Talimogene laherparepvec: Difference between revisions
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==Mechanism== |
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T-Vec has a dual mechanism of action, destroying cancer cells by directly destroying cancer cells it infects, and by helping the immune system recognize and destroy other cancer cells.<ref name=Evans2016rev/><ref name=Fukuhara2016rev/> |
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The virus invades both cancerous and healthy cells, but it cannot replicate in healthy cells because it lacks [[Infected cell protein 34.5]] (ICP34.5). When cells are infected with a virus they shut down and die, but ICP34.5 blocks this [[cellular stress response|stress response]], allowing the virus to hijack the cell's [[Translation (biology)|translation]] machinery to replicate itself. A herpesvirus lacking the gene coding for ICP34.5 cannot replicate in normal cells. However, in many cancer cells the stress response is already disrupted, so a virus lacking ICP34.5 can still replicate in them. When it does, it finally cause the cell to burst and die, which releases the copies of the virus.<ref name=Fukuhara2016rev/><ref name=Agarwalla2012rev>{{cite journal|last1=Agarwalla|first1=PK|last2=Aghi|first2=MK|title=Oncolytic herpes simplex virus engineering and preparation.|journal=Methods in molecular biology (Clifton, N.J.)|date=2012|volume=797|pages=1-19|pmid=21948465}}</ref> |
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The GM-CSF attracts [[dendritic cells]] to the site. Dendritic cells are immune cells that process and present antigens to the immune system so that the immune system can then identify and destroy the antigen source. The dendritic cells pick up the tumor antigens, process them, and then present them on their surface to [[Cytotoxic T cell|cytotoxic (killer) T cells]]. This programs the T cells to recognize the cancer cells as a threat. These T cells lead an [[immune response]] that seeks and destroys cancer cells throughout the body (e.g., tumors and cancer cells that were not directly injected with T-VEC).<ref name=Kauf2010>Kaufman HL, Kim DW, DeRaffele G, Mitcham J, Coffin RS, Kim-Schulze S. Local and distant immunity induced by intralesional vaccination with an oncolytic herpes virus encoding GM-CSF in patients with stage IIIc and IV melanoma. ''Ann Surg Oncol''. 2010;17(3):718-30. Available [http://www.ncbi.nlm.nih.gov/pubmed/19915919 here]</ref> |
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While T-Vec is using the cells's translation machinery to replicate, it also uses it make the cell create [[GM-CSF]]. In theory, GM-CSF attracts [[dendritic cells]] to the site, which pick up the tumor antigens, process them, and then present them on their surface to [[Cytotoxic T cell|cytotoxic (killer) T cells]] which in turn sets of an immune response. Whether GM-CSF is actually causing such an immune response in people to whom T-Vec was administered, was not certain as of 2016.<ref name=Evans2016rev/><ref name=Fukuhara2016rev/> |
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In this way, T-VEC has both a direct effect on injected tumors and a systemic effect throughout the entire body.<ref name=Nunez2013>Núñez MA. Tumor killer viruses. ''Mapping Ignorance''. January 9, 2013. Available [http://mappingignorance.org/2013/01/09/tumor-killer-viruses here]</ref> Because the [[adaptive immune system]] "remembers" a target once it has been identified, the effect of an oncolytic virus like T-VEC may be durable (e.g., prevent relapse). For this reason, T-VEC is injected into just enough tumors to start the immune process. |
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==Composition== |
==Composition== |
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Talimogene laherparepvec (tal im' oh jeen la her" pa rep' vek), (T-Vec, tradenamed Imygic, formerly called OncoVEXGM-CSF)[1] is biopharmaceutical drug to treat melanoma; it is a genetically engineered herpes virus (an oncolytic herpes virus). The drug was created and initially developed by BioVex, Inc. which was acquired by Amgen in 2011.[2]
With the announcement of positive results in March 2013, T-VEC became the first oncolytic virus demonstrated to be effective in a Phase III clinical trial.[3]
In October 2015, the US FDA approved T-VEC, under the brand name Imlygic, for the treatment of melanoma in patients with inoperable tumors.[4]
In January 2016 it was approved in Europe for some inoperable melanomas.[5]
Medical uses
The injectable formulation of T-VEC is approved for the treatment of melanoma in patients with inoperable tumors in the US.[4]
Imlygic is approved in Europe for adult patients with unresectable melanoma that is regionally or distantly metastatic — Stage IIIB, IIIC and IVM1a — and with no brain, bone, lung, or other visceral disease.[5]
Adverse effects
T-VEC has generally been well tolerated. The majority of adverse events were mild or moderate (Grade 1 or 2). The most common side effects are mild fatigue, chills, or fever. In the Phase III OPTiM trial, the most common serious side effect was cellulitis, reported in 2.1% of patients.
