Chapter 7 oncogenic viruses

Oncogenic viruses
and cancer vaccines
Dr Devang Patel

• Viral infections- causal role in 10% of all new cancers worldwide.
• A vast majority of cases (>85%) occur in developing countries
• developed countries-4% of new cases.
• M/A:
• two broad mechanisms: direct or indirect.
• indirect oncogenic mechanisms, the cells that give rise to the
malignant tumor have never been infected by the virus.
• the viral infection -inflammatory immune responses -accelerated
cycles of tissue damage and regeneration of noninfected cells-cancer

• Direct mechanisms, in which the virus-infected cell ultimately
becomes malignant, are typically driven by the effects of viral
oncogene expression or through direct genotoxic effects of viral gene
products.
• DNA viruses that depend on host cell DNA polymerases for replication
• viral gene products that promote progression into the cell cycle.
• A typical mechanism of direct oncogenic effects is through the
inactivation of tumor suppressor genes (p53 & RB)

direct “hit-and-run” mechanism.
• viral gene products may preserve cellular viability and promote cell
growth in the face of otherwise proapoptotic genetic damage during
the early phases of tumor development.
• This allows the precancerous cell to accumulate enough additional
genetic hits to eventually allow for cell growth and survival
independent of viral oncogene expression.
• Gradually loss of viral nucleic acids from the nascent tumor, perhaps
giving a cellular growth advantage due to the loss of “foreign” viral
antigens(evasion of immune clearance)

PAPILLOMAVIRUSES
• HPV types, including HPV16 and HPV18, play a causal role in
essentially all cases of cervical cancer (70%).
• HPVs associated with a high risk of cancer.
LOCATION %
PENIS 50
ANAL CANAL 88
VULVA 43
VAGINA 70
OROPHARYX NOT KNOWN

• late phase of life cycle-vegetative replication -is strictly dependent on host cell factors -
found only in differentiating keratinocytes near the surface of the skin or mucosa.
• Interestingly, a majority of HPV-induced cancers appear to arise primarily at zones of
transition between stratified squamous epithelia and the single-layer (columnar)
epithelia
• endocervix,
• the inner surface of the anus,
• tonsillar crypts.
• High-risk HPV types,, are usually transmitted by sexual contact, rarely cause visible warts,
and usually establish only transient infections in a great majority of exposed individuals.
• The lifetime risk of sexual exposure to a high-risk HPV type ->70%.
• Individuals who fail to clear their infection with a high-risk HPV type and remain
persistently infected are at much greater risk of developing cancer

• Papillomavirus - ds, closed-circular DNA molecules
• During the normal viral life cycle, the genome does not adopt a linear form, does
not integrate into the host cell chromosome, and remains as an
extrachromosomal episome or minichromosome.
• In addition to the late half of the viral genome, which encodes the L1 and L2
capsid proteins, HPVs encode six key early region genes: E1, E2, E4, E5, E6, and
E7.

The E6 protein
of high-risk
HPV types
triggers the
destruction of
p53 by
recruiting a
host cell
ubiquitin–
protein ligase,
E6AP. Another
important
oncogenic
function of E6
is the
activation of
cellular
telomerase
The interaction of E7
with pRB disrupts
the formation of a
complex between
pRB and E2F
transcription factors,
thereby blocking the
ability of pRB to
trigger cell cycle
arrest

Oropharyngeal Cancer
• Many of the tumors found in nonsmokers were found to have wild-type p53 genes,
raising the possibility that the tumor might be dependent on a p53-suppressing viral
oncogene (as seen in cervical cancer).
• Gillison and colleagues showed that nearly half of all tonsillar cancers contain HPV DNA,
most commonly HPV16.
• Interestingly, HPV positive oropharyngeal cancers tend to be less lethal than tobacco-
associated HPV-negative tumors.
• This finding has important implications for treatment of HPV-positive head and neck
cancers.

