Post on 20-Jun-2015
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The promise of mRNA vaccines
Zeena Nackerdien
Vaccines (1)
19th & 20th centurymilestones
1900s- 1980s
ToxoidVaccines(1900s)
1stcombinationVaccines(1948)
Salk and Sabinpolio Vaccines(1950s)
1st polysaccharidevaccine (1970s)
Glyco-conjugatechemistry(1980s)
1strecombinantantigenVaccines(1981)
mRNA vaccine
Peptide vaccines in HIV (2) & NSCLC (3)
1st therapeutic vaccine (prostate cancer)
2010
Reverse vaccinology
2013
2013-14
2008
21st centurymilestones
1. Delany I, Rappuoli R, De Gregorio E. Vaccines for the 21st century. EMBO molecular medicine. 2014;6(6):708-20.2. Jackson A, Kloverpris HN, Boffito M, Handley A,, et al. A randomised, placebo-controlled, first-in-human study of a novel clade C therapeutic peptide vaccine administered ex vivo to autologous white blood cells in HIV infected individuals. PloS One. 2013;8(9):e73765.3. Kotsakis A, Papadimitraki E, Vetsika EK, et al. A phase II trial evaluating the clinical and immunologic response of HLA-A2+ non-small cell lung cancer patients vaccinated with an hTERT cryptic peptide. Lung Cancer.86(1):59-66.
CMV
Cancer
Measles
B
RSV
Self-amplifying
RNA
Self-replicating
RNA
Favivirus
ds RNA
Influenza A/Puerto
Rico 8/34/virus
mRNA
Hepatitis C, HIV
Influenza, allergy
HIV
Avian influenza
Naked
Gene gun
Liposomes
Lipid nanoparticles
Electroporation
Type of vector
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Naked & encapsulated RNA vaccines used for different diseases
CMV, cytomegalovirus; RSV, respiratory syncytial virus4. Rodriguez-Gascon A, del Pozo-Rodriguez A, Solinis MA. Development of nucleic acid vaccines: use of self-amplifying RNA in lipid nanoparticles. International Journal of Nanomedicine. 2014;9:1833-43.
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mRNA vaccines (5)
RNActive® vs other mRNA vaccines: Enhanced protein
expression & favorable activation of immune system
Relevant mRNA vaccine features:1. Needs to cross only one membrane to be active in the cytoplasm2. No need for promoter3. Active in non-dividing cells4. Cost-effective5. Lyophilized vaccines retain full biological activity6. Practically any cell type, including DCs can be transfected with mRNA
DC, dendritic cell5. Kallen KJ, Thess A. A development that may evolve into a revolution in medicine: mRNA as the basis for novel, nucleotide-based vaccines and drugs. Therapeutic advances in vaccines. 2014;2(1):10-31.
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EXAMPLE TEXTmRNA
RNActive® vaccines (6)
Cap5’UTR ORF 3’UTR polyA
tail
Modifications with
naturally occurringA, C, G or U
Framework for modified RNAs used in RNActive® vaccines
“Self-adjuvanticity” bestowed by complexing with protamine5
Stage IIIB/IV NSCLCNCT00923312CV9201 cocktail
Prostate (hormone-refractory)
NCT00831467CV9103 cocktail
Results: Clinically tested RNActive® cocktails showed high immunogenicity rates for patients with pre-specified prostate cancer or NSCLC
Clinical trials (Prostate cancer & NSCLC)
6. Kallen KJ, Heidenreich R, Schnee M et al. A novel, disruptive vaccination technology: self-adjuvanted RNActive((R)) vaccines. Human vaccines & immunotherapeutics. 2013;9(10):2263-76.5. Kallen KJ, Thess A. A development that may evolve into a revolution in medicine: mRNA as the basis for novel, nucleotide-based vaccines and drugs. Therapeutic advances in vaccines. 2014;2(1):10-31.
IV1%
NSCLC schematicsa & 5-yr OS ratesb [2007] (7)
IA49%
IB45%
NSCLC, non-small cell lung cancer; OS, overall survival; a. Representative diagrams from UK Cancer Center (Wikipedia); b Calculated from patient data in the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database; not representative of outcomes for any given individual7. American Cancer Society. Non-small cell lung cancer survival rates by stage http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-survival-rates.
IIA30%
IIB31%
IIIB5%
IIIA14%
NSCLC immunotherapies: focus on checkpoint inhibitors & vaccines
Monoclonal antibodies, immune checkpoint inhibitors, therapeutic vaccines, and adoptive T cell transfer8
*Different clinical stages; Ig, immunoglobulin; CTLA4, cytotoxic T-lymphocyte-associated protein 4; PD-1, programmed cell death protein 1 and PDL-1, programmed death-ligand 14MAGE-3, melanoma antigen 3; NY-ESO-1, cancer vaccine consisting of an immunogenic peptide derived from the cancer-testis antigen8. Cancer Research Institute. Cancer Immunotherapy (Lung Cancer) 2014 http://www.cancerresearch.org/cancer-immunotherapy/impacting-all-cancers/lung-cancer.9. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252-64.
Antibody or Ig fusion proteinIplimumab/Tremelimumab/MDX-1106/MDX-1105/MK-3475
Targets* e.g.CTLA4/PD-1/PD-L18
Therapeutic vaccines
Targets* e.g.MAGE-3, NY-
ESO-1, surviving,
p53, mucin9
Afatinib clinical trial program (10)
2
3
4
56
7
8
1
LUX-LUNG TRIALS
LUX-Lung 1 (NCT0065613)LUX-Lung 2 (NCT00525148)LUX-Lung 3(NCT00949650)LUX-Lung 4 (NCT00711954)LUX-Lung 5 (NCT01085136LUX-Lung 6 (NCT01121393)LUX-Lung 7 (NCT01466660)LUX-Lung 8 (NCT01523587)
21LUX-HEAD-AND-NECK-TRIALS
LUX-head-and-neck 1 (NCT01345682)
LUX-head-and-neck-2 (NCT01345669)
10. Boehringer Ingelheim fact sheet: Afatinib clinical trial program 2014 :
http://us.boehringer-ingelheim.com/content/dam/internet/opu/us_EN/documents/Media_Press_Releases/2013/BI-Afatinib-Fact-Sheet-2013.pdf.
Investigational, oral, once-daily irreversible ErbB Family Blocker that
specifically inhibits epidermal growth factor receptor (EGFR or ErbB1), human epidermal
receptor 2 (HER2 or ErbB2), and ErbB4
Preclinical results showed combining mRNA-based
vaccines with radiation therapy significantly ↑tumor
suppressors, ↑ CD4+, CD8+ and NKT infiltration of mouse
tumors and ↓tumor-associated factors (12)
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Goal:IMPROVE OS
CV9202 + afatinib + chemoradiation in unresectable stage
3 NSCLC
CV9202 + afatinib in advanced or
metastatic EGFR-mutated NSCLC
RNActive® vaccine in 2 NSCLC settings
Afatinib: Indicated as first-line treatment of patients with metastatic
NSCLC whose tumors have EGFR-exon 19
deletions or exon 21 (L858R) substitution
mutations (11)
EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; OS, overall survival11. US Food and Drug Administration: Afatinib (approval) 2013, http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm360574.htm.12. Fotin-Mleczek M, Zanzinger K, Heidenreich R, Lorenz C, Kowalczyk A, Kallen KJ, et al. mRNA-based vaccines synergize with radiation therapy to eradicate established tumors. Radiation oncology (London, England). 2014;9:180.