SARS-CoV-2 immune responses in patients with lymphoma

Project Summary Non-Hodgkin lymphoma and chronic lymphocytic leukemia (NHL/CLL) patients have immune system deficits that arise from the cancer and are aggravated by lymphoma therapies, placing them at higher risk of morbidity and mortality after infection with viruses like influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients are strongly recommended to get vaccinated and boosted with SARS-CoV-2 mRNA vaccines, but antibody responses after vaccination in these patients are often impaired. SARS-CoV-2 vaccines also elicit T cell responses in healthy individuals that may be protective but previous studies indicate that T cells from NHL/CLL patients are also dysfunctional. Under the mentorship of Drs. Rafi Ahmed and Jonathon Cohen, I have assembled a cohort of over 600 NHL/CLL patients with over 1,300 longitudinal blood samples paired with clinical data that I have used to study the immune responses in this patient population. Using this cohort, I showed that most patients have lower antibody responses after SARS-CoV-2 vaccination than otherwise healthy individuals and that antibody responses correlate at least partly with lymphoma therapies. I have also shown that some patients produce spike-specific CD4+ and CD8+ T cells after vaccination. The longitudinal, antigen-specific CD4+ and CD8+ T cell responses after vaccination and infection have not been well characterized in NHL/CLL patients. I hypothesize that these patients have alterations in their CD4+ and CD8+ T cell responses after antigen stimulation, which are dependent on the underlying lymphoma subtype and lymphoma therapy. This proposal has 3 goals: 1) To evaluate the generation, differentiation, breadth, and persistence of SARS- CoV-2-specific CD4+ T cell responses in NHL/CLL patients after vaccination and infection using functional assays and single cell sequencing technologies; 2) To define the primary and memory SARS-CoV-2-specific CD8+ T cell responses after vaccination and infection through functional assays and single cell sequencing technologies; and 3) to support my transition from a trainee in Dr. Ahmed's laboratory to leading an independent research program. Successful completion of these studies will provide in-depth knowledge of the generation, evolution, breadth, and persistence of antigen-specific T cell responses in NHL/CLL patients after vaccination and infection. This knowledge will facilitate the design of interventions that may improve vaccine responses in these and other immunosuppressed patients, protecting them from potentially life-threatening viral infections like SARS-CoV-2 and influenza. Moreover, the insights on the generation and maintenance of adaptive immune responses against novel antigens obtained from these studies could help fuel the development of better cancer immunotherapies.