As cell and gene therapy continues to develop, the knowledge base around the uncertainties, risk factors and challenges of CGT has increased substantially. A vast trove of existing research now provides an on-ramp for experimental therapies to build off of. For example, past research can illustrate a road map of known obstacles which scientists can incorporate into mitigation strategies.
Government agencies are providing guidance on known risk factors. The European Medicine Agency, for example, recommends using a risk-based approach that prioritizes the quality, safety, and function of the source material.
Multiple risk factors include transmissible spongiform encephalopathy agents (“TSE”), viral contamination, cross-contamination, replication-competent viruses, microbiological contamination, and sterility integrity issues across the entire production chain, from storage and transport to environmental controls and the use (or absence of) dedicated equipment.
Challenges, Risks and Uncertainties
At MKA Insights, we find it helpful to sort cell and gene therapy risks into “challenges”, “risks” and “uncertainties”. These are defined as:
Challenges: Research-specific hurdles or limitations that must be overcome to better understand the disease or potential mechanism of action for a proposed cell and gene therapy.
Risks: Known issues with cell and gene therapies that pose a safety concern for patients when administered.
Uncertainties: Areas of uncertainty within cell and gene therapies that lack sufficient data but may pose future risks to patients.
Examples of challenges within the cell and gene therapy field include:
Challenge: Heterogeneity of Tumor Cells
Tumors have broad heterogeneity due to the complexities of mutations. This makes it difficult to identify a single antigen or clone that is uniformly effective in eliminating the targeted cells. Researchers often deploy various strategies to improve efficacy, including radiation and removal.
Challenge: Complex Tumor Microenvironments
Solid tumors feature complex tumor microenvironments (“TME”) that are not fully understood. They consist of a complex matrix of healthy and diseased tissue, densely packed with a life of its own.
Challenge: Limited Utility of Animal Models
Given the mode of action of cell and gene therapies on the human body, animal models have limitations in providing safety and efficacy data.
Even with humanized animal models, researchers do not fully understand the intended consequences of a therapy because they apply a fully human protein to rodents or non-human primates. As a result, it is difficult to have certainty about toxicological risks, especially in the context of the cascading effects of immune responses triggered by these therapies.
Risk: Immunogenicity and Immunotoxicity
Immunogenicity is the ability of a foreign substance to provoke an immune response in an individual. Immunotoxicity, a subset of immunogenicity, is the adverse effect that results from exposure to toxic substances, such as allergic hives.
In the field of vaccines, immunogenicity is a desired response. However, an immune response, such as the development of antibodies following a gene therapy treatment, is a risk to patients. “Many of the failures and high attrition rate when taking drugs from discovery to market are caused by issues with immunogenicity and immunotoxicity,” Lonza Head of Immunology Noel Smith, PhD, says. “In the case of cell and gene therapies, understanding immunogenicity and immunotoxicity is a fundamental requirement for understanding the efficacy and safety profile of prospective therapies.”
Understanding the immune response triggered by a prospective therapeutic allows researchers to better understand the desired (and undesired) impacts of a therapy.
Regulators require an “Immunogenicity Risk Assessment” as part of the investigational new drug filing. The data to support the assessment is dependent on the nature of the drug, the mode of action, route, frequency, patient factors and disease indication.
Risk: Graft versus Host Disease
A well-known risk associated with tissue transplantation is Host versus Graft Disease. This occurs when the host’s immune system starts attacking the newly-introduced tissue.
The converse can also be true. In Graft versus Host Disease, the attack comes via the transplanted tissue, which turns on the host’s body. Similar risks are present in cell and gene therapies.
Risk: Cytokine Release Syndrome
Cytokine release syndrome occurs when the immune system responds more aggressively to a therapy than anticipated. This can potentially result in organ or systemic failure.
Risk: Human Mouse Antibodies
Some therapeutics incorporate murine (mouse) antigens and antibodies, which can prompt an anti-mouse response in some patients. Unfortunately, a similar response was noted during the early use of murine antigens/antibodies for CAR-T use, which effectively limited the number of doses that could be received by patients.
Risk: Off-target / On-target / Non-specific
Cell and gene therapies use “immune modulators” to effect change. This type of therapy inherently carries more risk due to the potential for off-target binding.
Off-target binding occurs when the antigen expressed on the therapeutic binds with healthy tissue, resulting in off-target effects. Non-specific binding occurs when there is a lack of specificity to the antigen.
Given that cells travel within the body, the risk of off-target binding is real. Even when delivering gene therapy to a specific tissue, there is a risk of the therapies spreading within the body.
Risk: Viral Shedding
Gene therapies which use bacterial or viral vectors may cause shedding, which is when cells multiply and leave the body. This results in exposure to people in close contact with patients as well as an environmental risk.
Uncertainties: Prolonged activity post-administration
Given the nature of experimental gene therapies to influence genetic expression, researchers and regulators are carefully assessing the post-administration activity of the target therapeutic to better understand both short- and long-term effects of these therapies. Additionally, many therapies are studied over time. Insufficient time has passed to provide anecdotal evidence on the prolonged activity of these therapies post-administration.
Uncertainties: Gene therapy expression
Gene therapy products may interfere with the normal function of critical enzymes, hormones, or biological processes. Because therapies integrate into the DNA of a recipient to allow for long-term expression, genomic alterations could activate or inactivate neighboring genes, resulting in tumors.
We are optimistic that the growing body of knowledge around the risks, challenges and uncertainties associated with cell and gene therapies will accelerate breakthroughs. This, in turn, will contribute to more therapies which are developed and approved in shorter timespans.
