Call in the T-Cell Cavalry to Fight COVID in the Immunocompromised

Last year was one of collective confinement. The majority of us shuttered our doors to visitors, worked from home, and ventured out sparingly in hopes of evading the grasp of COVID-19. Now in 2021, thanks to vaccination rollout, those who have been vaccinated are hopefully on the path to normalcy. But not everyone is so fortunate. For some, 2021 will bring more isolation and loneliness than ever before, which is hard to imagine. I’m talking about immunocompromised adults and children. While much of the rest of the populace clinks glasses, hugs loved ones, and joins parties, immunocompromised individuals do not have the security of an effective vaccine, and for their health and safety will maintain their distance and watch the social revelry from the sidelines.

The normal vaccine response that elicits antibodies and immune cells to fight infection are absent in these immunocompromised individuals, who fall into two categories: those living with congenital or acquired diseases that weaken their immune system, or those with pre-existing conditions whose treatment requires dampening of the immune system (e.g., patients with blood cancers or transplant recipients). This vulnerable population represents a sizable proportion of the U.S. population. A 2018-2019 analysis in JAMA Network Open estimated that 2.8% of adults in America were on a treatment regimen that dampened their immune system. That percentage may seem small but extrapolate it to the entire U.S. population and you hit 9 million vulnerable people. This doesn’t even include immunocompromised individuals who are not taking immune-suppressing medication.

The plight of immune-compromised individuals has large-scale implications. This inability to combat the virus not only can be potentially life-threatening but can also lead to the continued evolution of mutant strains that infiltrate healthy populations. The so-called New York variant (B.1.526) was identified in a patient with advanced AIDS. Similarly, the highly transmissible and more deadly Alpha strain (B.1.1.7) emerged in a patient receiving immune suppressive treatment for a blood cancer.

So, while COVID-19 vaccines administered in the U.S. have been highly effective for mounting an antibody immune response in people with functional immune systems, it’s not enough to vanquish the contagion. In our fight against virus infection, another critical arm of the immune system is required: The T-cell immune response. While antibodies may prevent infection, these warriors destroy already infected cells. And initial research suggests they may be active even in absence of antibodies.

Just recently, researchers (including myself) published a study in the Journal of Clinical Immunology that showed that pediatric patients with primary immune deficiencies, who often fail to make protective immune responses to infections and vaccinations, show robust T-cell activity and immunity against SARS-CoV-2. These findings are important because if T-cell responses to COVID-19 are protective in this highly vulnerable population, this could suggest that a COVID-19-directed T-cell immunotherapy might benefit other profoundly immunocompromised patients. However, we still don’t know if such responses will persist to provide protective long-term immunity, especially against mutant strains of the virus.

Indeed, earlier findings published by me and my team in Blood, show T cells can be taken from the blood of recovered COVID-19 patients and multiplied in a lab, which could then be infused into bone marrow transplant patients whose immune systems can’t fight the virus on their own. In effect, this creates an army of trained coronavirus fighters to potentially provide protective T-cell immunity long-term to these highly immunosuppressed patients. My team and I submitted this coronavirus-killing T-cell therapy (CST) clinical trial proposal to the FDA and have recently received approval to start this first-in-human clinical research protocol to treat these vulnerable patients who are currently falling through the cracks in the vaccine fight against COVID-19.

Ongoing research in the race to outpace the pandemic has helped us to increasingly unravel the prominent role of T cells in long-term immunity. A study published in Nature showed patients who recovered from the 2003 SARS epidemic, whose antibodies faded within 2 to 3 years, had a robust T-cell response to SARS 17 years later. These T cells also recognize the SARS-CoV-2 nucleocapsid protein.

For immunocompromised patients, adoptive immunotherapy using T cells from recovered COVID-19 patients may be the answer when vaccines only offer partial protection. T cells could vanquish infected cells to limit the severity of disease or avoid hospitalization, and they remember a contagion for decades.

With the number of COVID-19 variants multiplying, this is an arms race. As a society, we need to deploy every weapon in our arsenal to ensure no one is left behind in the return to normalcy, especially not the most vulnerable. If antibodies were the infantry in our fight against the pandemic, then T cells are the cavalry. It’s time we call them in.

Catherine Bollard, MD, MBChB, is the director of the Center for Cancer and Immunology Research at the Children’s National Research Institute, director of the Program for Cell Enhancement and Technologies for Immunotherapy, and a member of the Division of the Blood and Marrow Transplantation at Children’s National Hospital in Washington, D.C.