the promise of mrna vaccines
DESCRIPTION
mRNA rather than DNA may become the nucleotide framework for new classes of drugs and vaccines. Exciting preclinical results in prophylaxis and initial clinical data in oncology suggest that mRNA technology could be translated into improvements in lung cancer and other diseases.TRANSCRIPT
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.