vaccination thérapeutique en oncologie -...
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Vaccination thérapeutique en Oncologie
Dr Denis Migliorini MDJournées Franco-Suisses de Pharmacie Hospitalière
24.04.2015Mâcon-Bourgogne
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• Interaction cancer/host immune system
• Immunotherapy History
• Target identification
• Different types of Vaccines
• Adjuvants/Vaccine Delivery
• Response assessment to immune therapies
• Future : Overcoming microenvironment/T celltherapies
• Our experience : Glioma
Plan
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Using the immune system ?
Incidence of cancers is increased in
constitutive and acquired immunodeficiencies
T cells may kill tumor cells
T cells invade tumors
intra-tumoral activated T cells is a
favorable prognostic factor for many cancers
spontaneous regressions are mediated by T cells
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Tumor immunity : how does it work ?
Cancer cells
APCs/DCs
T cell
Tumor Draining lymph node
CD80 CD86CD28
TCR
MHC +tumor peptide
APCT cell
tum
or
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• most potent professional APCs
• sentinels at peripheral tissues
uptake, process, and present pathogen to naive T lymphocytes at the lymphoid organs through MHC molecules
• bridge between innate and adaptive immunity
Biology of DCs
Ehrlich/Metchnikov
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Ag Processing/Presentation
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Immune evasion1. Loss of Ag expression
2. Immunosupp cell + cytokinesrecruitment
3. Exploiting PD1 immune checkpoint pathway
Hanahan D. Cell 2011
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• 1891, Dr. W. Coley first attempt to stimulate the immune system
• intratumoral injections
• of inactivated Strepto. pyogenes
• and Serratia marcescens
Coley WB. Contribution to the knowledge of sarcoma. Ann Surg 1891
Coley’s toxin
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• Despite effectiveness, skepticism by scientific community
• modern science has shown that Coley’s principles were correct
• BCG similar to Coley’s toxin : still being used intravesically for superficial bladder cancer
Lamm, D. L. et al. , NEJM 1991
Coley’s toxin
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History
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• approved two prophylactic vaccines :
For HBV (cause of liver cancer)
For HPV (70% of cervical cancers)
• One therapeutic vaccine :
Sipuleucel-T (1), prostate cancer patients
U.S. Food and Drug Administration (FDA)
(1)Kantoff P.W. et al. NEJM 2010
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Finn et al. 2008 NEJM
Three Ways for Self Antigens to Become Tumor Antigens
Targets ?
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• Active immunotherapy
Priming of lymphocytes by stimulation of dendritic cells with Ags
• Adoptive immunotherapy:
Passive administration of lymphocytes, ater
amplification/activation
Immune strategies
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• Vaccin therapeutic, not prophylactic
• Aim : activate various immune effector mechanisms to :
specifically attack and destroy cancer cells
and spare normal cells.
Alter tumor microenvironment
Therapeutic cancer vaccine : definition
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Therapeutic vaccines
1. synthetic peptides
• single peptide (EFGRvIII)
2. Genetic vaccines
• DNA/RNA•Viral vaccines
3. Cell based
•DC vaccines •Autologuous tumor cells•Allogeneic tumor cells• multiple peptides
(EphA2, IL-13Rα2, YKL-40, gp100; HSPPC-96, …)
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Cell vaccines
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• entire spectrum of tumor-associated antigens (TAAs)
• may be modified to confer higher immunostimulatory characteristics.
Autologous tumor cell vaccines
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• contain 2 or 3 established human tumor cell lines
• overcome many limitations of autologous tumor cell vaccine
Standardized/large-scale vaccine production
Easy manipulation for expression of immunostimulatory molecules
Cost effectiveness.
Allogeneic tumor cell vaccines
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• Canvaxin™ : 3 melanoma lines combined with BCG as an adjuvant
• belagenpumatucel-L : 4 NSCLC lines + TGF-b2
Allogeneic tumor cell vaccines
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DC vaccines
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Kaplan–Meier Estimates of Overall Survival.
Kantoff PW et al. N Engl J Med 2010
Sipuleucel T Provenge
APCs from PBMCsIncubated with PAPfused to GM-CSF.
4.1-month improvement in median survival
modest antitumor efficacyLabor intensive
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• Stimulation with costimulatory molecules
CD40, CD70, GITRL, 4-1BBL (CD137L), and OX40L
• proinflammatory factors
IL-12p70, IL-2, IL-18, CCR7,and CXCL10, also enhances DC functions
Modification of DCs to improve vaccine potency
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Anguille S. et al. Lancet Oncol 2014
Combination strategies for DC vaccines
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Clinical use of DCs for cancer therapy
Anguille S. et al. Lancet Oncol2014
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• Very potent tool to induce immune response
• variable that may affect the function in clinical trials :
Ag loading strategy
maturation status
route and frequency of administration
Adjuvants
Conclusion DC vaccines
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Genetic vaccines
DNA/RNA Vaccines
Viral vaccines
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Ex vivo transfection of somatic cells• myocytes, keratinocytes or DCs
• with viral or plasmid DNA vectors carrying the expression cassettes
• Those cells infiltrate muscle or skin as a part of the inflammatory response to vaccination
• Results in subsequent cross-priming or direct Ag presentation.
