Using our virus-based platforms, we calibrate our treatments to each cancer that we target. These viruses have been genetically engineered to minimize impact on healthy tissue, while maximizing the patient’s immune response to fight the tumor.
Immunotherapy has transformed the way we treat cancer.
However, typically only 15 to 40% of patients overall respond to such treatment.
Poor response of the immune system to treatment is sustained by the ability of the tumor to disguise antigen presentation and to generate an immunosuppressive microenvironment.
Clinically Advanced Solid Tumor Immunotherapy
CAN-2409 (international non-proprietary name: aglatimagene besadenovec) is an adenovirus-based replication deficient engineered gene construct encoding the thymidine kinase gene derived from the herpes simplex virus. It is injected directly into the tumor or target tissue. Localized injection is intended to minimize systemic toxicities associated with systemic intravenous administration, eliminating the requirement for complex immune evasion or tumor-specific targeting mechanisms, and focuses the immune response locally against the tumor, while also activating the desired systemic anti-tumoral response. The adenoviral construct is used as a vector to transport the thymidine kinase gene into the tumor cells at the site of injection. Thymidine kinase converts generic, FDA-approved anti-herpes drugs, such as ganciclovir, acyclovir and valacyclovir, which are used as prodrugs, into a toxic nucleotide analogue. These agents are widely available, inexpensive and are generally well-tolerated. Cells transduced with thymidine kinase gene undergo immunogenic cell death after exposure to these systemically administered prodrugs.
The prodrug-derived cytotoxic nucleotide analogs are designed to inhibit DNA replication and repair, leading to the death of multiplying tumor cells, and in particular of cells undergoing repair from radiation or chemotherapy damage. This oncolytic activity is immunogenic and exposes tumor antigens that can elicit a further tumor-specific immune response. Additionally, the virus itself stimulates a marked immune response.
Candel is evaluating the effects of treatment with CAN-2409 for prostate, brain, lung and pancreatic cancers in clinical trials. For more information on our studies in the clinic, please visit our Clinical Trials page.
Novel Herpes Simplex Viral Vector
CAN-3110 is a modified HSV with specific properties that can be leveraged in diverse clinical indications. Namely, CAN-3110:
■ Is engineered to provide oncolysis through tumor replication specifically in Nestin expressing cancer cells.
■ Has demonstrated statistically significant survival benefit in preclinical models of brain cancer
■ Has demonstrated a favorable tolerability profile, not reaching a dose limiting toxicity in the dose range tested in our Phase 1 trial.
■ Has shown a preliminary clinical signal in a difficult to treat brain cancer population, critically defined by a highly immunosuppressive environment.
■ Has been engineered to replicate in a range of other indications characterized by Nestin expression.
■ Is derived from the HSV platform that also provides the potential to support expansion of our pipeline with novel agents.
CAN-3110 is an engineered oncolytic HSV where the expression of ICP34.5, the gene responsible for viral replication, has been placed under the control of a tumor-specific Nestin promoter. This modification of the viral genome enables us to maintain the function of ICP34.5, an HSV protein that allows virus replication even in the presence of a suppressive interferon response, under a strict control and only in tumor cells.
ICP34.5 is often deleted in other HSV oncolytic viruses that may be less tumor selective with an intent of achieving favorable safety profile, but this often results in weak viruses characterized by poor replication ability and an ability to generate limited immune response.
Nestin is a cytoskeletal protein that is overexpressed in glioma cells, but it is absent in the healthy adult brain. In CAN-3110, ICP34.5 expression is controlled by the Nestin promotor enabling viral replication selectively in tumor cells. This replication-competent HSV construct provides tumor-specific cytolytic activity in animal models, while sparing healthy cells. As set forth below, data with a tool analogue of CAN-3110 in a mouse model of glioma has shown survival benefit over control vectors when the agent is administered to mice at both early and late stages of tumor growth, even after tumor implantation has led to neuropathology.
Candel is evaluating the effects of treatment with CAN-3110 for recurrent glioblastoma. For more information on this clinical study, please visit our Clinical Trials page.