Nonmelanoma Skin Cancer
• Epidermodysplasia verruciformis is a rare immunodeficiency that is characterized
by the appearance of numerous wart-like lesions across wide areas of skin.
• The lesions typically contain papillomaviruses such as HPV5 or HPV8.
• Cofactors in development of SCC - UV light and immunosuppression.
Bladder Cancer

POLYOMAVIRUSES
• ds DNA genomes
• The first 2 naturally human-tropic polyomaviruses, BK virus & JC virus
• BKV and JCV are known to cause kidney disease and a lethal brain disease called
progressive multifocal leukoencephalopathy, respectively, in immunosuppressed
individuals.
• Like their close relative SV40, BKV and JCV can cause various forms of cancer in
experimentally exposed animals
• BK Polyomavirus -documented in two tumours from a panel of muscle invasive
bladder carcinomas.
• The virus has also been found in several dozen cases of urinary carcinomas
affecting transplant recipients.

Merkel Cell Polyomavirus
• fifth known human polyomavirus
• Causes Merkel cell carcinoma
• presence of MCV DNA in about 80% of MCC tumors
• MCC is a rare but rapidly lethal form of cancer that typically presents as a fast-
growing violaceous lesion on sun-exposed skin surfaces
• a class 2A carcinogen (probably carcinogenic to humans).
• M/A: LXCXE motif that mediates inactivation of pRB function. MCV LT does not
appear to inactivate p53 function
• Cell mediated immunity can help clear MCC tumors that express MCV antigens

Life Cycle
• initial EBV infection occurs asymptomatically in early childhood.
• The infection is typically transmitted through the saliva.
• attachment to B lymphocytes followed by virus entry and establishment of long-
term nonproductive infection.
• B lymphocytes are abundant in the tonsillar crypts and mediate systemic
dissemination of EBV infection.
• Individuals who escape infection during childhood and instead first become
infected during adolescence or adulthood often develop infectious
mononucleosis, a syndrome associated with fever, lymphadenopathy,
pharyngitis, and fatigue.

• late-infected individuals who experience mononucleosis and high EBV viral load
are at increased risk of developing EBV-positive Hodgkin lymphoma
• After primary infection, EBV persists in the host by establishing latency in a small
number of resting B cells and undergoing periodic replication, mostly in the
oropharyngeal epithelium
• EBV-interfere with cell mediated immune responses so virus is not eradicated
after primary infection.

• All cases of endemic Burkitt lymphoma are EBV+.
• EBV is found only about 20% of sporadic cases of Burkitt lymphoma that
occur in immunocompetent individuals outside of malaria-prone regions.
• HIV+ have a 60- to 200-fold r/o Burkitt and other non-Hodgkin lymphomas,
and about half of HIV-associated lymphomas contain EBV.
• A hallmark - deregulation of the cellular Myc protooncogene
• tumorigenic role -a hit-and-run scenario in which an originally EBV-positive
precursor cell ultimately accumulated mutations that rendered it
independent of viral genes

Other diseases-
posttransplant lymphoproliferative disease (PTLD)
lymphocyte-depletion subsets of Hodgkin’s lymphoma
natural killer (NK)/T-cell lymphoma
• HIV infection - ↑ r/o developing aggressive B-cell lymphomas and
Hodgkin lymphomas.
• Lymphoma is a classic AIDS-defining condition, and HIV infection
status should be tested at presentation.
• Patients with AIDS also develop primary CNS lymphoma and
infrequently plasmablastic lymphoma; both are almost always EBV-
infected.

• In southern China, nasopharyngeal carcinoma (NPC) affects 25 out of
1lac people, accounting for 18% of all cancers in China.
• Most other world regions have a 25- to 100-fold lower rate of NPC.
• EBV is present in nearly all cases of NPC, both in endemic and
nonendemic regions
Other tumors-
• gastric adenocarcinomas
• over 90% of gastric lymphoepithelioma-like carcinomas

Prevention and Treatment
• The reduction of immunosuppressive drugs
• control of HIV infection
• Ganciclovir and related antiherpesvirus drugsby inhibiting viral DNA
polymerase
• rituximab (an antiCD20 mAb)
• Vaccine not yet available.

