CAR-T and TCR-T therapies that involve engineering a patient’s own immune cells with antigen-specific receptors have revolutionized blood cancer treatment. Now scientists at Duke-NUS Medical School are exploring the possibility of turning the approach against COVID-19.
The idea of using CAR/TCR-T cell therapy has already been proposed for treating chronic viral infections such as HIV and hepatitis B. Based on previous research, Antonio Bertoletti from Duke-NUS’ emerging infectious diseases research program suggest these immunotherapies might also be useful in treating SARS-CoV-2, the virus causing the current pandemic.
“We demonstrated that T cells can 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,” Bertoletti said in a statement.
These types of therapies involve modifying patients' own T cells with either a chimeric antigen receptor (CAR) or a T-cell receptor (TCR) that can recognize specific antigens associated with cancer, and then guiding the immune cells to eradicate the targets when infused back into the patients.
In a 2011 article published in the Journal of Virology, Bertoletti led a team that generated TCR-T cells that can go after SARS, another coronavirus that caused a deadly outbreak in China and other countries in late 2002 and early 2003.
The team showed that those TCR-redirected T cells displayed a functional profile similar to that of SARS-specific memory CD8 T cells from people who recovered from SARS-CoV infection. Based on the findings, the researchers suggested that TCR-T cells represent a promising prophylactic or therapeutic treatment for SARS.
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CAR-T cells have been explored in other viruses. A research team from the Albert Einstein College of Medicine and the University of Pittsburgh, for example, designed “duoCAR-T cells” that target three sites on the HIV envelope glycoprotein. In the lab, the cell therapy eliminated up to 99% of immune cells infected with different strains of HIV.
Despite the promise of T-cell therapies, however, Bertoletti and colleague Anthony Tanoto Tan cautioned about potential safety concerns of using them to treat viral infections affecting vital organs. For one thing, CAR-T treatments have been linked to the dangerous side effect called cytokine release syndrome, in which overreactive immune cells launch an inflammatory response that can destroy organs, they said in a recent Journal of Experimental Medicine commentary. Similar cytokine storm effects have been reported in some severe COVID-19 patients, leading to potentially life-threatening lung inflammations.
“[T]he infusion of T cells stably expressing pathogen-specific CAR/TCR poses the risk that these T cells might proliferate and wipe out all the infected cells that might be the majority of the infected organ,” Bertoletti and Tanoto Tan wrote in their article.
To address that problem, Bertoletti and colleagues are using mRNA electroporation to engineer CAR/TCR T cells, which they say can limit their inflammatory capability and shorten the functional activity. That may offer a safer way to use engineered immune cells to treat viral diseases.
Several organizations are also working on cell therapies for COVID-19. AlloVir and Baylor College of Medicine have teamed up to develop an off-the-shelf therapy that entails exposing donor T cells to cytokines combined with viral fragments so the new cells can target the novel coronavirus. Celgene spinoff Celularity just started clinical trial of its cancer treatment CYNK-001 for COVID-19. The drug turns placental stem cells into one-size-fits-all natural killer cells.