Today we are delighted to have a guest post by Dr Chris Lazarski to talk about their interesting work.
Background: Vaccines are a critical tool to protect the majority of people from viral infection. However, some people require a more involved treatment strategy to treat persistent viral infections. These people may be immune suppressed because they have received a bone marrow transplant to treat cancer, they have a genetic deficiency which stops T and B cells from growing, or their viral infection is not responding to traditional anti-viral drugs. Our goal was to provide novel treatments for these critically ill children who have run out of alternatives.
Who am I: I am a Staff Scientist at Children’s National Hospital in Washington DC and manage our Flow Cytometry Core. I have a PhD in Immunology from the University of Chicago, and have investigated T cell responses to vaccines and infections for 23 years. I am a part of the Immune Testing and Characterization Lab within Children’s National Hospital, and help characterize the safety and efficacy of T cell products manufactured by our in-house good manufacturing practices (GMP) lab .
Conflicts: Our authors, including me, have submitted patents on the manufacturing of T cell products for therapy.
Who we are and what we do: We work within Children’s National Hospital as part of the Program for Cell Enhancement and Technologies for Immunotherapy (CETI) to provide novel immune treatments for our pediatric patients. Our group expands T cells outside of the body to grow tens of millions of cells for re-infusion back into patients. This boosts their immune system to help them fight viral pathogens and tumors. Our method expands specific T cells for viruses by adding short fragments of virus proteins, called peptides, and growth factors called cytokines to the culture.
How does our work relate to people with MS: Many people with MS use therapies which dampen their immune response, such as ocrelizumab, cladribine and alemtuzumab. People with MS are more susceptible to viral infections while on these treatments, which is analogous to the children in our care who are immunosuppressed. Our method of infusing T cells back into immunosuppressed children would be directly applicable to treating MS patients who cannot mount T cell responses against SARS-COV2.
How does our work relate to SARS-COV2: Our focus is to design and create therapeutics for patients suffering from persistent viral infections, and we have had substantial success treating CMV, EBV, Adenovirus, and BK virus infections. We wanted to investigate whether we could continue that success for people suffering from SARS-COV2 infections, because we know that vaccines may not be as effective as needed in people who are immunosuppressed. Our ultimate goal would be to test whether infusing T cells targeting SARS-COV2 early in the course of infection would help prevent a persistent case of COVID19..
How did we do these experiments: Before we can treat any infected people, we need to test whether T cells can be grown against SARS-COV2, and what these T cell products recognize. To do this, we collected peripheral blood from 15 unexposed donors and 46 convalescent (recovering) donors who were recovering from mild to severe symptomatic COVID19 disease. We expanded T cells from this blood in rapid 10-day cultures using small fragments from four SARS-COV2 proteins according to our established protocols using good manufacturing practices (GMP) required for human use. After 10 days, we investigated what types of T cells grew in the cultures and what SARS-COV2 proteins they recognized.
What did we find: We can expand T cells that are specific for SARS-COV2 according to our standard 10 day GMP compliant protocol. Most of these T cell products recognize the membrane, and several also recognize the spike and nucleoprotein of SARS-COV2. We found two seronegative controls also showed reactivity against SARS-COV2 spike. We also identified which portion of the membrane, spike, and nucleoprotein our T cells react against, and found they recognize regions common to other coronaviruses. This may explain why two controls recognized the spike protein.
What can we do with this information? Our group now has a clinical trial that uses T cell products directly from bone marrow donors, and also a trial that uses a bank of 3rd party products unrelated to the donors. We are investigating whether these 3rd party products are safe and can work just as well as if they were from a related donor, to create an “off the shelf” library of T cells that can help patients suffering from CMV, EBV, and Adenovirus. Our goal would be to duplicate this 3rd party bank for SARS-COV2 and start a clinical trial testing related and unrelated donor T cell products. Demonstrating that we can grow T cells against SARS-COV2 and identifying what they recognize is a critical first step in this process.
Where can I read more about this: This work is published in the journal Blood and is available at https://doi.org/10.1182/blood.2020008488. We have clinical trials led by Dr. Michael Keller and Dr. Catherine Bollard targeting viral infections which can be read on clinicaltrials.gov. We have other trials targeting tumors also on clinicaltrials.gov, and have many publications reviewing our results using T cell therapies.