KAPOSI SARCOMA
HERPESVIRUS(HHV-8)
• Kaposi sarcoma
• Multicentric
castleman’s disease
• Primary effusion
lymphoma
Lymphoproliferative disorders

• Diagnosis-biopsy and symptomatology
Rx:
• ganciclovir, which targets the late-phase thymidine kinase gene, can prevent the
formation of new KS lesions in HIV-positive.
• combination ART, which can induce significant responses, especially in ART-naive
patients.
• Patients who do not respond to ART are most frequently treated with systemic
administration of peg-doxorubicin, with paclitaxel as second-line therapy

MCD
• Occurs at increased frequency in AIDS patients
• S/S:intermittent flares of inflammatory symptoms, including fever,
night sweats, and wasting
• lymphadenopathy, splenomegaly, anemia, thrombocytopenia,
hyponatremia, increased levels of C-reactive protein, low albumin
• Diagnosis-LANA-positive plasmablasts
• median survival <2 yrs
• advent of new therapies, including rituximab alone or with liposomal
doxorubicin plus high-dose zidovudine and valganciclovir, the
prognosis is markedly improved.

PEL
• about 4% of all HIV-NHL.
• The tumor cells, generally clonal, are uniformly infected with KSHV
and in 80% of cases are coinfected with EBV
• recent results suggest that KSHV-infected mesothelial cells give rise to
PEL cell through a process of transdifferentiation
• Rx: chemo regimens used for aggressive lymphomas in combination
with ART can lead to long-term remissions in <40% of patients

ANIMAL AND HUMAN RETROVIRUSES
• Retroviruses may be classified as endogenous or exogenous depending on
whether they appear in the germline
• Retroviruses may also be classified as ecotropic, xenotropic, or polytropic
depending on whether they infect cells of the same animal species from
which they are derived, infect cells of a different species, or both.
• Amphotropic retroviruses infect cells of the species of origin without
producing disease but infect cells of other species and may produce
disease.
• Retroviruses that produce disease after a long incubation period are
termed lentiviruses
• Another group of retroviruses that are not clearly associated with disease
are known as spumaviruses and include human and simian foamy viruses.
• HTLV1 is the only retrovirus known to be oncogenic in humans.

• HIV-1 infection is also associated with a variety of malignancies but
only through indirect effects of suppressing immunity
• Four species of HTLV have been identified. HTLV-1 was identified in
1980 as the first human retrovirus associated with cancer
• HTLV-2, HTLV-3, and HTLV-4 are not known to be associated with
disease in humans

HTLV-1
• Transmission-
• sexually,
• by contaminated cell-associated blood products, or
• by breastfeeding.
• Only 2% to 5% of HTLV-1–infected individuals develop disease.
• Diagnosis-serologic assays.
• Circulating tumor “flower cells” are helpful in the diagnosis
• HTLV-1 is associated with various inflammatory disorders, including uveitis,
polymyositis, pneumonitis, Sjögren syndrome, and myelopathy.
• Infected patients are susceptible to certain infectious disorders (e.g.,
staphylococcal dermatitis) and opportunistic infections
• Vaccines have not been developed for HTLV infections

Treatment-
• Combination chemotherapy for lymphoma or
acute-type ATLL with the infusional etoposide,
prednisone,vincristine, and doxorubicin (EPOCH)
regimen or the LSG-15 regimen results in complete
remission rates of 15% to 40%
• anti-CCR4 antibody, mogamulizumab can be used
• Lenalidomide has activity in relapsed or recurrent
ATLL
• Allogenic hematopoietic stem cell transplantation
may result in long-term, disease-free survival
four subtypes of
ATLL:
(1) Smoldering
ATLL
(2) Chronic ATLL
(3) Lymphoma-
type ATLL
(4) Acute-type
ATLL

