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