Chimeric antigen receptor-modified T (CAR-T) cell therapies are an effective treatment for some blood cancers such as B cell-lineage lymphoma and leukemia. Although often successful in the elimination of tumors, CAR-T cells—which are T cells taken from the patient and engineered to recognize and attack tumor antigens—often have widespread effects, collaterally destroying non-malignant B cell-lineage cells. This side effect, along with the cancer itself or underlying anti-tumor treatments, “can lead to long-standing B cell depletion and hypogammaglobulinemia and can put individuals at risk for infection for months and maybe years after CAR-T cell therapy, even when the underlying malignancy has been cured,” said Dr. Carla Walti, the lead author on a recent Journal for ImmunoTherapy of Cancer publication.
Vaccination is generally the most successful strategy to prevent respiratory infection, illness, and death, but the efficacy of vaccination before and after CAR-T-cell therapy is unknown, as CAR-T cell patients may have impaired immune responses that are not well primed by vaccines. Specifically, patients with B cell-lineage cancers may have impaired antibody production, as antibodies are made by a subset of B cells. To study this question, Dr. Walti from Dr. Joshua Hill’s group in the Vaccine and Infectious Disease Division and collaborators from Fred Hutch and the University of Washington performed a study of the humoral immunogenicity elicited by the inactivated influenza vaccine (IIV) in CAR-T-cell therapy patients compared to non-immunocompromised controls. The subjects were immunized either before or after CAR-T-cell therapy and their blood subsequently tested for the increased presence of vaccine-elicited antibodies compared to baseline.
In the group receiving IIV before CAR-T-cell treatment, 40% of people generated neutralizing antibody responses to at least one out of four influenza vaccine strains out to day 30 post-CAR-T treatment, with one patient retaining neutralizing titers over 100-days post treatment. Of the remaining 60%, one generated an increase in antibody titers at day 30 post-treatment. In the group receiving immunization after CAR-T-cell therapy, 31% of the group robustly responded to at least one IIV strain at 30 days post-immunization, while an additional 46% generated a moderate response. Together, these results suggest that both cohorts experienced a modest average increase in IIV-induced antibody titer, although those who were immunized pre-CAR-T-cell therapy experienced a relatively rapid decrease in antibody titers. The authors further explored possible predictors of immunogenicity to IIV, but found that factors such as age, sex, type of malignancy, or time post-CAR-T-cell therapy did not correlate with immunogenicity and importantly, low B cell counts and hypogammaglobulinemia did not preclude responses.
This study is the first to investigate pre-CAR-T-cell therapy vaccination and one of the first to test vaccine immunogenicity after CAR-T-cell therapy. Together, this work demonstrated that despite substantial tumor- and anti-tumor treatment-induced immunodeficiencies, vaccination against influenza either before or after CAR-T-cell therapy induced robust antibody responses to at least one vaccine strain in 31-40% and partial responses in 60-77% of individuals in the study. “Although more work is needed, we believe that this data supports consideration for vaccination before and after CAR-T cell therapy and irrespective of B cell depletion and hypogammaglobulinemia,” said Dr. Walti.
Going forward, the authors are “currently working on studies investigating vaccine responses to additional vaccines in a larger cohort,” and further studies are necessary to identify predictors of vaccine-induced immunity, Dr. Walti said. However, this work also “illuminated relatively impaired antibody responses to the seasonal inactivated influenza vaccine in CAR-T cell therapy recipients. This indicates suboptimal protection from infection and the need for additional infection-prevention strategies” in this vulnerable cohort, Dr. Walti explained. “The data from our study have illuminated relatively impaired antibody responses to the seasonal inactivated influenza vaccine in CAR-T cell therapy recipients. This indicates suboptimal protection from infection and the need for additional infection-prevention strategies,” Dr. Walti said.
Walti CS, Loes AN, Shuey K, Krantz EM, Boonyaratanakornkit J, Keane-Candib J, Loeffelholz T, Wolf CR, Taylor JJ, Gardner RA, Green DJ, Cowan AJ, Maloney DG, Turtle CJ, Pergam SA, Chu HY, Bloom JD, Hill JA. Humoral immunogenicity of the seasonal influenza vaccine before and after CAR-T-cell therapy: a prospective observational study. Journal for ImmunoTherapy of Cancer 2021;9:e003428. Doi:10.1136/jitc-2021-003428
This work was supported by the Swiss National Science Foundation, the National Institutes of Health National Cancer Institute, the American Society for Transplantation and Cellular Therapy, the Washington Vaccine Alliance, and Juno Therapeutics.
UW/Fred Hutch Cancer Consortium members Steven Pergam, Jim Boonyaratanakornkit, Joshua Hill, Cameron Turtle, David Maloney, Andrew Cowan, Damien Green, Rebecca Gardner, and Justin Taylor contributed to this work.