος (“own, personal, distinct”) = malignant transformation
Personalized Human Vaccine Production Fusion and Id sequence determination Tumor biopsy Hybridoma scale-up (automated) Affinity purification Id protein matches each patient’s tumor
Vaccine components • Idiotype of the Ig antigen of a Bcell 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 GM-CSF KLH
Types of vaccines • Therapeutic • Secondary prevention • Prevention (e. g. infectious diseases)
NCI/Biovest Phase III Trial: 2 -Stage Study Design (Id Vaccine) Chemo LN Bx Stratify for IPI 1, cycles of PACE 2 2: 1 Randomization Assign CR (Control) 6 - 12 months 6 - 8 months ITT • 2 prospective efficacy analyses • Primary endpoint: disease-free survival • 14 sites enrolled patients from 2000 -2007 6 months m. ITT 1 low, low-intermediate or high-intermedia high groups 2 < 8 or > 8 cycles
Disease Free Survival from Randomization (m. ITT) Median Follow-up 56. 6 mo (range 12. 6 – 89. 3) Id vaccine( n=76) Control vaccine (n=41) Median DFS Id vaccine = 44. 2 mo Control vaccine = 30. 6 mo Events Id vaccine = 44 Control vaccine = 29 Cox PH Model log-rank p=0. 045 HR = 0. 62; [95% CI: 0. 39, 0. 99] (p=0. 047) Schuster , Neelapu et al. (Kwak) J Clin Oncol 29: 2787, 2011
Disease Free Survival for Patients with Ig. M-isotype lymphomas: a potential predictive biomarker Median Follow-up 56. 6 mo (range 12. 6 – 89. 3) N = 60 Ig. M-Id vaccine N = 35 Control N = 25 Median DFS Ig. M-Id vaccine = 52. 9 mo [95% CI: 40. 2, NA] Control = 28. 7 mo [95% CI: 21. 0, 39. 8] Events Ig. M-Id vaccine = 17 Control = 20 Schuster , Neelapu nd et al. (Kwak) J Clin Oncol 29: 2787, 2011 52 ASH Annual Meeting, Orlando, FL
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
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. CD 20 m. Ab (rituximab)-containing chemotherapy regimens • Making further improvements in the vaccine product (e. g. 2 nd generation DNA fusion vaccines)
2 nd generation DNA Vaccine Strategy • Maintain or improve efficacy • Reduce Manufacturing Time – For Protein Vaccines: 3 -6 months – For DNA Vaccines: 4 -5 weeks
Next generation vaccine development: genetic fusions Antigen Presenting Cell (APC) Receptor Targeting Biragyn et al. [Kwak] Nature Biotech 1999 and Science 2002
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. 5 ml intramuscular injection rotated between thighs • Dosing Cohorts: – Cohort 1: 500 g – Cohort 2: 2500 g • Schedule of Administration: Wk 0 Wk 4 RP 100457, Cancer Prevention & Research Institute of Texas (CPRIT; Kwak) Multiple Myeloma SPORE, Project 2 (Thomas/Neelapu) Wk 8
Activated T Cell Production with Artificial APCs Cellular and Vaccine Production Facility CVPF Artificial APC: Bead Anti-CD 3 Anti-CD 28 Tc. R/CD 4 Signal 1 CD 28 CTLA 4 Signal 2 Growth 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
Activated T Cell Production Ex Vivo 1. Leukapheresis, enrich, deplete, or isolate cells of interest 5. Quality Control Reinfuse cells 4. Remove beads, wash and concentrate cells 3. Large scale cell expansion 2. Stimulate cells with a. APC
Combining Active and Passive Immunotherapy 100 Hypothesis 10 % Tumor specific T cells in vivo “Threshold for cure” 1 0. 01 Cancer Vaccine T cell expansion ex vivo
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)
Objectives • Primary – Whether infusions of Id-KLH primed CD 3/CD 28 activated autologous lymphocytes mediate a more intense Id-specific immunity than KLH-primed CD 3/CD 28 activated autologous lymphocytes • Secondary – To demonstrate that Id-KLH primed CD 3/CD 28 autologous lymphocytes can be infused safely and effectively in more than 80% of eligible patients – To determine whether Id-KLH primed CD 3/CD 28 activated autologous lymphocytes are as safe and as well tolerated as the KLH-primed CD 3/CD 28 activated autologous lymphocytes – To determine if the presence of Id-specific immunity correlates with disease response
Overview of the Clinical Trial Multiple Myeloma SPORE, Project 1 (Qazilbash/Kwak)
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 Ig. M 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
Acknowledgements Kwak Laboratory • Soung-chul Cha • Hong Qin • Sheetal Rao • Daniel Paick • Ippei Sakamaki • Flavio Baio • James Weng • Beata Lerman • Guowei Wei • Kunhwa Kim • Sung Doo Kim Center for Cancer Immunology Research Sapna Parshottam Sattva Neelapu Sheeba Thomas Dept. of SCTCT Richard Champlin Muzaffar Qazilbash EJ Shpall/Ian Mc. Niece Grant support • Leukemia & Lymphoma Society SCOR (7262 -08) • Myeloma SPORE (NCI P 50 CA 142509) • Do. D CDMRP (W 81 XWH-07 -1 -0345) • CPRIT (RP 100457)
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