Guest Post:Cell Therapies to Treat Viral Infections

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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.

About the author

BartsMSBlog

12 comments

  • We do have T cell products that target EBV transformed B cell tumors in people that arise after transplant. These lymphomas are called PTLD or Post Transplant Lymphoproliferative Disorder. Atara is creating T cell products also targeting PTLD related diseases, although our methods for expanding the cells are different. You can never “clear” EBV from the body because it is a lifelong infection resident in B cells. You can only suppress EBV infected B cells from dividing, which is what a normal, healthy T cell response does.

    • Chris,

      Thanks for your really interesting post. Two questions:

      You say you can never clear EBV from the body. What about the vaccines being developed against EBV? Will they not help a person get rid of the virus if they become infected (as with other vaccines)?

      Do you have any thoughts on Prof G’s hypothesis that EBV is the likely trigger / root cause of MS?

      • I don’t know if a vaccine targeting EBV would be successful in stopping it from establishing itself within B cells. EBV, HSV, varicella (chicken pox), and HIV all establish permanent, lifelong infections in people, and T cells are the only way to keep them from flaring out of control. Which is why you get shingles when you get old as your T cell response dwindles, and why HIV is so hard to control and so hard to make a vaccine for (since it lives inside those same T cells that would control it). The majority of people are EBV+, and likely we are exposed early in childhood within day care centers. Vaccines for EBV would probably work to help reduce the more symptomatic phase of EBV infection (the lytic cycle which would be swollen lymph nodes, fatigue, fever from cytokines and infected cell lysis). Whether people with MS have exhausted lytic specific T cells and would benefit from a fresh infusion of anti EBV cells is a clear area of interest.

        I think the EBV related hypothesis underlying MS is very attractive, because it is difficult to explain why these strong immunosuppressive drug therapies can’t stop progression. There are many other flags, such as the links between people on medication for HIV and the reduced rate of MS, and the clear EBV positivity of people with MS. There hasn’t been a follow up that I can find for the case report of the person with MS and HIV who was treated with zidovudine/lamivudine and hadn’t had a relapse in the 3 years of the study time. Those drugs may target EBV’s lytic cycle, rather than latent cycle.

        I would really hope that another clinical trial could be set up to test a more potent anti-EBV antiviral different from raltegravir that already failed, because the cost of those anti-virals should be inexpensive compared to the yearly cost of current MS treatments (even crab drugs).

  • Chris,

    Thanks for the interesting post on T cell immunity in SARS CoV-2 and also in MS therapeutics. I have a couple of questions. Regarding cross immunity of T cells reactive SARS CoV-2 spike protein in the general population. It seems a percentage of the population has some level of cellular immunity to the spike protein even though they were never exposed (purportedly) to COVID-19. These people are asymptomatic due to cross reactive immunity to other coronaviruses. Do you have any thoughts on this phenomenon and do you think that there may be some benefit to exposure to common cold coronaviruses, similar to cowpox protection to smallpox in milkmaids back in the day?

    Secondly, what is your opinion on the use of meganucleases or CRISPR cas9 in ridding the genome of latent herpes viruses? There seems to be one promise in treating latent HSV that lies dormant in ganglia in order to cure. Might we be able to apply this technology to CMV, VZV and B-cell latent EBV?

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