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Center for Cervical Disease
at Johns HopkinsCL Trimble, MD
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Fast facts: cervical cancer
• Cervical cancer is preventable• Cervical cancer is the second leading
cancer killer of women worldwide• Cervical cancer happens in the setting of a
common viral infection• Cervical disease is more common in
women of lower socioeconomic means• Cigarette smoking triples the risk of
cervical disease
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Persistent HPV infectionCervical cancer
HPV16E6 and E7
Additional “hits”
Normal cervix CIN3 Invasive cancer
Immortalized cells Transformed cells
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System Failures leading to Cervical Cancer Diagnosis
Women do notcome in for screening
Health care providersdo not screen women
at visits
Colposcopy forabnormal screen
not done
Patient does not getappropriate therapy
Patient gets
Cervical cancer
Source: P Pronovost
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Cervical Cancer Mortality Rates by SEA (Age-adjusted 1970 US Population): White Females,
1950-1998
6.37 – 9.67 (highest 10%)5.83 – 6.365.46 – 5.825.12 – 5.454.82 – 5.114.47 – 4.814.26 – 4.463.89 – 4.253.46 – 3.882.19 – 3.45 (lowest 10%)
U.S. rate = 4.64 / 100,000
Jon Kerner, PhD. Division of Cancer Control, NCIJon Kerner, PhD. Division of Cancer Control, NCI
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Source: Maryland Cancer Plan Web Site
Maryland Cervical Cancer Mortality Rates by Geographical Area: Comparison
to U. S. Rates, 1994- 1998
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Johns Hopkins Center for Cervical Disease
Patient care/outreach
ResearchTeaching
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Objectives: Maryland Cancer Plan
6.1: Conduct a follow-back study to determine factors that contribute to women developing and/or dying from invasive cervical cancer.- different screening strategies- different treatment algorithms
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Retrospective Cohort Review of JHH and JHBMC patients with Squamous Cervical Cancer between 1984-2002
Women with Diagnosis
Squamous Cell Carcinoma Of Cervix
Socio-Demographic
s?
Barriers to Care /Barriers to
Access?
Medical, Gyn, and Sexual history?
Who are they?Who are they? What happened?What happened? Why?Why?
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Squamous cancer of the cervix, JHH/JHB, 1984-2002
Ethnicity
Caucasian 79%
African American
19%
Asian 1%
Other 1%
Mean age 45 (24-87)
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Age distribution of cervical cancer cohort
20-29
30-39
40-49
50-59
60-69
70-79
>80
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JHH cervical cancer patients: 1984 - 2002
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Cohort CharacteristicsExposure to Health Care system in the year prior to diagnosis
• OB/Gyn Office (65%)• Emergency Department
(22%)• Primary Care Provider
(36%)
Medical Co-Morbidities • None reported (43%)• 1 or more (57%)
–HTN (23%)–Respiratory dz (17%)–DM (9%)–Psychiatric (8%)
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Cohort CharacteristicsInsurance • Private Insurance (45%)
• Government Aid (29%)• None (12%)
Telephone • Yes (97%)
Employment • Yes (54%)
Marital Status • Married (52%)• Single/Widowed (34%)
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Cohort CharacteristicsTransportation •Self (55%)
• Public, arranged (4%)• Private, arranged (21%)• Unknown (20%)
Education • Not Completed HS (12%)•Completed HS (36%)• Unknown (52%)
Caregiver • Yes (59%)• No (41%)
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Cohort Characteristics
Recent Hospitalization • Yes (25%)• No (75%)
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Cohort Characteristics
Recent Hospitalization • Yes (25%)• No (75%)
Maryland legislation mandates that women admitted to hospitals be offered a Pap test
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Thinking out of the box: in-reach
- Hopkins hospital in-house screening program: 1999-2002 (n = 1,117)
- Compared with outpatient screens from all of our clinics (n= 111,933)
- Cervical cancer precursors were nearly 5-fold higher in the hospitalized patients than in our outpatient clinics
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Outreach: Cervical cancer screening at the Hispanic
Apostolate• Abnormal rate is high (12.2%)• Comparison: abnormal rate in JHH
outpatient clinics is 7% (close to the national rate)
• Comparison: abnormal rate in in-reach screening program at Hopkins: is 15.5%
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Making a difference, starting at home
• Identify increased-risk populations in our catchment area
• Extend continuity of care to CRF sites• Make the best treatment options
available to our patients
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Johns Hopkins Center for Cervical Disease
Multidisciplinary effort involving clinicians, immunologists, pathologists, virologists, oncologists, nurses, epidemiologists, biostatisticians: expertise on many levels
Mission: to improve screening, triage, and treatment, and to develop and evaluate interventions to prevent HPV-associated cancers of the lower genital tract
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Tumor progressionCervical cancer
HPV16E6 and E7
Additional “hits”
Normal cervix CIN3 Invasive cancer
Immortalized cells Transformed cells
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HPV Genome
benign malignant
Host genome Host genome
E2
L2
L1 LCR E6
E7 E1
E2
CIN 1Low grade PreinvasiveHPV DNA is episomal
CIN 2/3High gradePreinvasive
HPV DNA has integrated into host genome
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HPV Genome
benign malignant
Host genome Host genome
E2
L2
L1 LCR E6
E7 E1
E2
CIN 1Low grade PreinvasiveHPV DNA is episomal
CIN 2/3High gradePreinvasive
HPV DNA has integrated into host genome
Prophylactic vaccines
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HPV Genome
benign malignant
Host genome Host genome
E2
L2
L1 LCR E6
E7 E1
E2
CIN 1Low grade PreinvasiveHPV DNA is episomal
CIN 2/3High gradePreinvasive
HPV DNA has integrated into host genome
ctl
Therapeuticvaccines
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HPV vaccines: the beginning of the end of cervical cancer
• Koutsky, et al, NEJM 2002– 2392 women, HPV16-naïve– Prophylactic VLP vaccine– 100% efficacy at 7 months
• ICAAC 2004 42 months of follow up– Vaccine efficacy: 94%
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HPV prophylaxis: why pursue therapeutic vaccines?