Hepatitis B virus
• ds DNA
• Hepadna virus family
• HBV replication is not
cytotoxic.
• liver injury is due to the host
immune response, primarily
T-cell and proinflammatory
cytokine responses

• About 5% of infections in adults and up to 90% of infections in
neonates result in a persistent infection,
• 20% of persistently infected cirrhosis
Rx:
• Chronic HBV infection can be managed with alpha interferon
• Nucleoside/nucleotide analogs, such as lamivudine, telbivudine,
entecavir, adefovir, and tenofovir, inhibit HBV reverse transcriptase
and limit HBV replication in a majority of patients.
• Entecavir and tenofovir -in patients with high HBV DNA load or
multidrug resistance.

• Although these drugs effectively control HBV, they typically fail to cure the
infection due to the long-term persistence of the covalently closed circular
double-stranded DNA form of the viral genome.
• Current results suggest that long-term anti-HBV therapy can reduce the risk of
HCC by about 50%.
• Hepatitis D virus (HDV) occurs only in individuals coinfected with HBV.
• HDV infection results in more severe complications than infection with HBV
alone, with a higher likelihood and more rapid progression to cirrhosis and HCC.

Hepatitis C Virus
• ss RNA virus of the Flaviviridae family
• replicates in the cytoplasm and does not integrate into the host cell genome
• Older treatments for HCV infection utilized 24 to 48 weeks of pegylated IFN-α and
ribavirin.
• Treatment with IFN and ribavirin alone produces sustained virologic response
(SVR) in 70% to 80% of subjects.
• Treatment options for HCV infection have changed dramatically with the advent
of the NS5B polymerase inhibitor sofosbuvir
• The new treatment regimens show SVR rates >90% against all HCV genotypes
after 8 to 12 weeks and have markedly fewer side effects than IFN-based
treatments.
• The current cost of a 12-week course of sofosbuvir treatment is $84,000

Pathogenesis of HBV & HCV
• depress innate immune responses by inhibiting TLR signaling through
effects of HBx and NS3-4A.
• JAK-STAT signaling inhibition.
• High levels of HBx block activation of the NF-κB pathway, whereas HCV C
and NS5A block apoptosis by the activation of AKT and NF-κB, respectively.
• The C and NS5A proteins may also induce epithelial–mesenchymal
transition, which is important for liver fibrosis, through effects on
transforming growth factor β and Src signaling

• HBV and HCV also disrupt tumor suppressor proteins
• HCV NS5B ubiquitin ligase modify pRB and induce its degradation,
whereas HBx and HCV C proteins both inhibit p16INK4a and p21 cell
cycle inhibitors, which leads to inactivating phosphorylation of pRB.
• The HBx and HCV C, NS3, and NS5A proteins deregulate p53 tumor
suppressor activity by compromising p53-mediated DNA repair.
• Both HBV and HCV promote characteristics of cancer stem cells.

• HBV and HCV infections are diagnosed by serologic assays and/or
antigen assays in the case of HBV.
• Quantitative PCR are utilized to measure virus load.
• No vaccine has been identified that protects against HCV
• Recombivax HB, which utilizes a recombinant HBsAg produced in
yeast cells, has been available for HBV prevention for more than 30
years.

• Because an early diagnosis of HCC is a key to successful treatment
• Surveillance in HCV-infected individuals with cirrhosis using
ultrasound every 6 months.
• Viral eradication does not fully eliminate the risk of HCC and
continued surveillance is still recommended in cirrhotic patients.
• HCC amenable to liver transplantation is usually defined as either one
tumour measuring ≤50 mm in diameter or two to three tumors
measuring ≤30 mm in diameter without vascular extension or
metastasis (Milan criteria).

