Download Anal Cancer and Human Papilloma Virus - Dana

Anal Cancer in Women and the
Human Papilloma Virus
Kimberly Perez, MD
Gastrointestinal Medical Oncology
November 6, 2015
Disclosures
• I have no relationships to disclose.
• I will discuss the use vaccines in a manner not
approved by the U.S. Food and Drug
Administration.
• But in accordance with ACIP
recommendations.
Epidemiology: Anal Cancer in Women
• Represents 0.4% of all new cancer cases in the
United States.
• Incidence is 1.8 per 100,000 persons overall,
with 2 per 100,000 in women.
• Incidence has been rising 2.2%/year in men
and women.
• It is estimated that 4,630 women in 2015 will
be diagnosed with anal cancer in the United
States, and 610 will die of their disease.
American Cancer Society, 2015
Human Papilloma Virus – HPV
• Genome consists of a circular double-stranded
DNA molecule of ~8000bp
• HPV types differ by >10% in the LI gene
sequence
• 199 different HPV types have been fully
sequenced, and nearly all cluster into three
genera: α-HPV, β-HPV, and γ-HPV
• α-HPV isolate from mucosal and genital
lesions; β and γ isolate from skin
Anal cancer and HPV
• Distribution of HPV genotypes in the anus is more
heterogeneous than in the cervix, and it has been
demonstrated that a greater proportion are of
low-risk HPV types
• Most common non-oncogenic HPV-53 and -66
• Most common oncogenic HPV-51, -52 and -16
• Detection of anal HPV is associated with:
– a higher lifetime number of anal and vaginal sex
partners
– younger age at first anal intercourse
– history of Chlamydia and anogenital warts.
Types by histologic/genomic subtypes
Overall Distribution, Overall Prevalence of HPV among 2107 Young Adult
Women from Costa Rica
Castro et al. J Infect Dis. 2012; 206: 1103
Mechanism of HPV Infection
• Progression of infection is similar to cervical
cancer which occurs over 1 to 3 decades.
• Persistent infection of the same HPV type
leads to high-grade squamous intraepithelial
anal lesions eventually resulting in anal cancer
• Despite this similarity, cervical cancer is 4
times more common than anal cancer. This
may be due to higher clearance rate in anal
cancer.
Clearance of HPV anal infections
• 87% of anal HPV infections are cleared within
the 1st year
• Rate of clearance of HPV from those with HPV
anal infection: 9.2 per 100 woman-months
with a median duration of 150 days.
– Slowest clearance were HPV-59 (350 days) and
HPV-58 (252 days).
– Median clearance for HPV-16 and -18 were 123
and 212 days respectively.
Clin Infect Dis. 2009; 48(5): 536
Sequential cervical and anal HPV
infection
• Acquisition of anal HPV infection increases
significantly among women with a cervical HPV
co-infection with 1 or more additional HPV types
• Risk of incidental cervical HPV infection increases
significantly among women with an anal HPV
infection of 1 or more additional HPV types
compared to women without a preceding anal
HPV infection.
• Risk of acquisition of a new anal HPV infection
increased 20-29% among women with an cervical
co-infection with any HPV type
Goodman et al. The Journal of Infectious Diseases 2011;
203: 335-340
Castro et al. J Infect Dis. 2012; 206; 1103
Cancer Risk based on HPV subtype
• Relative Risk varied by phylogenetic species
• α3/α15 and α1/α8/α10 types are associated with
a greater likelihood of infecting the anus among
women with a preceding same-type infection at
the cervix.
• Risk of cervical HPV infection following an anal
HPV infection with a concordant genotype was
8.8 (95% CI: 6.4-12.2). α 9/α11 had a slightly
higher probability than other HPV types
Goodman et al. J Infect Dis
2011; 201(9): 1331
Co-infection correlation with cervical
cancer
Veo et al. Tumor Biol. 2015; 36: 5399
Prognostic implications
• Single-institution, retrospective analysis
• 50 patients; stage I-III anal squamous cell carcinoma
treated with concurrent chemotherapy and radiation
• 84% were HPV+ (90% HPV-16)
• HPV+ had more advanced disease at diagnosis (stage
IIIA 45.2%, stage IIIB 28.6%) compared to HPV- (stage
IIIA 37.5%, stage IIIB 0%)
Results:
– 5yr DFS – HPV+ 92.5% vs HPV- 50%
– 5yr OS – HPV+ 93.3% vs HPV- 66.7%
Rivenda et al. ecancer. 2015; 9:529
- 9-valent HPV Vaccine
- ADVAXIS immunotherapy– BrUOG study
THERAPEUTIC IMPLICATIONS
Will the 9-valent vaccine impact the
incidence of anal cancer?
