HPV, Cancer Genes, and Raising Expectations

Transcription

1 HPV, Cancer Genes, and Raising Expectations Douglas R. Lowy Laboratory of Cellular Oncology, Center for Cancer Research National Cancer Institute, National Institutes of Health Keynote Lecture, IFCPC World Congress Orlando, FL April 6, 2017 The views expressed are my own and do not necessarily reflect those of NCI/NIH

2 Disclosures National Institutes of Health (NIH) has patents on papillomavirus L1 virus-like particle (VLP) vaccine technology. I am an inventor. NIH has licensed L1 VLP technology to Merck and GlaxoSmithKline, the two companies with commercial versions of the vaccine. I will discuss potential off-label uses of the FDAapproved vaccines: protecting against HPV-positive oropharyx cancer and fewer vaccine doses Licensees of other NIH technologies of which I am an inventor: GlaxoSmithKline, Sanofi, Shanta Biotech, Cytos Biotech, Aura Biosciences, Etna Biotech, Acambis, PanVax

3 Outline of Presentation Epidemiology of HPV-associated cancer and its implications First & Second Generation preventive HPV vaccines Safely reducing the number of vaccine doses

4 Implications of Identifying HPV as the Main Cause of Cervical Cancer Natural history of HPV infection/pathogenesis of cervical cancer Identification of non-cervical HPV-associated cancers HPV-based cervical cancer screening Likely to replace cytology for primary screening Ancillary tests under study: p16-ink4a (E7 inactivates prb, which increases p16 expression); methylation of specific sites in viral genome HPV-based interventions Preventive vaccine (FDA approved) therapeutic vaccine, antivirals, etc?

5 IARC s Globocan 2012 projection: Cervical cancer mortality rates continue to increase in Low- & Middle-income countries 400, , , ,000 Low- & Middle- Income countries 200, , , ,000 17,000 17,000 CRPV High income countries Projections developed from Globocan 2012

6 USA: HPV-associated Non-cervical Cancers Affect Both Genders and are as Common as Cervical Cancer HPV16/18 Cervix ~70% Anus Male Female Vulva/vagina Penis HPV cases Total cases >90% Oropharynx 0 2,000 4,000 6,000 8,000 10,000 12,000 Annual number of cases Pap screening has reduced cervical cancer incidence by ~80% No approved screening tests for other HPV-associated cancers Incidence of HPV-positive oropharynx cancer increased >3-fold MMWR, 2012; Chaturvedi et al, J Clin Oncol, 2011; Gillison, Chaturvedi, and Lowy., 2008

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8 Cancer genes: Oncogenic microbial agents are molecular targets Genes and proteins of oncogenic microbial agents (e.g., HPV) are as much molecular targets as B-raf, EGFR, etc. Microbial targets (such as HBV, HCV, and HPV): theoretical translational advantages over cell-encoded targets Foreign genes and proteins; 1) easier to develop specific interventions against them than against cell-encoded genes or proteins 2) serious side effects less likely

9 Precision Medicine in Primary Prevention HPV infection: usually self-limited, confers some resistance to re-infection; HPV vaccine mimics main natural immune response that restricts re-infection Population-wide use of preventive vaccines: induces herd immunity; resistant viral mutants do not develop NB: Herd immunity: decreased prevalence of infectious agent

10 Many Collaborators: If you want to go quickly, go alone; If you want to go far, go together Patricia Day Rhonda Kines Cynthia Thompson Tara Berman Chris Buck, Diana Pastrana - LCO, CCR, NCI Bethesda Nicolas Cuburu Susana Pang Alessandra Handisurya Carla Cerqueira Aimee Kreimer, Allan Hildesheim, Mark Schiffman, Mahboobeh Safaeian, Ligia Pinto - DCEG, NCI, Bethesda Peter Choyke, Marcelino Bernardo - Molecular Imaging, CCR, NCI, Bethesda Jeffrey Roberts FDA, Rockville Rolando Herrero IARC, Lyon, France Laboratory of Cellular Oncology, CCR, NCI Bryce Chackerian - University of New Mexico Reinhard Kirnbauer - University of Vienna, Austria John Schiller

11 Choosing an appropriate molecular target for a preventive HPV vaccine Licensed vaccines: mainly preventive, induce neutralizing antibodies HPVs contain viral oncogenes (E5, E6, E7); need subunit vaccine lacking oncogenes. Two HPV proteins can induce neutralizing antibodies: capsid proteins L1 and L2. L1 contains the most immunogenic neutralization epitopes; conformational OUR HYPOTHESIS: L1 self-assembles, makes empty particles with correct conformation, induce high levels of neutralizing antibodies.