Anticancer vaccines
• The first class -to prevent persistent infection of oncogenic microbes.
• Ex. HBV & HPV vaccines
• The second class -prevent premalignant neoplasia to invasive cancers.
• targeting microbial antigens in a precancer would be considered
prophylactic from the point of view of cancer.

Types of cancer vaccines
1)Tumor cell vaccines:
• These vaccines are made from actual cancer cells that have been
removed from the patient during surgery.
• The cells are altered (and killed) in the lab to make them more likely
to be attacked by the immune system and then injected back into the
patient.
• The patient’s immune system then attacks these cells and any similar
cells still in the body.
• Autologous OR Allogeneic

2)Antigen vaccines:
• These vaccines boost the immune system by using only one antigen (or a few),
rather than whole tumor cells.
• Antigen vaccines can be specific for a certain type of cancer, but they are not
made for a specific patient like autologous tumor cell vaccines are.
3)Dendritic cell vaccines: Sipuleucel-T (Provenge), which is approved for the
treatment of advanced prostate cancer, is an example of a dendritic cell vaccine.
• Dendritic cells are special immune cells in the body that help the immune system
recognize cancer cells.
• They break down cancer cells into smaller pieces (including antigens), and then
hold out these antigens so other immune cells -T cells can see them

• The T cells then start an immune reaction against any cells in the body that
contain these antigens.
• Dendritic cell vaccines are made from the person in whom they will be used.
• The process used to create this type of vaccine (known as an autologous vaccine)
is complex and expensive.
• Clinician removes some immune cells from the patient’s blood and expose them
in the lab to cancer cells or cancer antigens, as well as to other chemicals that
turn the immune cells into dendritic cells and help them grow.
• The dendritic cells are then injected back into the patient, where they should
cause an immune response to cancer cells in the body.

4)Vector-based vaccines: These vaccines use special delivery systems
(called vectors) to make them more effective. They aren’t really a separate category
of vaccine; for example, there are vector-based antigen vaccines.
• Vectors are special viruses, bacteria, yeast cells, or other structures that can be
used to get antigens into the body. The vectors are often microbes that have been
altered to make sure they can no longer cause disease.
• Vectors can be helpful in making vaccines for a number of reasons.
• they can be used to deliver more than one cancer antigen at a time, which might make
the body’s immune system more likely to mount a response.
• vectors such as viruses and bacteria might trigger their own immune responses from the
body, which could help make the overall immune response even stronger.
• these vaccines might be easier and less expensive to make than some other vaccines.

OVERVIEW OF INFECTIOUS AGENTS causing CANCER
The International Agency for Research on Cancer (IARC) approved carcinogenic
microbes.
• 8 viruses- HBV;HCV; EBV; KSHV,); HTLV-1; and HIV-1.
• 3 parasites- Schistosoma haematobium, Opisthorchis viverrini, and Clonorchis
sinensis.
• 1 bacterium-H.pylori
• In addition, Merkel cell polyomavirus, designated as a probable carcinogen by the
IARC
• All of these agents are considered to be direct carcinogens, with the exception of
HIV-1, whose immunosuppressive activities indirectly potentiate carcinogenesis
by promoting persistent infections of other oncogenic microbes

HEPATITIS B VACCINES (ENGERIX-B, RECOMBIVEX-HB)
• In lower income countries, HBV transmission is primarily from mother to infant
and from child to child.
• In developed countries, transmission is more often transmitted percutaneously or
sexually
• 1st gen vaccines are based on HBsAg particles purified from the blood of
chronically infected individuals
• 2nd gen vaccines, the first licensed vaccines generated by recombinant DNA
technology genetically engineered yeast (mostly Saccharomyces cerevisiae)