Serrano et al. Eur J of Cancer.
2015; 51:1732
ADXS11-001 Lm-LLO
Immunotherapy and Chemo/IMRT
for Anal Cancer
Kimberly Perez, Howard Safran, Kara-Lynne Leonard, Thomas
Dipetrillo, Nicholas Oldenburg, Adam Klipfel, Steven Schecter, Matthew
Vrees, Leslie Roth, Nishit Shah, Lakshmi Rajdev, Kayla Rosati
Brown UniversityOncology Group Research Consortium
ADXS11-001
• HPV DNA is present in the majority of anal cancer
• ADXS11-0011 immunotherapy is a live attenuated Listeria
monocytogenes (Lm) bioengineered to secrete an HPV-16 E7 protein
fused with a truncated fragment of listeriolysin O (tLLO)
• tLLO is a virulence factor of Lm. It enables the bacterium to escape
from the phagolysosome.
• Innate powerful immune response to Lm, especially to listeriolysin
(tLLO). Unlike peptides or viruses, there is no immune tolerance or
neutralizing antibodies
• Biosafety level 1-2. No fecal, urine shedding or person-to-person
transmission; vector cleared within 24 hours with antibiotics.
ADXS11-001 Is Taken Up By Antigen Presenting Cells (APC)
• After infusion of Lm-LLO
immunotherapy, Lm are
taken up by APC.
• Since listeriolysin can
break through the
phagolysosome, the
fusion protein tLLO-E7 is
free in the cytoplasm of
APC and activate MHC
class I and class II
immune responses
• HPV transformed tumors
now “seen” as pathogeninfected and targeted by
T-Cells
ADXS11-001 with mitomycin/5-FU/IMRT for Locally
Advanced Anal Cancer: Brown University Study
Open Label Phase 1/2 Study
•
•
•
•
N = 25
Primary stage II-III anal cancer
High risk of recurrence
HPV-positive
ADXS11-001
1x109 cfu x 4 (1 prior to chemoRT and 3 post, q 28 days) as a 500 ml infusion over 30 min
Biopsy
Diagnosis
Biopsy
6 months
6 weeks IMRT
Mito/5-FU
ADXS11-001 #1
Day -10 to 14
•
•
28 days
28 days
Follow up
Primary Efficacy
Endpoint:
6-month CR-rate
Mito/5-FU
ADXS11-001 #2
Day +10 post IMRT
ADXS11-001 #3
ADXS11-001 #4
Premeds with Naprosyn (500 mg BID, day -1 & 0) & Promethazine (25 mg BID, predose 8 hr)
Ampicillin is given day 3-9 after each ADXS11-001 dose
Patient Characteristics (N=11)
Age, years
<50
>50 but <75
Median
Range
No.
1
9
62
37-71
Male
Female
5
6
II
III
4
7
N0
6
N1
N2
N3
0
1
4
Sex
Stage
Lymph node
involvement
ADXS11-001 Related Toxicities
Adverse
Event
Flu-like
Symptoms
Migraine
Hypotension
HypoK*
Chills/rigors
Nausea
Back pain
Fever
Grade 2
Grade 3
Grade 4
1
1
1
3
2
1
2
1
2
1
*These AEs occurred during dosing time point but are also included
with overall AEs.
Acute Grade 3 toxicities
related to ADXS11-001:
− Chills/rigors (N=2)
− Back pain (N=1)
− All toxicities were within
24 hours of dosing
Preliminary RFS Data
On ADXS11-001
T4N3
11
T3N0
10
T3N0
9
T3N3
8
T2N0
7
T4N0
6
T3N3
5
T4N0
4
T2N2
3
T3N3
Patient progressed systemically
Patient expired unrelated to study treatment
2
0
200
400
600
Relapse Free Survival (Days)*
Note: Patient #1 enrolled but was never treated on study
800
1000
* as of Sep 27, 2015
Conclusion
• It is common for anal and cervical HPV infections
to occur consecutively
• The high degree of genotype-specific
concordance indicates a common source of
infection.
• HPV+ anal carcinoma may be associated with an
improved prognosis.
• Due to the significant correlation between anal
cancer and HPV, immunotherapy will be playing a
larger role in therapeutic protocols.