• easy delivery and activation of various arms of immunity
Aurisicchio & Ciliberto, 2012
Genetic vaccines
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• bacterial plasmids
• constructed as a shuttle to deliver and express TAA
• bacterial DNA itself acts as PAMPs to stimulate TLRs
DNA vaccines
Barber, 2011; Beutler et al., 2006; Spies et al., 2003, Liu 2011
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• mRNA from autologous tumor tissues
• Diff with DNA vaccines :
• Total RNA vaccine (various TAA) : reduce the possibility of tumor escape
• Less side effects or autoimmune diseases due to rapid degradation and clearance
RNA Vaccines
Carralot et al., 2005; Scheel et al., 2005; Wolff et al., 1990
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• viral vectors :
low disease-causing potential
low intrinsic immunogenicity
engineered to encode TAAs +/-immunomodulating molecules.
Viral vaccines
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Peptide vaccines
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• MAGE-1 is the first gene reported to
encode a human TAA recognized by T cells
• target only one epitope or a multiple epitopes of the TAA
• able to induce antigen-specific T-cell responses
• Disappointing clinical outcomes
Peptide vaccines
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Schwartzentruber, D. J., et al. (2011) N Eng J Med, 364, 2119–2127.
this was the first phase III trial todemonstrate a clinical benefit for a peptide vaccine in melanoma
gp100 peptide vaccine and interleukin-2in advanced melanoma
Phase III trial
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• TAAs are poorly immunogenic in nature
• pioneering work of Charles Janeway
• adaptive immune responses are preceded by innate immunity receptors triggered by microbial components : PAMPs
• via TLRs on DCs, engages innate and adaptive immunity
Janeway, C. A., Jr. (1992). Immunology Today
Adjuvants
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Adjuvants
Bobanga I et al., Vaccine 2013
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• In vivo
T cell infiltration of tumor
Autoimmunity
Dth
• In vitro
ELISA or ELISPOT for cytokine release
Intracellular cytokine
T cell proliferation
Peptide MHC tetramer
Cytotoxic T cell function
CTL plas frequency
Immunomonitoring of response
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Wolchok J. et al., Clin Cancer Res 2009
Comparison between WHO criteria and IrRC
Response assessment
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Therapeutic approaches to overcome immune tolerance
Maus M.V. et al. Blood 2014
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T cell therapy
Tumor Draining lymph node
Cancer cells
DCs
T cell
1. Therapeutic vaccine
2. Cell therapy with engineered T cells
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T cell
TCR
CD3ζ
Tumor cell
MHC/pgranzyme
perforin
introduction of a high-avidity
TCR
introduced
TCR
T cell
Tumor cell
MHC/p
introduction of an
antibody CAR engineering
T cell
Tumor cell
native
TCRCD3ζ
antibody
CD3ζ
TCR and CAR T cell engineering
TCR engineering
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Chimeric Ag Receptor
June, C. H. Principles of adoptive T cell cancer therapy. J. Clin. Invest. 2007
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Tumor microenvironment
Restifo N. et al. Cancer Res 2012
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Front Immunol. 2013 May 15;4:116
Reshaping tumor Microenvironment
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T cell targets for immunoregulatory antibody therapy.
Mellman I. et al. Nature 2011
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Our experience
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The wish list for glioma antigens
Antigen expressed by glioma in vivo
Presented as MHC-peptides complexes and recognized by CD8 T cells
Wide expression in tumors and by many patients
Little or no expression on normal tissue
tumor cell
Normal
tum
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Identification of glioma-associated antigens
GLFVTARIL
ELVRQATIG
AAGIGILTV
GIFGTLAVL
RTAGIWYVL
TAARIGLVI
ALFVTARIL
sequencing
32 HLA-A2+ patients
3686 HLA-A2-
restricted peptides
tumorMHC/peptide
peptides
Peptide Source protein
BCA478-486 BCAN (Brevican )
CHI10-18 CHI3L2 (Chitinase 3-like 2)
CSP21-29 CSPG4 (Chondroitin sulfate proteoglycan 4)
FABP7118-126 FABP7 (Fatty acid binding protein 7, brain)
IGF2BP3552-560 IGF2BP3 (Insulin-like growth factor 2 mRNA binding protein 3)
NLGN4X131-139 NLGN4X (Neuroligin 4, X-linked)
NRCAM692-700 NRCAM (Neuronal cell adhesion molecule)
PTP195-203 PTPRZ1 (Protein tyrosine phosphatase, receptor-type, Z polypeptide 1)PTP1347-1355
TNC3-11 TNC (Tenascin C)
- function associated with tumorigenesis
- absent/low expression in healthy tissues
- proteins over-expressed in glioma
- immunogenic
selection process
immatics biotechnologies GmbHTubingen, Germany
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Phase I/II clinical trials in GBM patient with the IMA950 vaccine
UK
45 patients
GM-CSF
USA
25 patients
GM-CSF
cyclophosphamide
imiquimod (TLR7/8 agonist)
Geneva
16 patients
Poly-ICLC (TLR3 agonist)
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Personalized glioma vaccines
GAPVACGlioma actively personalized vaccine consortium
• peptides are compared to a pool of pre-defined peptides known to be presented by GBM tumors
• peptides are eluted from the patient’s tumor • tumor is sequenced
• mutated peptides are identified
• the patient is vaccinated with these peptides
Step 2: mutated antigens
• the patients is vaccinated with mutated peptides
Step 1: overexpressed antigens
PI: W. Wick, HeidelbergCo-PI: PY. Dietrich, Geneva
N = 20 pts (7 centers) Combination with adjuvant TMZ chemotherapy
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• Feasibility and toxicity already proven
• Efficacy only in a minority of patients
• Less immune editing when multiple peptide approach
• Importance of chosing the right set of peptides
• HLA restriction is limiting factor
• T cell therapy seems to overcome vaccine hurdles
Conclusion
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