Concepts about therapy with modified virus in melanoma The case for Talimogene(T-VEC)
May 25, 2015
Concepts about therapy with modified virus in melanoma
The case for Talimogene(T-VEC)
Oncolytic virus: Concept
Oncolytic virus: non pathogenic viral particles; produces infection and killl tumoral cells
Oncotrópics virus: tropism for neoplastic cells but they are not killed.
Oncolmmunology 2:6; 2013
ONCOLYTIC VIRUS
Ciclo reproductivo de los virus.1-Fijación2-Penetración3-Desenvolvimiento4-Síntesis (4a-Transcripción, 4b-Traducción, 4c-Replicación del genoma)5-Ensamblaje6-Liberación
ONCOLÍTYC VIRUS: BACKGROUND
1950s: starting the field. 1960s poliovirus and adenovirus. 1991 Martuza et al que VHS genetically modified
could be used in gliobalstoma in mice. .
Science 1991
Oncolmmunology, June 2013
ONCOLYTIC VIRUS: TYPE OF VIRUSES
1. Adenovirus (glioma,sarcoma, head and neck, Ca páncreas, CCR, Ca prostate, ovary…)
2. Virus herpes simple (VHS): glioma, breast ca., melanoma, páncrea, head and neck.
3. Coxsackie virus.
4. Parvovirus (glioblastoma multiforme).
5. Reovirus (gliomas, melanoma, solid tumours).
6. Virus vaccinia (hepatocarcinoma).
ONCOLYTIC VIRUSES: Immunogenic activity
The antineoplastic effect of these viruses is not only a consequence of a cytopathic
effect
IALSO IMMUNE RESPONSE!!
Talimogene laherparepepvec (T-VEC)
lHerpes simple virus type 1 genetically modified (genes ICP34.5 e ICP47 for GM-CSF humanos) INDUCTION IMMUNE RESPONSE FOR THE PATIENT.
First oncolytic virus that has shown efficacy in Phase III clinical trial.
Talimogene laherparepepvec (T-VEC)
Modification Result
Use of new HSV-1 strain (JS1)
Improved tumor cell killing ability compared with other strains
Deletion of ICP47 Enables antigen presentation
Deletion of ICP34.5 Prevents HSV infection of non-tumor cells, providing tumor-selective replication
Earlier insertion of US11 Increases replication and oncolysis of tumor cells
Insertion of human GM-
CSF gene Enhances anti-tumor immune response by recruiting and stimulating dendritic cells to
tumor site
Talimogene laherparepepvec (T-VEC)
Phase II, 50 patients , estage IIIC-IV,. Intratumoral injection 4 ml x 10(6) pfu/ml followed by4 mL x 10(8) pfu/ml every 2 weeksx 24:
Concept od Durable response rate (DRR):: rate of objective overall response that began at any point within 12 m of initiation of therapy and lasted continously for more then 6 monts and longer
- 26 % overall response (16 % RC, 10% RP).
- 20% estabilization
- OS 1 and 2 years: 58 y 52 %.
- Low toxicity.
Talimogene laherparepepvec (T-VEC)
OPTiM TRIAL
(N=436)
Melanoma irresecable, IIIB a IV
T-VEC inyectado sobre lesiones o guiado por US
(N=295)
GM-CSF s.c
(N= 141)
4 ml x 106 pfu/ml 1 vez 4 ml x 108
pfu/ml/2 sem x 2 años
125 mcg/m2
diario
J Clin Oncol 2013; 31 (suppl; abstr LBA 9008)
OPTiM TRIAL: RESULTS
-Primary endpoint: durable response rate (DRR) (16 vs 2%, p< 0.001).
Mayor benefit stage IIIB-IIIC (33 vs 16% in estadio IV).
-Response rate: 26%.
-10.8 % complete response..
- non significanti OS (p< 0.7): 23.3 vs 19 months.
-Risk death reduction21%.
T-VEC: SIDE EFFECTS
CONCLUSIONS:
Oncolytic viruses can kill tumoral cells and induce a immune response in the patient.
Several Phase III clinical trials.
Herpes virus yand adenovirus more common.
T-VEC (OncoVex) is the first virus tested in phase III in melanoma with promising results