A provocative paper from Duke-NUS Medical School, published in the Journal of Experimental Medicine in March 2020, discusses the possibilities of creating new receptors on a sick person's own immune cells as a means of controlling the infection. This therapy is already being used to treat certain cancers with marked success.
The principle of T cell-based treatment
The human immune system uses two types of immune response, namely, the innate and the adaptive arms of immunity. The innate type responds to any new infection indiscriminately, by gobbling up the invader while shouting out for help if there are signs of a heavy invasion. The adaptive type, based on immune cells called T and B lymphocytes, is relatively delayed but far more fine-tuned, specific and durable, designed to lock on to the foreign particle, memorize its contours, and eliminate it even while making a permanent record for future reference. This ensures that the next time around, instant recognition and intense fightback occurs.
In many cancers, this marvelously detailed and versatile immune capacity is already being used by engineering specific recognition sites ('receptors') onto a patient's own T cells. Two types of receptors are used: chimeric antigen receptors (CARs) or a classical T cell receptor (TCR). CARs are artificial receptors made in the laboratory whereas TCRs are naturally found on the surface of T cells.
CAR T-Cell Therapy. T-Cell binding to a tumor cell using Chimeric Antigen Receptor (CAR). Image Credit: Alpha Tauri 3D Graphics / Shutterstock
The engineered lymphocytes are now directed against the tumor's antigens, or recognition molecules, triggering tumor kill by these and following immune cells. TCRs are now available for a variety of viruses and seem to have the same antiviral activity as those generated by the body itself, at least in the laboratory.
A fundamental difference between them is, however, that engineered T cells with CARs/TCRs are monoclonal, reacting to a single specific antigen, in contrast to the more generalized range of viral antigens reacted to by naturally produced T cells. Scientists are probing if this will mean a higher chance of selection of escape variants with the former.
Using engineered T cells in infectious disease
Although lifestyle diseases remain a growing concern, infectious diseases, especially in developing countries, significantly contribute to global morbidity and mortality. However, immunotherapy has been somewhat restricted to cancer or inflammatory diseases such as arthritis, says co-researcher Patrick Casey.
Scientists do not agree on using this therapy to combat infectious disease, citing high production costs among other reasons. The treatment involves specialized personnel and equipment and may need to be administered for an indefinite period of time. The logistical issues drive up costs, making it impractical for most viral infections.
Instead, many researchers feel, scarce resources should be invested in vaccines and small molecule therapy that prevent viral, bacterial, or parasitic replication. This approach is logical. Yet the concept could be exploited in some areas, argue specialists, who point to the potential of this therapy to combat chronic infections like the Hepatitis B virus (HBV). In such incurable conditions, a combination of antivirals and CAR/TCR T cell therapy could be effective, researchers suggest.
Difficulties of CAR/TCR therapy in HIV infection
The reasons for the slow take-up of CART or TCR-engineered T cells in the treatment of HIV are many. Most importantly, antivirals today make it possible for HIV patients to live normally. Successful CAR/TCR therapy must compete by eradicating all latent HIV infection within T cells through cell kill. HIV is also a virus that mutates readily. It is also expressed at very low levels in cells with latent infection, but reactivation of infection is potentially dangerous. HIV antiviral therapy also reduces the antigen expression to very low levels, making the virus almost undetectable by the T cells.
HBV and T cell therapy
Current HBV infection treatment with antivirals suppresses viral replication but cures only 5% of patients. In contrast, antivirals cure 95% of HBC infections.
"We argue that some infections, such as HIV and HBV, can be a perfect target for this therapy, especially if lymphocytes are engineered using an approach that keeps them active for a limited amount of time to minimize potential side effects," says researcher Anthony Tanoto Tan.
The hepatitis B virus contains certain peculiarities that make it more suited to CAR/TCR T cell therapy and render the therapy more likely to work without destroying healthy cells or harming the organs affected by the virus, the researchers state.
These features include the persistence of antigen production even while the antiviral therapy blocks DNA synthesis, lower odds of mutation due to the compact genome where one DNA sequence is translated into a variety of proteins, and the severe impairment of the patient's own specific T cell response to HBV.
Rather than depending on the severely restricted HBV-specific immunity, therefore, engineering T cells can restore a robust and sizeable T cell immune population to eradicate the virus in combination with other agents, as demonstrated in animal experiments.
In introducing T cells that carry the memory of HBV antigens in the form of specific CAR/TCR, the risk is always present that they could proliferate, and eliminate the infected cells so completely that they also wipe out the liver, whose cells harbor the virus.
The team uses mRNA electroporation to introduce the CAR/TCR receptors, for less than 72 hours. This means that the modified cells only function for a limited period of time. They are less powerful in their antiviral response but may trigger other immune responses which enhance the success of the therapy.
The use of such measures not only reduces the side effects but may initiate a host response that acts synergistically with the transferred adoptive T cells. Nonactivated T cells could also be induced to express CAR/TCR by mRNA electroporation, resulting in cells that express low levels of the lytic enzymes perforin and granzyme. This makes inflammatory and cell lysis reactions less likely but preserves antiviral activation capabilities. As a result, side effects are minimized.
Overcoming difficulties for a cure
The researchers say they "cannot deny the existence of practical difficulties and safety concerns that still prevent the widespread clinical translation of CAR/TCR-T cell therapy for infectious diseases." Yet, they call for more work and expansion of knowledge in this field to counter the dangers and obstacles, rather than giving up on the possibilities of curing incurable and debilitating viral infections.
"We demonstrated that T cells could be redirected to target the coronavirus responsible for SARS. Our team has now begun exploring the potential of CAR/TCR T cell immunotherapy for controlling the COVID-19-causing virus, SARS-CoV-2, and protecting patients from its symptomatic effects," said investigator Antonio Bertoletti.
Bertolettti, A., and Tan, A. T. (2020). Challenges of CAR- and TCR-T cell–based therapy for chronic infections. Journal of Experimental Medicine. 217 (5): e20191663. https://doi.org/10.1084/jem.20191663