• Prophylactic vaccines will only be effective if everyone gets immunized.
• The herd burden of HPV infection is massive.
• Cultural barriers exist to vaccination for a sexually transmitted infection
• Curing early disease would also help us to figure out what is a good immune response.
• Science/discovery do not transpire out of a social context. (cancer vaccines, transplant, autoimmune diseases)
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Center for cervical disease at Hopkins
Clinical trials infrastructure Validated readouts
Established patient referrals and cohort
retention Evaluation of immunotherapies in
HPV disease
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Phase I/II clinical trials: HPV 16 E7-targeted therapeutic vaccines
• Target population: healthy women with preinvasive HPV16-associated disease of the cervix
• Two parallel cohorts– HIV-negative– HIV-positive
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CIN2/3 clinical trials
T = 0 T = 6 wks T = 15 wks T = 19 wks
v1 v3v2T = 4 wks T = 8 wks
Interval colposcopy Cone resection Postop check
Observational cohort study
Phase I/II vaccination trial: pNGVL4a-Sig/E7(detox)/HSP70
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CIN 2/3 cohort study
Patient characteristicsMedian age (in years) 30.y (range 18-67y) < 25 25 (25%) 25-34 53 (53%) >35 22 (22%)average time to resection 123.8 d ethnicity
African American 26 (26%)Hispanic 3 (3%)White 67 (67%)Asian 4 (4%)
Reported number of partners 8.1 (1-50)Tobacco smoking
Current 42 (42%)Former 2 (2%)Never 56 (56%)
Hormonal contraceptive use 52 (52%)
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Spontaneous regression over 15 weeks: CIN2/3
Week 0 Week 15
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Interaction between HLA class I and HPV : effect on disease
behavior
Variable Estimated O.R. 95% C.I. p-value
Months 1.01 0.86-1.19 0.87
HPV16 0.20 0.06-0.73 0.01 *
HLA*A201 0.90 0.03-29.44 0.95
~HPV16*~HLA*A201
32.12 0.97->999.999 0.05 *
Trimble et al, SPORE 2004
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CIN2/3 clinical trials
T = 0 T = 6 wks T = 15 wks T = 19 wks
v1 v3v2T = 4 wks T = 8 wks
Interval colposcopy Cone resection Postop check
Observational cohort study
Phase I/II vaccination trial: pNGVL4a-Sig/E7(detox)/HSP70
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GMP-Grade pNGVL4a-Sig/E7(detox)/HSP70GMP-Grade pNGVL4a-Sig/E7(detox)/HSP70DNA VaccineDNA Vaccine
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HPV vaccines at JHH
• Combination strategies• Needle-free delivery• Continued outreach
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(reverse translation)
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Vaccination strategies
(age 12)
Prophylactic vaccination
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Vaccination strategies
(age 12)
Prophylactic vaccination (boost)
(age 25)
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Vaccination strategies
(age 12)
Prophylactic vaccination (boost)
(age 25)
Prophylactic vaccination
screening
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Vaccination strategies
(age 12)
Prophylactic vaccination (boost)
(age 25)
Prophylactic vaccination
screening
+HPV-->therapeutic vaccine
Lesion--> therapeutic vaccine
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Vaccination strategies
(age 12)
Chimeric vaccination(combination prophylactic
and therapeutic)
(boost)
(age 25)
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HPV vaccines: long-term goals
• Combine prophylactic and therapeutic approaches on a population basis
• Eliminate the need for cumbersome screening
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Johns Hopkins Center for Cervical Disease
Drew Pardoll, TC Wu, Shiwen Peng, Patti Gravitt, Richard Roden, Chienfu Hung, Will Yutzy, Keerti Shah, Rick Daniel, Barbara Wilgus-Wegweiser, Cathy Wehner, Lynn Richards, Audrey Bruce, Paula Sparks, Andrea Elko, Bernice Horton, Brigitte Ronnett, Deb Armstrong, Dotty Rosenthal, Steve Piantadosi, Elizabeth Garrett, Mihaela Paradis, Judy Lee, Betty Chou, Caroline Fidyk, Chuck Drake, Cornelia Trimble