The concept of viruses to treat human malignancy is not new. In the mid 1890’s William B. Coley, a New York surgeon, noted that infections could result in an impressive tumor response.[1] Not much later, Louis Pasteur observed that patients with cervical cancer showed regression after being vaccinated with an attenuated rabies virus. By the mid-twentieth century scientists understood that some viruses were able to invade almost any cell in the body and kill it. However, it would not be easy to turn this ability into a viable anticancer treatment. Researchers found that viruses were either too strong, prompting a lethal immune response, or not strong enough.
With more observation and anecdotes going back more than a century, advances in molecular biology have now made it possible to alter the viral genome. A number of these viruses, includingherpes simplex virus type 1 and the polio virushave shown viable anticancer activity.
Earlier this year early-stage (Phase I) clinical report confirmed that agenetically modified polio virus engineered byMatthias Gromeier, MD, a molecular biologist at Duke University’s Preston Robert Tisch Brain Tumor Center,injected directly into the brains of patients with glioblastoma showed promising results. In developing the genetically modified polio virus (also known as PVS-RIPO,Gromeier removed part of the virus? genetic material. As a result,the ‘Duke-virus’ can’t reproduce in health cells and itcan’t cause paralysis or death. However, in cancer cells it can replicate, allowing it to releases toxins that kill specific cancer cells.But challenges remain.
…talimogene laherparepvec or T-VEC is the first clinical and regulatory validation of an oncolytic virus as a therapy…
Talimogene laherparepvec
This week the U.S. Food and Drug Administration(FDA) has, based on therapeutic benefits demonstrated in a pivotal study (study 005/05, referred to asOPTiM), approved the Biologics License Application for talimogene laherparepvec, also known as T-VEC (Imlygic?; Amgen). Talimogene laherparepvecisa genetically modified oncolytic viral therapy indicated for the local treatment of unresectable cutaneous, subcutaneous and nodal lesions in patients with melanoma recurrent after initial surgery. The drug, which is the first enclitic viral therapy approved by the FDA, has not been shown to improve overall survival or have an effect on visceral metastases. [2][3][4]
Herpes simplex virus type 1
Talimogene laherparepvecis a genetically modified herpes simplex virus type 1 designed to replicate within tumors and produce an immunostimulatory protein called granulocyte-macrophage colony-stimulating factor (GM-CSF). When injected directly into the tumor, the drug causes the tumor to rupture anddie in a process called lysis, while, at the same time releasing tumor-derived antigens, which along with virally-derived GM-CSF, may promote an anti-tumor immune response. However, the exact mechanism of action is unknown and isbeing further investigated.
“IMLYGIC is the first clinical and regulatory validation of an oncolytic virus as a therapy, whichAmgenis proud to bring to patients with a serious form of skin cancer. Not all melanoma patients currently benefit from available therapies, and IMLYGIC represents an important new option that can provide meaningful durable responses for patients with this aggressive and complex disease,” notedSean E. Harper, M.D., executive vice president of Research and Development atAmgen. “Immunotherapy is an exciting area for cancer research, and we are currently studying IMLYGIC in combination with other immunotherapies in advanced melanoma and other solid tumors.”
Unique approach
“Advanced melanoma remains a complex disease to treat, requiring the use of several modalities over the course of a patient’s therapeutic journey,” explainedHoward L. Kaufman, M.D., the principal investigator for the pivotal trial (OPTiM), associate director for Clinical Science at theRutgers Cancer Institute of New Jerseyand president of theSociety for Immunotherapy of Cancer. “As an oncolytic viral therapy, talimogene laherparepvechas a unique approach, and provides another option for treating eligible patients with unresectable disease that has recurred after initial surgery.”
Metastatic melanoma continues to be one of the most difficult-to-treat cancers because it is often insensitive to chemotherapy, can be highly aggressive and can require several different types of treatment depending on the stage and location of the disease and health of the patient. [5][6]Despite new therapeutic options, additional treatments are needed ? particularly for patients with metastatic disease.
OPTiM Study
The approval of talimogene laherparepvecis based on data from Study 005/05, referred to asOPTiM.OPTiMwas a Phase III, multicenter, open-label, randomized clinical trial comparing talimogene laherparepvecto GM-CSF in patients with advanced melanoma (Stage IIIB, IIIC, or IV) that was not surgically resectable. The primary endpoint of the study was durable response rate (DRR), defined as the percent of patients with complete response (CR) or partial response (PR) maintained continuously for a minimum of six months.
The OPTiM studyenrolled 436 patients. In the study, 16.3% of patients treated with talimogene laherparepvecachieved a durable response compared to 2.1% of patients treated with GM-CSF (p<0.0001). Of the patients who experienced a durable response, 29.1% had a durable CR and 70.8% had a durable PR. In the study, the median time to response was 4.1 (range: 1.2 to 16.7) months in the talimogene laherparepvecarm.
The most common adverse drug reactions in talimogene laherparepvectreated patients were fatigue, chills, pyrexia, nausea, influenza-like illness and injection site pain. Most adverse reactions reported were mild or moderate in severity and generally resolved within 72 hours. The most common grade 3 or higher adverse reaction was cellulitis.[3]
Availability and costs
Amgenintends to make talimogene laherparepvecavailable to patients in the U.S. within a week. The companyanticipates the average cost of the therapy to be approximately$65,000. Given that talimogene laherparepvecrepresents a novel and first-in-class oncolytic viral therapy,Amgenexpects variability of the drug dosing from patient to patient. Therefore,Amgenintends to work with the healthcare community to implement a program that helps limit the average cost of the therapy to$65,000for eligible participating institutions. To help select patients with no or limited drug coverage access the novel drug, the company will make the drug available throughThe Safety Net Foundation. Amgen will also develop a co-pay coupon program for through the Amgen FIRST STEP? Programto help commercially insured patients meet their co-payment obligations.
References
[1] Bickels J, Kollender Y, Merinsky O, Meller I.Coley’s toxin: historical perspective. Isr Med Assoc J. 2002 Jun;4(6):471-2.
[2] Review of FDA hematology/oncology approvals from March 2013 to September 13, 2015 [Overview] Last accessed September 14, 2015.
[3] Andtbacka, H et al. Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Me
lanoma. J Clin Oncol. 2015:2812-2814.
[4] Lawler SE, Chiocca EA. Oncolytic Virus-Mediated Immunotherapy: A Combinatorial Approach for Cancer Treatment. J Clin Oncol. 2015;33(25):2812-4.
[5] American Cancer Society. Melanoma Skin Cancer. [Overview]. Last accessed October 14, 2015. [6] Faruk Tas. Metastatic Behavior in Melanoma: Timing, Pattern, Survival, and Influencing Factors. J Oncol, 2012; 2012: 647684.
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