 | This article needs additional citations for verification. (October 2016) |
Pharmacology
Mechanism
T-Vec has a dual mechanism of action, destroying cancer cells by directly destroying cancer cells it infects, and by helping the immune system recognize and destroy other cancer cells.[6][7]
The virus invades both cancerous and healthy cells, but it cannot replicate in healthy cells because it lacks Infected cell protein 34.5 (ICP34.5). When cells are infected with a virus they shut down and die, but ICP34.5 blocks this stress response, allowing the virus to hijack the cell's translation machinery to replicate itself. A herpesvirus lacking the gene coding for ICP34.5 cannot replicate in normal cells. However, in many cancer cells the stress response is already disrupted, so a virus lacking ICP34.5 can still replicate in them. When it does, it finally cause the cell to burst and die, which releases the copies of the virus.[7][8]
While T-Vec is using the cells's translation machinery to replicate, it also uses it make the cell create GM-CSF. In theory, GM-CSF attracts dendritic cells to the site, which pick up the tumor antigens, process them, and then present them on their surface to cytotoxic (killer) T cells which in turn sets of an immune response. Whether GM-CSF is actually causing such an immune response in people to whom T-Vec was administered, was not certain as of 2016.[6][7]
Composition
T-Vec is a biopharmaceutical drug; it is an oncolytic herpes virus that was created by genetically engineering a strain of herpes simplex virus 1 (HSV-1) taken from a person infected with the virus, rather than a laboratory strain.[6] Both copies of the viral gene coding for ICP34.5 were deleted and replaced with the gene coding for human GM-CSF, and the gene coding for ICP47 was removed.[6][7][9]
History
 | This section needs more reliable medical references for verification or relies too heavily on primary sources. (November 2015) |  |
Melanoma clinical trials
Clinical efficacy in unresectable melanoma has been demonstrated in phase III clinical trials.
The phase II clinical trial was published in 2009. Fifty patients with advanced melanoma (most of whom had failed previous treatment) were treated with T-VEC. The overall response rate (patients with a complete or partial response per RECIST criteria) was 26% (16% complete responses, 10% partial responses). Another 4% of patients had a surgical complete response, and another 20% had stable disease for at least 3 months. On an extension protocol, 3 more patients achieved complete responses, and overall survival was 54% at 1 year and 52% at 2 years—demonstrating durable responses.[10]
Consistent with other immunotherapies, some patients exhibited initial disease progression before eventually generating the full immune response. Responses were seen in both injected and uninjected tumors (including those in visceral organs), demonstrating systemic immunotherapeutic effects. Treatment was well tolerated, with only Grade one or two drug-related side effects, most commonly mild flu-like symptoms.[10]
This global, randomized, open-label trial compared T-VEC with subcutaneously administered GM-CSF (2:1 randomization) in 430 patients with unresectable stage IIIB, IIIC or IV melanoma. The primary endpoint was durable response rate (DRR), defined as a complete or partial tumor response lasting at least 6 months and starting within 12 months of treatment.[3]
T-VEC offered superior benefits in metastatic melanoma. DRR was achieved in 16% of patients receiving T-VEC compared with only 2% in the GM-CSF control group (P<.0001). The greatest benefit was seen in stage IIIB or IIIC melanoma, with a 33% DRR vs 0% with GM-CSF. The objective response rate (any response) with T-VEC was 32%, with 17% of patients experiencing a complete response (complete disappearance of melanoma throughout the body). This demonstrated that T-VEC has a systemic immune effect that destroys distant, uninjected tumors.[11]
The most common side effects with T-VEC were fatigue, chills and fever.
Further survival data showed that for patients who hadn't previously been treated for their melanoma (half the trial patients) death risks were reduced by 51% and that for patients who had been treated before metastasis (also half of the trial patients; stages 3b, 3c and IV M1a) death risk was reduced by 44%, which were statistically significant results (p<0.001).[11]
The OPTiM trial was the first Phase III proof of efficacy for a virus-based oncolytic immunotherapy.[citation needed]
Results reported in 2015 showed a durable response rate (DRR) in patients with Stage IIIB, IIIC and IVM1a melanoma of 25.2%, versus 1.2% in patients treated with GM-CSF.[5] The median overall survival (OS) for the Imlygic-treated patients treated was 41.1 months, versus 21.5 months in those given GM-CSF.[5]
Head and neck cancer clinical trials=
Clinical efficacy in squamous cell cancer of the head and neck (SCCHN) was demonstrated in a Phase II trial. A Phase III trial was started but terminated without explanation.[12]
In the Phase II trial 17 patients with stage III or IVA SCCHN received one of 4 different doses of T-VEC along with concomitant cisplatin and radiotherapy. 93% of patients had a pathological complete response confirmed by neck resection. 82% of patients had a complete or partial radiologic response per RECIST criteria. The remaining patients had stable disease, with no patient experiencing disease progression. At the median post-treatment follow-up of 29 months, all patients continued to show loco-regional control with disease-specific survival at 82%. T-VEC was well tolerated and had a similar safety profile to that seen in the melanoma trials (Grade 1 or 2 side effects only, the most common being mild flu-like symptoms). 77% of patients remained relapse-free as of 2010.[13][14]
A Phase III trial was initiated in 2010 by BioVEX.[12] After Amgen acquired T-VEC in, they halted the trial due to the "changing therapeutic landscape for patients"— presumably the discovery of HPV status as a major prognostic risk factor.[15]
Challenges and Future Research
While T-VEC has been shown to reduce the size of skin and lymph node lesions as seen in the third clinical trial, the FDA has stated that this treatment has not been proven to show any improvement in overall survival and also has had no effect on melanoma's ability to spread.[16] Therefore, melanoma can still spread to other parts of the body, such as the brain, bones, liver, lungs, and other internal organs. Once the melanoma spreads to these other internal organs, the disease is unable to be treated using T-VEC since T-VEC has to be injected directly into the melanoma lesion and so another cancer treatment must be used.
