COVID19 is spreading rapidly across the globe and has caused more than 400,000 deaths, most of which occurred in people with underlying comorbidities. Most patients presented for chimeric antigen receptor (CAR) T-cell therapy against B-cell malignancy have poor immune function. Their immune function is further suppressed by lymphodepleting regimens administered before CAR T-cell infusion and B-cell aplasia and hypogammaglobulinemia caused by CAR T cells. Thus, patients treated with CAR T-cell therapy are at a higher risk of COVID19-related morbidity and mortality. However, whether COVID19 vaccines induce immune protection in patients treated with CAR T-cell therapy remains unknown. Studies have suggested that T-cell immunity is critical to the control of infection by human coronaviruses. In addition, SARS-CoV-specific memory T cells but not memory B cells persist in patients long after recovery from infection. Thus, given the importance of antiviral T-cell immunity and depletion of B cells in patients treated with CAR T-cell therapy, it is critical to understand how B-cell malignancy and CAR T-cell therapy affect long-term T-cell immunity induced by COVID19 vaccines. In the last twelve years, we have identified multiple signaling pathways essential for antiviral T-cell immunity and gene signatures associated with effective long-term immune protection by antiviral T cells. In particular, we have recently characterized a stem-like CD8 T cell population that resists T-cell exhaustion and exhibits superior immunity against viruses and tumors. These stem-like CD8 T cells can be induced by vaccination and persist decades in human after vaccination. Thus, stem-like CD8 T cells might endure the immunosuppression caused by malignancy and cancer treatment and mediate potent immunity against SARS- CoV-2. Here, we hypothesize that stem-like CD8 T cells induced by a COVID19 subunit vaccine mediate long- term antiviral immunity after CAR T-cell therapy. Most current experimental models of CAR T-cell therapy rely on severely immunocompromised mice lacking T and B cells and are not suitable for studying the immune response induced by COVID19 vaccines. To evaluate the vaccine-induced T-cell immunity against SARS-CoV- 2 in CAR T-cell treated mice, we will employ a novel mouse model of anti-CD19 CAR T-cell therapy against B- cell ALL using wildtype C57BL6 mice with intact immune system. Our study will shed light on the development of vaccination strategy to generate effective immune protection against COVID19 for patients treated with CAR T-cell therapy.

Public Health Relevance

Although patients presented for CAR T-cell therapy are at a higher risk of COVID19-related morbidity and mortality, whether COVID19 vaccines induce immune protection in these patients remains unclear. The goal of this study is to understand the effect of CAR T-cell therapy on vaccine-induced long-term T-cell immunity against COVID19. The results from this study will help develop vaccination strategies to protect patients treated with CAR T-cell therapy from COVID19.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Center Core Grants (P30)
Project #
3P30CA046934-32S7
Application #
10199682
Study Section
Program Officer
He, Min
Project Start
1997-04-04
Project End
2021-01-31
Budget Start
2020-09-18
Budget End
2021-01-31
Support Year
32
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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