• Most are formulated with an aluminum phosphate or aluminum hydroxide
adjuvant and are generally delivered in a 3 dose series at 0, 1 or 2, and 6 months
IM.
• However, an HBsAg vaccine containing a proprietary CpG adjuvant (a Toll-like
receptor 9 [TLR9] agonist) was recently approved in the US for a 2 dose regimen
in adults.
• Combination vaccines are available.
• side effects :mild pain, erythema, and swelling at the site of injection

• in 1992, the WHO recommended universal vaccination programs targeting
infants, with the first dose optimally delivered within 24 hours of birth.
• It is especially important to prevent infant infections because early age of
acquisition is a strong risk factor for establishment of chronic infection, the
prerequisite for cirrhosis and HCC.
• Over 180 countries have introduced infant HBV vaccination programs, with 3 dose
coverage estimated to be approximately 75%.
• A reduction in chronic HBV infection rates of greater than 90% has been seen in
countries with high-coverage infant vaccination programs

• M/A: vaccines are thought to protect primarily by the induction of HBs antibodies
that bind the virus and prevent infection of hepatocytes
• PEP- A serum anti-HBs concentrations of 10 mIU measured 1 to 3 months after
the last immunization is considered a reliable marker for protection.
• This level is reached in approximately 90% of young people after 3 doses but less
often in older adults.

• Antibody responses decline over time, often becoming undetectable.
• Nevertheless, vaccinees who initially achieve the 10 mIU level remain protected
from HBV-induced hepatitis, presumably due to the ability of their HBs-specific
memory B cells, and perhaps T cells, to mount a protective anamnestic response.
• Protection has been observed for 20 to 30 years in a number of settings.
Therefore, booster vaccinations are not generally recommended
• HBV has no animal reservoir; thus, elimination of HBV infection in a population is
an achievable goal.

HPV VACCINES
• based on nonenveloped virus-like particles (VLPs) that mimics the outer
shell of the authentic virus.
• 3 vaccines are currently licensed
1)Cervarix is a bivalent vaccine (16,18).
• It is produced in recombinant baculovirus-infected insect cells and contains
a proprietary adjuvant consisting of an aluminum salt plus the TLR4 agonist
monophosphoryl lipid A, a detoxified form of lipopolysaccharide (LPS).
2)Gardasil is a quadrivalent vaccine -6, 11, 16, and 18.
• It contains a standard aluminum salt adjuvant and is produced in S.
cerevisiae.
3)Gardasil-9 is similar to Gardasil, but with the addition VLPs of oncogenic
types 31, 33, 35, 45, 52, and 58

• The clinical efficacy trials -protection against CIN grades 2 and 3 was virtually 100% at the
end of the 4-year trials and has remained so in longer term follow-up, now up to a
decade.
• Strong protection against vulvar and vaginal intraepithelial neoplasia and genital warts
was also demonstrated in the Gardasil trials.
• Based on the ages of the efficacy trial cohorts FDA approved Gardasil for females aged 9
to 26 years in 2006 and Cervarix for females aged 9 to 25 years in 2009.
• An efficacy trial in young men led to FDA approval of Gardasil for prevention of genital
warts and anal cancer (based on prevention of anal intraepithelial neoplasia) in males in
2009. The current age recommendation is 9 to 26 years.
• Gardasil was simultaneously licensed for prevention of anal cancer in women.
• None of the vaccines are approved for prevention of HPV- associated oropharyngeal
cancer (OPC).

• Protection from infection by other HPV types was limited to a few closely related
types (i.e., HPV31, HPV33, and HPV45) and was partial at best.
• In addition, the vaccines had no detectable effect on infections present at the
time of vaccination. For this reason, routine vaccination prior to initiation of
sexual activity is strongly encouraged.
• Seroconversion rates are virtually 100%
• The general expectations are that booster doses will not be required to maintain
these protective antibody levels long term
• The biggest issue- low vaccination rate.

