Biology-Based Treatment Technology: Oncolytic Poliovirus Recombinant [1]

1. History

1.1. Originates from anecdotal reports of tumor remissions folowing immunizations with live attenuated viruses/co-incidental infection [1]

1.1.1. Since the late 1800s, doctors have observed that some patients with cancer go into remission, if only temporarily, after a viral infection [4]

1.1.2. Principle: Conditional replication and cytotoxicity in cancerous cells combined with reduced propagation in normal tissues, aka patheogenic potential [1]

1.2. Oncolytic viruses - group of viruses that infect and kill tumor cells [2]

1.2.1. Can be found in nature/ modified in the laboratory [2]

1.2.2. Viewed as tools for directly killing cancer cells [2]

1.2.3. Considered to be a form of immunotherapy [2]

1.3. PVS-RIPO is a genetically recombinant, non- pathogenic poliovirus chimera with tumor [1]

1.3.1. Other Name: Sabin Type 1 poliovaccine [1]

1.3.2. Founded at the Duke Cancer Institute by Dr. Gromeier and his collagues [2]

1.4. ONLY one oncolytic virus - genetically modified form of HVP for treating melanoma - has been approved by the FDA [3]

2. Limitatons of PVS-RIPO

2.1. Oncolytic Poliovirus uses targeted DNA manipulation that can shut down cell protein production in the body [1]

2.1.1. Genetic manipulation of viruses can hinder simple removal of select viral functions without affecting cytotoxicity in all cells [1]

2.2. The poliovirus does not have perfect targeting of tumor cells and is prone to destroying local healthy cells as well [1]

2.2.1. But, the availability of specific chemotherapy or vaccines (against poliovirus) can help mitigate concerns about the potential unintended public health consequences of virus administration [1]

2.3. Intratumoral virus administration produced rapid histological changes in xenografts [1]

2.3.1. Attempts to isolate virus from lesions 28 days after PVS-RIPO admistration FAILED, possibly correlating with the absence of viable tumor cells [1]

2.4. There is no explaination for the effects of the combined virus signal to the protein synthesis machinery [1]

2.4.1. Unclear due to the multiple signaling events and the heterogeneity of eukaryotic translation templates [1]

2.4.1.1. It is speculated that signal transduction to the protein synthesis machinery produces a range of discrete changes [1]

2.4.2. Control of eIF4G function remains poorly understood [1]

2.4.2.1. eIF4G engages in complex interactions with translation factors [1]

2.4.2.2. Potential functional consequences of post-translational modification of eIF4G are significant [1]

3. Benefits of PVS-RIPO

3.1. It unleashes potent cytotoxic effects on infected cancer cells [1]

3.1.1. Produces sustained anti-tumoral responses in animal tumor models has been recorded [1]

3.2. Displays an inability to translate its genome in untransformed neuronal cells, but effectively does so in cells originating from primary tumors in the CNS [1]

3.3. Favors an unconventional viral translation initiation mechanism in cancerous cells [1]

3.4. Genetic stabillity of PVS-RIPO upon long-term serial passage in HeLA cells in lab [1]

3.4.1. Intratumoral virus administration produced rapid histological changes in xenografts [1]

3.4.1.1. After 10 days, xenografts had shrunk considerably [1]

3.4.1.1.1. The central core contained potentially viable tumor cells [1]

3.4.1.1.2. Surrounding had fibrotic periphery, which was presumably free of tumor cells [1]

3.4.1.2. After 18 days, there was no evidence of significant viable tumor cells in majority of the animals [1]

3.4.1.2.1. Former xenograft appeared to have been replaced by a scar [1]

3.4.1.3. Virus recovered from two consecutive serial passages in GBM xenografts [1]

3.4.2. It also maintained cell type-specific conditional replication phenotype upon prolonged serial passage in GBM cells in vitro and in vivo [1]

3.4.3. Provides important information about possible mechanisms responsible for efficient PVS-RIPO propagation and cytotoxicity in tumor [1]

4. Mechanisms

4.1. Enlists the help of human pathogens in the fight of cancer [1]

4.1.1. Virus infects a tumor cell, the virus makes copies of itself until the cell bursts [2]

4.2. Tumor Selectivity of Oncolytic Viruses

4.2.1. To enhance the immune response to the tumor through a variety of strategies, including by combining oncolytic virus therapy and immunotherapy [2]

