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.