• All were initially approved for 0.5 ml IM *3 injections over a 6 mth period.
• Subsequently, it was found that the ab responses to 2 doses, at 0 and 6 months, in girls
and boys younger than age 15 years were noninferior to the responses to 3 doses in the
individuals aged 15 to 26 years evaluated in the efficacy trials.
• These findings led to 2 dose WHO recommendation for those aged 9 to 14 years in 2014
and its subsequent adoption in the US.
• A randomized trial to formally compare the protection afforded by 1 vs 2 doses of
Cervarix and Gardasil-9 in 10- to 16-yearold girls is now under way.
• Because L1 is not expressed in latently infected keratinocyte stem cells residing on the
epithelial basement membrane, current HPV vaccines are unlikely to eradicate existing
infections.
• Like keratinocyte stem cells, cervical cancers and precursor lesions rarely or never
express L1. Thus, the existing L1-based vaccines seem unlikely to serve as therapeutic
agents for treating cervical cancer.

Recent advances
• Two types of next-generation HPV vaccines are currently in human clinical trials.
• One newer vaccine approach targets the papillomavirus minor capsid protein L2.
An N-terminal portion of L2 appears to represent a highly conserved “Achilles’
heel” epitope that is required for key steps of the infectious entry process.
• Another category of vaccines seeks to elicit T-cell-mediated immune responses
against the E6 and E7 oncoproteins.

Side effects
• Initial infusion-related events usually present within the first 24
hours after administration.
• >10%:
• Central nervous system: Chills (53%; grades ≥3: 2%), fatigue
(41%; grades ≥3: 1%), headache (18%; grades ≥3: <1%),
dizziness (12%; grades ≥3: <1%), pain (12%)
• Gastrointestinal: Nausea (22%; grades ≥3: <1%), vomiting (13%
grades ≥3: <1%), constipation (12%; grades ≥3: <1%)
• Hematologic: Anemia (13%)
• Hypersensitivity: Severe infusion related reaction (71%; grade
3: 4%)
• Neuromuscular & skeletal: Back pain (30%; grades ≥3: 3%),
myalgia (12%; grades ≥3: <1%), weakness (11%; grades ≥3: 1%)
• Miscellaneous: Fever (31%; grades ≥3: 1%), citrate toxicity
(15%)
• 1% to 10%:
• Cardiovascular: Hypertension (8% grades ≥3: <1%),
hemorrhagic stroke (4%)
• Dermatologic: Diaphoresis (5%; grades ≥3: <1%), skin rash (5%)
• Gastrointestinal: Anorexia (7%), acute ischemic stroke (4%)
• Genitourinary: Hematuria (8%)
• Neuromuscular & skeletal: Musculoskeletal pain (9%; grades
≥3: <1%), muscle spasm (8%; grades ≥3: <1%), neck pain (6%),
tremor (5%)
• Renal: Hematuria (8%)
• Respiratory: Flu-like symptoms (10%), dyspnea (9%; grades ≥3:
2%)
• <1%, postmarketing, and/or case reports: Cerebrovascular
accident, eosinophilia, hypotension, myasthenia gravis,
myocardial infarction, myositis, paresthesia (grades ≥3),
pulmonary embolism, rhabdomyolysis, sepsis, syncope,
transient ischemic attacks, tumor flare, venous thrombosis

T-VAC(Imlygic, talimogene laherparepvec)
• oncolytic virus therapy, a treatment that uses a virus to infect and kill cancer cells
while avoiding normal, healthy cells.
• T-VEC is made from a genetically modified herpes virus, commonly known as the
cold sore virus.
• T-VEC is injected into melanoma tumors. The virus then replicates within the
cells, causing them to rupture and die. So it is a local treatment
• The exact way that T-VEC works in the immune system is not fully known.

