Oncolytic virotherapy

Information about Oncolytic virotherapy

Published on June 11, 2016

Author: e_gops

Source: slideshare.net

Content

1. Case study T.P 4 yrs. /M Generalized Fatigue Protuberant abdomen × 2 weeks Feb 1951 LEO,USA

2. O/E Vitals - stable GE – palpable lymph nodes in the cervical, epitrochlear, and inguinal areas P/A – Hepatosplenomegaly

3. Relevant Lab results Hb – 5.6 g /dL TLC – 175000 cells /mm3 N3L97 BM –Bone-marrow aspiration revealed 98.5 per cent lymphocytes (81% small, 14.5% intermediate, 2% large, 1% blast) Platelets – 150000/ mm3 Diagnosis – Lymphoblastic Leukemia

4. Treatment and follow up Inj. Saccharated Iron oxide 4.8 gm. i.v. Over 33 day period Discharged (without much improvement on May 2) Readmitted on May 15th - developed scattered watery vesicles on the face, scalp, and neck with fever typical of varicella, with subsequent crops of the eruption until May 23.

5. Oncolytic Virotherapy Dr.Gopisankar M G

6. Virus – A drug ?? A drug is defined as a chemical substance of known structure, other than nutrient or an essential dietary ingredient which when administered to a living organism, produces a biological effect “Slimy Liquid Poison “

7. “Drugs don’t work in patients who don’t take them.” General C. Everett Coop

8. General Properties of Viruses Acellular Organisms Obligate intracellular parasites Nucleoprotein Lipid overcoat Uses host metabolic machinery and ribosomes assemble into particles called VIRIONS

9. Viruses cannot make energy or proteins independent of a host cell Viral genome are RNA or DNA but not both Viruses lack the enzymes necessary for protein and nucleic acid synthesis Viruses do not have the genetic capability to multiply by division Viruses occupy the twilight zone that separates the ‘living’ from the ‘nonliving’

10. 1800 1900 2000 1798 ‘85 ‘92‘84 ‘98 1915 1939 1948 -1955 1952 1952 1985 20051903 Virology milestones

11. Annual meeting of Academy of Medicine September 18, 1903 ( Dr.George Dock ) Birth of oncolytic virotherapy Cleveland , Ohio Report of Influenza making leukemia better WBC count reduced from 365000 to 7500 per µL He cited a number of similar cases

12. Dr. George Dock (1860 - 1951) Professor of Medicine University of Michigan “It might seem that the process could be imitated, and a symptomatic, if not a causal, treatment be discovered”

13. Leviditi and Nicolou found that vaccinia virus and herpes virus caused regression of mouse skin tumors and sarcoma Chickenpox improved the count and lymph node status in case of lymphatic leukemia Measles produces improvement in the case of leukemia, Hodgkin’s, and Burkitt’s lymphoma Rabies vaccination favorably modified the course of carcinoma of the cervix

14. Observations Trials

15. How to study the anticancer effect? Virus pharmacokinetics Virus pharmacodynamics

16. Virus Pharmacokinetics Absorption Distribution Metabolism Excretion

17. Dosage and Administration TCID50 - 50% Tissue Culture Infective Dose Plaque forming units(pfu) Focus forming assay Haemagglutinin assay Electron microscopic methods Flow cytometry TRPS(Tunable Resistive Pulse Sensing)

18.  Moraten dose ≥108 TCID50  prolonged survival after administration of the strain in murine intraperitoneal model of human ovarian cancer 1×107 pfu of the second generation HSV inoculated into brain resulted in no adverse effects in mice Virus JX-594 maximum tolerated dose was 1×109 pfu ONYX 015 even when administered up to 1011 pfu did not cause any dose limiting toxicity.

19. Dose –dependent increase in levels of the inflammatory cytokines Optimal dose for bystander response also Maximal dosage

20. How to find the adequate dose ? Conducting dose range studies and doing tumor biopsies to recover the virus JX594 an oncolytic vaccinia virus is under trial for HCC appeared in tissue biopsies only when the threshold dose was more than 109 IU

21. Controlling the availability Controlled release viral preparations are available for Adenovirus Polymer coat Lipid layer Polyethylene glycol

22. Routes of administration Intra tumoral ( Most common ) Oral, rectal, inhalation, intra-arterial, intraperitoneal, intramuscular or intravenous are also tried Convection Enhanced Delivery

23. Distribution Details like Bioavailability , half life of the virus Pre dose titers  community exposure The virus levels may spike several times over a period of time due to replication

24. Viral titer over time or viral RNA/DNA/proteins in blood can be calculated over a time period

25. Surrogate markers

26. Visual analysis - fluorescent labeling of the vector Transcription units coding for soluble marker peptides are inserted by genetic engineering - β- hCG, CEA  BBB – parvo virus

27. Gamma camera images of MV-NIS treated mice in the s.c. xenograft model

28. Histochemical detection of β- galactosidase

29. Metabolism and excretion Peak activity of virus will increase due to replication Non replicative vectors are developed - limited success Major route of elimination  Immunological mechanism