12 HPV Virion Prophylactic HPV Vaccines Are L1 Virus Like Particles (VLPs) L1 coding region Insert L1 in Baculovirus expression vector Produce L1 in insect cells L1 spontaneously assembles into VLPs L1 VLP vaccination Induces high titers of neutralizing antibodies Shown first for BPV-1, then for HPV16 HPV16 L1 VLPs Non-infectious, Non-oncogenic Reinhard Kirnbauer et al. PNAS 1992; J Virol 1993

13 First generation HPV vaccines: Composed of Multiple Types of HPV L1 VLPs Gardasil (quadrivalent, Merck) 70% of Cervix Cancer 90% of Genital Warts >90% of Non-cervix Cancer HPV16 HPV18 HPV6 HPV11 Cervarix (bivalent, GlaxoSmithKline) Three intramuscular injections over 6 months

14 Summary of phase III HPV vaccine trials Close to 100% protection against new infection by HPV vaccine types Protects against cervical & non-cervical infection and disease; screening only for cervical disease Limited cross-protection against non-vaccine HPV types Bivalent vaccine: more immunogenic & more crossprotective against non-vaccine HPV types Vaccination not therapeutic; natural history of prevalent infection not altered

15 High Efficacy of VLP Vaccine Repetitive structure of VLP intrinsically immunogenic Tissue-associated neutralizing antibodies exudated at potential sites of infection Levels of exudated antibodies high, similar to serum levels, not lower level of non-disrupted genital tract HPV highly susceptible to neutralizing antibodies

16 High titer antibodies induced by HPV vaccination prevent basement membrane binding Virion No Infection Stratified squamous epithelium Basement membrane Virion STOP Dermis Based on Patricia Day et al, Cell Host Microbe 16: , 2010

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18 Further reduction in cervical cancer by adding more HPV Types to L1 VLP Vaccine % % % 80.3% 82.9% 85.2% 87.4% 88.8% 90.1% 91.3% 92.3% Adapted from Munoz et al, Int J Cancer 111: , 2004

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20 Goals of HPV Vaccination Directly reduce risk of infection and disease in vaccinees Indirectly reduce risk by reducing prevalence of HPV vaccine types in general population (herd immunity)

21 Age-dependent decrease in genital warts in Australian women after HPV Vaccine Implementation in 2007 >30 years years <21 years Ali et al, BMJ 2013 Ali et al, BMJ 2013

22 Herd Immunity: Decreased incidence of genital warts in heterosexual Australian men following female HPV vaccine implementation in 2007 >30 years years <21 years Ali et al, BMJ 2013

23 Herd immunity: Decreased prevalence of HPV6/11/16/18 in heterosexual Australian men following female HPV vaccine implementation in 2007 Chow et al, Lancet Oncol 17:68-77, 2017

24 Henrietta Lacks (HeLa cells) had Cervical Adenocarcinoma Pap smear screening: more sensitive for squamous cell carcinoma than adenocarcinoma ~ 90% of cervical adenocarcinoma caused by HPV16 or HPV18 Henrietta Lacks: HPV 18 cervical adenocarcinoma not detected by cytology Her cancer should now be preventable by the HPV vaccine or by HPV-based screening

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26 Current global vaccination patterns will only have a marginal reduction on cervical cancer of_support/nvs/hpv/hpv-vaccine-infographic 1600_source.jpg

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28 Decreased prevalence of HPV16/18 in the US despite limited HPV vaccine uptake: year old girls (51% received 1 or more doses) % decrease % decrease 0 CRPV Oncogenic HPVs Except for HPV16,18: Not vaccine targeted Oncogenic HPV 16,18: Vaccine targeted Adapted from Markowitz et al, Pediatrics 2016