4.2.2. Viruses that exhibit inherent selective cytopathogenicity for transformed human cells e.g. Reovirus, Myxoma Virus[1]

4.2.2.1. Therefore, viral replication/pathogenesis is naturally restricted in normal human tissues [1]

4.2.2.2. Mechanism Basis: Virus propagation in normal human tissues is tightly controlled via innate immune responses, accounting for their low inherent pathogenic potential [1]

4.2.2.3. Tumor cells, that exhibit deficient innate immunity, may permit replication and cell killing of human orphan virsues [1]

4.2.3. Viruses with oncolytic agents that require sophisticated genetic manipulations in order to achieve tumor selectivity because of inherent pathogenic potential e.g. HSV, Poliovirus [1]

4.3. Creation of PVS-RIPO

4.3.1. Achieved by manipulating the viral 5'UTR and a cis-acting gnetic element involved in trasnlation regulation [1]

4.3.2. Initiates viral protein syntehsis via interaction of eIF4G with the viral RNA [1]

4.3.3. Consists of the genome of the live attenuated poliovirus serotype 1 (SABIN) vaccine (PV1S) with its cognate internal ribosomal entry site (IRES) element replaced with that of human rhinovirus type 2 (HRV2) [5]

4.4. Uses of PVS-RIPO

4.4.1. SUMMARY: Has toxic effects on infected cancer cells and sustained anti-tumoral effects in animal models have been observed [1]

4.4.1.1. Results from both the repressive factors in the CNS and the functions specifically favoring viral, cap-independent translation in cancer [1]

4.4.2. Has cytopathogenic property for transformed human cells, which allows for cell killing in cancerous cells [1]

4.4.3. selective propagation and cytotoxicity could be stemmed from unrelated functional studies of the IRES:eIF4G relationship [1]

5. Phase 1 Clinical Trial: PVSRIPO for Recurrent Glioblastoma (GBM) [5]

5.1. Study Type: Interventional (Clinical Trial) [5]

5.2. Intervention/Treatment: Biological: Recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO) [5]

5.3. Purpose of the Study:

5.3.1. To determine the maximally tolerated dose (MTD) and the Recommended Phase 2 Dose (RP2D) of PVSRIPO when delivered intracerebrally by convection-enhanced delivery (CED) [5]

5.3.2. To obtain information about clinical response rates to intratumoral inoculation of PVSRIPO [5]

5.3.3. To estimate the effects of PVSRIPO administered at the optimal dose [5]

5.4. Actual Enrollment: 61 participants

5.4.1. PVSRIPO is delivered directly into the tumor

5.4.1.1. In the dose escalation phase(DEP), dose levels were rapidly escalated as preclinical data suggested that dose-limiting toxicity (DLT) would not occur at any of the five dose levels that were being evaluated. Decisions concerning dose escalation for subsequent patients were based upon the occurrence of DLT during the first 4 weeks after treatment administration. [5]

5.4.2. Minimized the # of patients treated at low-dose levels during the DEP [5]

5.4.2.1. Used a two-step continual reassessment method (CRM) design that included an escalation step and a model-guided step [5]

5.4.3. After completion of Dose Escalation and determination of MTD

5.4.3.1. Continued patient accural occured to aid in the determination of the Recommended Phase II Dose (RP2D and gather more information about patient safety [5]

5.4.3.1.1. Decision was made to treat future study patients at Dose level -1

5.5. Current Primary Outcome Measures - Oct. 29, 2018

5.5.1. Maximium Tolerated Dose (MTD) is estimated to be less than 20% [5]

5.5.1.1. Based on the first 9 patients treated where 1 patient at dose level 1, 1 pateint at dose level 2, 1 patient at dose level 3, 2 at dose level 4 and 4 at dose level 5 [5]

5.5.2. Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) is reported [5]

5.5.2.1. DLT: Grade 3 or Grade 4 toxicity that is not reversible within 2 weeks, life-threatening event, or treatment-related death [5]

5.5.3. Patients have not experienced undue side effects from the administration [5]