30. Poor correlation between viral titers and increasing antibody titer PEGylation of virus reduces immunogenicity Virus will concentrate in the RES and from there it is slowly removed by immune mediated mechanisms Pre conditioning of the MPS receptors - polyinosinic acid , clodronate-loaded liposomes , gamma globulins , gadolinium chloride MPS follows saturable kinetics

31. Cell carriers and stem cells Cells can function as vehicles for therapeutic virus They escape immune attack Natural habitat Stress situation – low PH , hypoxia Stem cells have tumor homing properties Due to chemokines produced during carcinogenesis

32. Virus Pharmacodynamics Mechanism of action of virus Aberrant pathways Nonfunctioning of certain normal pathways Certain receptor over expression in the cancer cells

33. Signaling Pathways Interferons have anti viral and anti proliferative actions Their antiviral mechanism involves activation of PKR pathway, 2-5A synthases and activation of some specific proteins PKR gets activated if comes in contact with ds RNA derived from virus It phosphorylates itself and other substrates like eIF2 which is a translation initiation factor of viral translation Phosphorylation leads to eIF2 inactivation and thus inhibition of virus and host protein translation

34. CD46 (membrane co-factor protein) is overexpressed in cancer cells compared to normal cells to protect them from complement mediated destruction. Measles virus have a tropism to CD46 and they uses this receptors to enter into the cells The oncolytic activity of CVB3 (Coxsackie B3 virus) is found to be proportional to the percentage of CAR expressing cells times the percentage of DAF expressing cells

35. Use of a CD20-targeted recombinant measles virus can be used a substitute to Rituximab in the FCR Fludarabine, Cyclophosphamide, and Rituximab regimen for lymphoma management

36. MOI Multiplicity of infection (MOI) ratio It is the ratio of infectious agents to the targets As the MOI increases the percentage of cells infected with at least one viral particle also increases It is used for quantifying the affinity of the cells and viruses

37. Augmenting the immune response against cancer Release of tumor associated antigens (TAA) Augusto et al used Adeno viral vector with HSV-TK protein which functions as a super antigen and stimulates T cells and secretion of cytokines like IL-2 Local intratumoral injection of viruses will have a global effect

38. Combination virotherapy  Virus and chemotherapy  Virus and Radiotherapy  Virus and other treatments  Virus with virus

39. Virus and chemotherapy G207 and cisplatin 1726 and mitomycin C ONYX-015 and cisplatin/5FU ONCOS-102 + GM-CSF Cyclophosphamide

40. Virus and Radiotherapy (Radiovirotherapy) Lytic activity of NV1020 was enhanced with radiation in HuH7 xenografts in athymic mice G207 and radiation in cervical cancer is found to have increased efficacy

41. Virus with other treatments ONCOS-102 is a chimeric Ad5/knob3 vector added with GM-CSF production Hyaluronidase enzyme along with Ad5/35GFP fiber- chimeric adenovirus which enhanced virus transduction and spread within prostate cancer Losartan enhances the intratumoral spread of oncolytic HSV as it disturbs the transforming growth factor beta1 signaling

42. Virus with virus  Interferon sensitive VSV which is a RNA virus is combined with pox virus encoding a secreted interferon antagonist had better oncolytic effect due to VSV and better intratumoral spread due to pox

43. Advantages Safer drugs Less chance of transmission Bystander response Virus drugs can be deposited in resection cavity which will track the remaining neoplastic cells thus reducing the risk of recurrence

44. Obstacles Immune attack Metastatic cases Adequate animal models Some metastatic lesions won’t respond Repeated histopathology confirmation

45. Risks and Adverse effects New regulations Immunocompromised Massive cytokine release Drug interactions – Reo virus when trialed for solid tumors it raised the ALT/AST levels in patients who were taking acetaminophen and thus should be avoided The same drug if used with cyclosporine will lose its therapeutic benefit in tumor models

46. Approved Drugs 1. Talimogene laherparepvec (Oncovex) T-VEC was approved by US FDA in 2015, with the brand name ‘Imlygic’ for the treatment of malignant melanoma in patients with inoperable tumors Oncolytic herpes simplex virus type 1. The neurovirulence factor ICP34.5 is inactivated by recombinant DNA technology to prevent neuronal involvement and is replaced with GM CSF encoding genes It is administered intralesionally as 0.4mL of 106 to 108 pfu/mL.

47. In OpTIM study, T-VEC was compared with G-CSF alone. Durable response rate lasting ≥ 6 months (16.2 vs2.1%, p<0.001) was superior in the T-VEC arm Median overall survival was 23.3 months compared to other arm which was 18.9 months. T-VEC compared with ipilimumab (anti CTLA4) showed 56% response rate.

48. The Future 0 50 100 150 200 250 300 1945 1955 1965 1975 1985 1995 2005 2015 NUMBER OF REGISTERED ONCOLYTIC VIRUS STUDIES (1952 - 2015)

49. 36 12 6 5 5 3 3 3 3 3 3 2 2 2 2 2 2 2 1 1 1 1 1 0 5 10 15 20 25 30 35 40 Trials registered in clinicaltrials.gov.in (2004 - 2016)

50. Thank you

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