Chapter 7 oncogenic viruses

general oncology from devita presentation

1. Oncogenic viruses and cancer vaccines Dr Devang Patel

2. 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

3. 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)

4. 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)

5. 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

6. 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

7. 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.

8. 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

9. 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.

10. 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

11. 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.

12. 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

13. 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.

14. 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.

15. 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

16. 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.

17. 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

18. 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.

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

20. 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

21. 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.

22. 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

23. 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 .

24. 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

25. 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

26. 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

27. 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

28. 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.

29. 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.

30. 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

31. 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

32. 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.

33. 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.

34. 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).

35. 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.

36. 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

37. 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

38. 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.

39. 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.

40. 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

41. 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 1 st gen vaccines are based on HBsAg particles purified from the blood of chronically infected individuals 2 nd gen vaccines, the first licensed vaccines generated by recombinant DNA technology genetically engineered yeast (mostly Saccharomyces cerevisiae)

42. 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

43. 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

44. 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 .

45. 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.

46. 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

47. 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).

48. 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.

49. 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.

50. IAP

51. 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.

52. NCCN

53. 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

54. 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.

55. 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

56. Patients receive T-VEC as an intralesional (into the tumor ) injection. After the initial injection, patients receive 2 nd 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.

57. 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).  

58. 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

59. 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

60. 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.

61. Thank you