Another issue with T-VEC is that it is made with live herpes simplex type I virus. Therefore, melanoma patients who are pregnant or have a suppressed immune system cannot undergo this treatment because they could get a herpes viral infection.
Because T-VEC has to be injected directly into the melanoma lesion, the next step in oncolytic virus research is to engineer an oncolytic virus that can be injected directly into the bloodstream to attack cancer cells that aren't on the body's surface. If successful, there could be a larger range of cancers that could be treated using oncolytic virus therapy.
Approvals
T-vec was approved by the US FDA to treat melanoma in October 2015 and was approved by the EMA in December of that year.[6]
Costs
Research
As of 2016, T-vec had been studied in early stage clinical trials in pancreatic cancer, soft-tissue sarcoma, and head and neck squamous-cell carcinoma; it had also been tested in combination with checkpoint inhibitors ipilimumab and pembrolizumab.[6]
External links
See also
References
- ^ "Talimogene laherparepvec". AdisInsight. Retrieved 16 October 2016.
- ^ [ Amgen buys a cancer drug maker. New York Times
- ^ a b Amgen press release. Amgen announces top-line results of phase 3 talimogene laherparepvec trial in melanoma. Mar 19, 2013. Available here
- ^ a b "FDA approves Amgen's Injected Immunotherapy for Melanoma". Reuters. 27 October 2015.
- ^ a b c d Metastatic Melanoma Therapy, Imlygic, Now Available in EU
- ^ a b c d e f Bilsland, AE; Spiliopoulou, P; Evans, TR (2016). "Virotherapy: cancer gene therapy at last?". F1000Research. 5. PMID 27635234.
- ^ a b c d Fukuhara, H; Ino, Y; Todo, T (3 August 2016). "Oncolytic virus therapy: A new era of cancer treatment at dawn". Cancer science. PMID 27486853.
- ^ Agarwalla, PK; Aghi, MK (2012). "Oncolytic herpes simplex virus engineering and preparation". Methods in molecular biology (Clifton, N.J.). 797: 1–19. PMID 21948465.
- ^ Liu, BL; et al. (February 2003). "ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties". Gene therapy. 10 (4): 292–303. PMID 12595888.
{{cite journal}}: Explicit use of et al. in:|first1=(help) - ^ a b Senzer NN, Kaufman HL, Amatruda T, et al. Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor–encoding, second-generation oncolytic herpesvirus in patents with unresectable metastatic melanoma. J Clin Oncol. 2009;27:5763-5771. Available here
- ^ a b Andtbacka RHI, Collichio FA, Amatruda T et al. OPTiM: A randomized phase III trial of talimogene laherparepvec (T-VEC) versus subcutaneous (SC) granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment (tx) of unresected stage IIIB/C and IV melanoma. J Clin Oncol 31, 2013 (suppl; abstr LBA9008). Available here
- ^ a b ClinicalTrials.gov. Study of safety and efficacy of OncoVEXGM-CSF With cisplatin for treatment of locally advanced head and neck cancer. NLM Identifier: NCT01161498. Available here.
- ^ Harrington K, Hingorani M, Tanay M, et al. A phase I/II dose escalation study of OncoVexGM-CSF and chemoradiotherapy in untreated stage III/IV squamous cell cancer of the head and neck. J Clin Oncol. 2009;27:15s(suppl; abstr 6018). Available here
- ^ Harrington K, Hingorani M, Tanay M, et al. Phase I/II study of oncolytic HSVGM-CSF in combination with radiotherapy and cisplatin in untreated stage III/IV squamous cell cancer of the head and neck. Clin Cancer Res. 2010;16:4005-4015. Available here
- ^ Amgen press release. Amgen's second quarter 2011 revenue increased 4 percent to $4.0 billion. Jul 29, 2011. Available here.
- ^ Lawrence, Leah (October 28, 2015). "FDA Approves First Oncolytic Virus With New Melanoma Therapy". Cancer Network. Retrieved September 20, 2015.