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30 Moving to two vaccine doses for young adolescents Immune response in girls and boys <15 years old stronger than older teenagers Young adolescents: 2 doses separated by 6 months produce an immune response even greater than the efficacy trials Iverson et al., JAMA Nov 21. doi: /jama [Epub ahead of print] October 2016: FDA approves and ACIP recommends 2 doses for nonavalent vaccine for adolescent girls and boys 9-14

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32 One-three doses of bivalent vaccine induce 4 years of protection against persistent (6 months) HPV infection with HPV16/18 HPV vaccine Number Vaccine Number Number Rate per efficacy of doses arm of women of events 100 women % (95% CI) 3 doses 2 doses 1 dose Control % HPV % Control % HPV % Control % HPV % 84 (77-88) 81 (63-94) 100 (79-100) Similar results in GSK PATRICIA trial: Kreimer et al, Lancet Oncol 16:775-86, 2015 Unknown whether these results can be extrapolated to Gardasil (Merck) Kreimer et al, JNCI 103: , 2011

33 HPV16 Antibody GMT (EU/mL) HPV16 geometric mean titers among seronegatives doses, 2-doses (0/6 months) 2-doses (0/1 months) 1-dose * 1* 6* Study Visits (months) Naturally infected Seropositivity cutoff Mahboobeh Safaeian et al, Cancer Prevention Research 6: , 2013

34 HPV16 Antibody Geometric Means (EU/mL) HPV16 geometric mean titers among seronegatives: Costa Rica Vaccine Trial (Bivalent vaccine) doses 2 doses 1 dose Naturally Infected retest 84 Months of Follow-up month data from Safaeian et al, Cancer Prevention Research 6: , 2013; month data from Safaeian et al, under review

35 Moving towards a randomized controlled trial to test the efficacy of a single vaccine dose No precedent for 1 dose of a protein-based sub-unit vaccine to induce stable antibody titers for several years May be attributable to two factors: VLPs are highly immunogenic ASO4 (the adjuvant in Cervarix) is a TLR4 agonist See Schiller & Lowy, J Infect Dis 211:1373-5, 2015 A randomized controlled trial to rigorously test the efficacy of 1 dose (NCI + Gates Foundation)

36 Randomized controlled efficacy trial in Costa Rica to test efficacy of 1 dose vs. 2 doses A 4-arm non-inferiority trial in year old girls: compare protection from 1 dose and 2 doses of bivalent vaccine (Cervarix, GSK) and 9-valent vaccine (Gardasil9, Merck) Unethical to have a placebo arm; measure current HPV prevalence in young women in same area Main hypothesis: Protection induced by 1 dose is not inferior to 2 doses Second hypothesis: Protection will be similar for 1 dose of either vaccine (evaluates possible role of adjuvant; Merck uses alum, GSK uses AS04) Principal investigators: Aimee Kreimer & Paula Gonzalez See Kreimer et al, J Natl Cancer Inst, 2015, for 1 dose trial concept

37 Some implications of demonstrating 1 dose can confer strong protection Can change standard of care globally Giving 1 dose is less expensive and logistically easier; especially important in low resource settings If 1 dose were to cost $3, 100% vaccine coverage of a global birth cohort of girls (~60 million) would cost ~$180 million Consider utilizing a VLP structure when developing future vaccines against other agents

38 A possible future consideration: vaccinate multiple birth cohorts at once A 1 dose vaccination campaign for all girls/women (or 30) years old; perhaps with an associated cervical cancer screening campaign See Bosch et al, Nature Rev Clin Oncol 13:119-32, 2016 for a proposed multidose vaccination & screening campaign Modification to 1 dose proposed by Mark Schiffman The goals: faster reduction in cervical cancer risk and herd immunity for a wide age range Effectiveness of this approach would need to be demonstrated Requires a much greater up-front investment compared with yearly vaccination of a single birth cohort

39 Summary and Conclusions Basic research led to identification of HPV as the cause of several cancers and to development of the HPV vaccine Second generation HPV vaccines with activity against a broader range of HPV types can achieve the greatest reduction in HPV-associated disease The high immunogenicity of the vaccines means long-term protection can be induced with fewer than 3 doses