• In 2015, the U.S. Food and Drug Administration (FDA) approved T-VEC as the first
oncolytic virus therapy.
• The FDA approved T-VEC for patients with advanced melanoma (Stage IIIB, IIIC or
IV) that cannot be completely removed with surgery.
• The treatment is injected directly into tumors that are:
• Cutaneous (in the skin)
• Subcutaneous (under the skin)
• Nodal (within lymph nodes)
• T-VEC may not be right for certain patients, such as those who:
• Are pregnant
• Have a weakened immune system caused by an immune deficiency, blood or bone marrow
cancer (such as leukemia or lymphoma), steroid use, or HIV/AIDS

• Patients receive T-VEC as an intralesional (into the tumor) injection.
• After the initial injection, patients receive 2nd dose 3 wks later.
• Patients receive subsequent doses every 2 wks for at least 6 months, until no
injectable tumors remain or other treatment is required.
• patient can receive T-VEC for 6 months or longer.

• Patients usually continue to take this medication for a period of time, until their
melanoma worsens or they experience unacceptable side effects.
• Goals:
• Destroy melanoma cells
• Shrink melanoma lesions in the skin and lymph nodes
• T-VEC has not been shown to improve OS or to shrink metastatic melanoma
(melanoma that has spread to the brain, bone, liver, lungs or other organs).

Side effects
• Most reactions resolved within 72 hours.
• >10%:
• Central nervous system: Fatigue (50%),
chills (49%), headache (19%)
• Gastrointestinal: Nausea (36%), vomiting
(21%), diarrhea (19%), constipation (12%)
• Local: Pain at injection site (28%)
• Neuromuscular & skeletal: Myalgia (18%),
arthralgia (17%), limb pain (16%)
• Respiratory: Flu-like symptoms (31%)
• Miscellaneous: Fever (43%)
• 1% to 10%:
• Central nervous system: Dizziness (10%)
• Endocrine & metabolic: Weight loss (6%)
• Gastrointestinal: Abdominal pain (9%)
• Respiratory: Oropharyngeal pain (6%)
• Frequency not defined:
• Cardiovascular: Deep vein thrombosis,
vasculitis
• Dermatologic: Cellulitis, dermatitis,
exacerbation of psoriasis, skin rash, vitiligo
• Gastrointestinal: Oral herpes
• Infection: Bacterial infection (systemic),
herpes virus infection
• Ophthalmic: Herpes simplex keratitis
• Renal: Glomerulonephritis
• Respiratory: Acute asthma, pneumonitis

PROPHYLACTIC VACCINES FOR CANCERS OF NONINFECTIOUS ETIOLOGY
• Shared mutated antigens such as KRAS, which drives development of many human
tumors and is mutated very early, even in premalignant lesions, are attractive tumor-
specific antigens.
• KRAS has not performed well as a therapeutic vaccine, but it may be the perfect antigen
for including in a preventative vaccine.
• In addition to the immunosuppressive tumor microenvironment affecting the KRAS
therapeutic vaccines, another problem was the very low level of expression of the
mutated peptides on the tumor cell surface, which was too low to be recognized by
KRAS-specific T cells to activate them to kill the tumor.
• However, in the setting of prevention where a strong immune response and immune
memory can be generated, even low levels of mutated KRAS peptides on the first few
premalignant cells might be enough to trigger memory T cells that require less antigen to
be activated and allow them to eliminate abnormal cells to prevent tumor development

• Next in line as prophylactic vaccine antigen candidates are the shared tumor-
associated antigens that contain well-known epitopes expressed differently on
tumor cells compared to normal cells.
• Good examples are the extensively studied overexpressed antigens such as
HER2/neu, MUC1, hTERT, survivin, WT1, and others.
• HER2 vaccines have been very effective in preventing spontaneous breast cancer
development in HER2 transgenic mice
• CT antigens and oncofetal antigens have the same potential to be more
immunogenic in the absence of cancer and safe. Due to the unique patterns of
expression of CT antigens, vaccine-elicited immunity would be presented with its
target only if a tumor starts to develop.

Chapter 7 oncogenic viruses

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Chapter 7 oncogenic viruses