The rapidly developing field of synthetic biology—including the subfield of synthetic immunology—is putting a plethora of new tools into the hands of basic and translational scientists and enabling new technologies that are transforming molecular biology and medicine. Chimeric antigen receptor (CAR) T-cell technology is a shining example of the promise of using synthetic immunology to enhance human health.
Each new advance in technology, however, also requires appropriate oversight to ensure the safety of investigators, laboratorians, animal care workers, clinical staff, and—in the case of clinical trials—human study subjects. In this article, we will look at special considerations for institutional ethical and safety review of clinical trials involving synthetic immunology.
For research involving National Institutes of Health (NIH) funding, a key safety role is played by Institutional Biosafety Committees (IBCs). Under the NIH Guidelines for Research Involving Recombinant and Synthetic Nucleic Acid Molecules, all institutions that receive NIH funding for molecular biology, and all clinical trial sites engaged in human gene transfer research using products developed with NIH funding, must have an IBC registered with the NIH. As a result, there are currently more than 1200 IBCs registered in the NIH IBC system.
Each IBC roster must include scientific experts as well as community members who live nearby and are unaffiliated with the research institution. Each new research protocol—clinical or nonexempt nonclinical—subject to the NIH Guidelines must be approved by an IBC registered for the relevant institution. For human gene transfer clinical trials, such research must be approved both by an IBC, which is tasked with mitigating risks to study subjects, research staff, the general public, and the environment, and by an institutional review board (IRB), which is tasked with ensuring ethical treatment of study subjects.
For such reviews to be effective, it is important that between them the committees include members that understand both the molecular and the clinical factors that should inform the risk assessment for each protocol. As with other emerging technologies, the deployment of synthetic immunology in clinical trials requires that oversight committees retain members familiar with the attendant clinical, procedural, ethical, and compliance issues.
CAR T-cells as examples of synthetic immunology in the clinic
CARs are constructed by joining together an antigen-targeting domain, a transmembrane domain, and activation-signaling domains from various genetic origins to confer novel antitumor functions to T cells. For example, both CAR T-cell products with current FDA marketing approval use a tumor-targeting domain (derived from a mouse antibody against the human B-cell tumor antigen CD19) plus signaling domains derived from human immune activating receptors (CD28 or 4-1BB). CAR T-cell products under development use a broad array of tumor-targeting domains, and a variety of activating domains, to direct T-cell responses against different types of cancer. Each of these components and approaches involve potential risks and benefits that must be carefully considered by oversight committees.
A primary concern for new CAR T-cell therapies is the fact that, unlike CD19, other antigens found on tumors may also be found on healthy cells that are essential for patient survival. This means that even if a CAR T cell is very specific for the target, it may still damage healthy tissue, creating an on-target/off-tumor effect. Furthermore, there is a risk that CAR T cells may cross-react with normal antigens on noncancerous cells and damage healthy tissue—an “off-target” effect. The risk of off-target and off-tumor effects must be considered as part of the general risk assessment for CAR T-cell therapies.
Even in the absence of measurable off-target and off-tumor effects, CAR T-cell therapy can have serious side effects. These especially include cytokine release syndrome (CRS) and certain types of neurotoxicity and cerebral edema. It appears that newer CAR T-cell approaches have reduced the frequency of these side effects; nevertheless, the ongoing risk of such serious adverse events must be taken into account.
Once the genetic construct encoding the CAR has been designed, it must be efficiently delivered to T cells. The majority of CAR T-cell approaches under development rely on autologous T cells, so the new CAR T-cell product must be manufactured for each recipient from that subject’s own cells. This means that the method of delivering the CAR genetic construct to freshly isolated T cells must be very efficient.
The FDA-approved CAR T-cell products achieve efficiency using similar methods. For both products, T cells are transduced with a retroviral or lentiviral vector that inserts the artificial gene construct into the chromosome of the host cell in a semi-random manner. Earlier versions of this technology sometimes ended up causing vector-transduced cells to become cancerous through a process known as insertional mutagenesis or insertional oncogenesis. The risk of insertional oncogenesis from the current generation of vectors appears to be greatly diminished but must still be incorporated into any risk assessment for these therapies.
Some CAR T-cell products in development use different gene delivery methods that are not designed to integrate into the chromosome and thus pose minimal risk of insertional mutagenesis. As each new gene delivery technology is moved into the clinic, IRBs and IBCs must be prepared to execute well-informed risk assessments.
A key component of IBC oversight is assessment of the research site. The site must have appropriate facilities, training, and procedures to ensure safety of the subjects, staff, and the public with respect to biohazardous materials used in the research. CAR T-cell research involves primary human T cells, which are a possible source of bloodborne pathogens (BBPs). IBCs overseeing CAR T-cell research must ensure that the research facilities and procedures are appropriate for BBP containment.
In addition, each protocol must undergo a risk assessment to assess the presence of other transmissible agents associated with the investigational product. Current CAR T-cell clinical protocols generally do not include gene transfer agents that pose a significant risk of transmission, such that universal precautions for BBPs are generally adequate biocontainment. It should be noted that some preclinical approaches to CAR T-cell therapy do include infections or transmissible components, such that each protocol must be subject to careful risk assessment by the IBC, and additional biocontainment steps recommended as appropriate.
Biosafety and ethical oversight of synthetic biology
The promise of synthetic immunology to advance human health can be fulfilled only if the public maintains trust and confidence in the scientific research enterprise. IRBs and IBCs both play key roles in ensuring scientific and ethical integrity, safety, and public engagement in research.
For synthetic biology projects, oversight committee members should be familiar with potential risks and pitfalls related to potential adverse events in study subjects as well as potential research-related exposures and illnesses in clinical staff and members of the public who come into contact with study subjects. Properly informed IRBs and IBCs can serve as valuable partners with sponsors and investigators in the process of bringing new therapies from bench to bedside.
Daniel Kavanagh, PhD, is senior scientific advisor, gene therapy at WCG (WIRB-Copernicus Group). Previously, he was on the faculty at Harvard Medical School, where he conducted gene therapy research and was vice chair of an Institutional Biosafety Committee overseeing human gene transfer studies.