advances in immunotherapy for lymphomas and myeloma
TRANSCRIPT
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)• OncoPep (consultant)
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
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)
PreclinicalIsolate antigen
Package in Delivery system
Idiotype: A clonal marker and model tumor antigen
Mature B cellsLymphoma *
= malignant transformation *
Idio-: Defn: Ancient Greek ἴδιος (“own, personal, distinct”)
Personalized Human Vaccine Production
Tumor biopsy
Fusion and Id sequencedetermination
Hybridoma scale-up
Affinity purification
Id protein matches each patient’s tumor
(automated)
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
Types of vaccines
• Therapeutic
• Secondary prevention
• Prevention (e.g. infectious diseases)
NCI/Biovest Phase III Trial: 2-Stage Study Design
LNBx
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 groups2 < 8 or > 8 cycles
6 - 12 months 6 months6 - 8 months
(Id Vaccine)
(Control)
ITT mITT
Disease Free Survival from Randomization (mITT)
log-rank p=0.045
Median Follow-up 56.6 mo (range 12.6 – 89.3)
Median DFSId vaccine = 44.2 moControl vaccine = 30.6
mo
Events Id vaccine = 44Control 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
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 = 35Control N = 25
Median DFSIgM-Id vaccine = 52.9 mo
[95% CI:40.2,NA]Control = 28.7 mo
[95% CI:21.0,39.8]Events IgM-Id vaccine = 17Control = 20
Schuster , Neelapu et al. (Kwak) J Clin Oncol 29:2787, 2011
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-CD20 mAb (rituximab)-containing chemotherapy regimens
• Making further improvements in the vaccine product (e.g. 2nd generation DNA fusion vaccines)
2nd generation DNA Vaccine Strategy
• Maintain or improve efficacy
• Reduce Manufacturing Time– For Protein Vaccines: 3-6 months– For DNA Vaccines: 4-5 weeks
Biragyn et al. [Kwak] Nature Biotech 1999 and Science 2002
Next generation vaccine development: genetic fusions
Antigen Presenting Cell (APC) Receptor Targeting
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)
J Immunol 1997; 159: 5921 Science 1997; 276: 273Immunol. Rev. 1997; 160: 43Mol. Ther. 2004; 9; 902Exp. Opin. Biol. Ther. 2008; 8: 475
J Immunol 1997; 159: 5921 Science 1997; 276: 273Immunol. Rev. 1997; 160: 43Mol. Ther. 2004; 9; 902Exp. Opin. Biol. Ther. 2008; 8: 475
Anti-CD3Anti-CD3Anti-CD28Anti-CD28
Artificial APC: Bead Artificial APC: Bead
Signal 1Signal 1
GrowthGrowth
CD28 CTLA4 CD28 CTLA4TcR/CD4TcR/CD4
Signal 2Signal 2
Activated T Cell Production with Artificial APCsCellular and Vaccine Production Facility CVPF
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
100
10
1
0.1
0.01
T cell expansion
ex vivoCancerVaccine
“Thresholdfor cure”% Tumor
specificT cells in
vivo
Hypothesis
Combining Active and Passive Immunotherapy
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 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
Overview of the Clinical Trial
Figure D1. Schematic overview of the clinical protocol.
Imm
unoa
sses
smen
t
R
Id-KLH/GM-CSF Priming vs
Placebo vaccine
Id-KLH/GM-CSFBooster
Vaccines /Placebo
T cellTransfer
LymphodepletionChemotherapy
Day 0 Day 2Day -14
Apheresis
T cell expansion
B
A
Plasma-pheresis
Elig
ibili
tyTu
mor
Res
tagi
ng
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 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
AcknowledgementsCenter 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)