Patients’ Humoral Immunity Is Preserved, With Low Rates of Viral Infections, After Anti-CD19 CAR T-Cell Therapy

The two commercially available chimeric antigen receptor (CAR) T-cell products both target cells expressing the CD19 antigen, which is present on malignant and nonmalignant B cells, introducing the possibility that a patient’s humoral immunity may be depleted after treatment. Little is known about the long-term effects of this treatment on patients’ immunity, but a new study provides reassurance that pathogen-specific antibodies and pre-existing humoral immunity are preserved in CAR T-cell–treated adults with B-cell malignancies. This immunity is preserved even in patients who had a complete response (CR) and B cell aplasia.

The findings were published in Blood Advances by Joshua A. Hill, MD, from the Fred Hutchinson Cancer Research Center in Seattle, Washington, and co-authors.

The authors hypothesized that, because long-lived plasma cells are CD19-negative and should not be direct targets of CD19 CAR T cells, humoral immunity would be preserved after treatment. To test this hypothesis and determine the effects of CAR T-cell therapy on immunity, investigators evaluated the incidence of viral infections and changes in serum immunoglobulin (IgG) concentrations, measles-specific IgG concentrations, and the antiviral antibody repertoire in 40 patients who received CD19-directed treatment.

“[The results] point to the need to design studies that help us to understand whether prophylactic intravenous immune globulin is beneficial in [CAR T-cell therapy recipients].”

—Joshua A. Hill, MD

The participants had relapsed/refractory CD19-positive acute lymphocytic leukemia, chronic lymphocytic leukemia, or non-Hodgkin lymphoma and had received lymphodepleting chemotherapy and anti-CD19 CAR T-cell infusion. All patients experienced a CR that lasted for at least six months and did not require additional antitumor treatment.

Per study protocol, researchers assessed total serum IgG concentration before lymphodepletion and then at approximately one, six, and 12 months after CAR T-cell infusion. Patients also were monitored for viral infections that occurred more than 90 days after CAR T-cell infusion and measles IgG concentrations, as a marker of humoral immunity.

All data were collected from up to 90 days before CAR T-cell therapy and until the time of either a new anti-tumor treatment for relapse or one of the following occurred:

  • new malignancy
  • death
  • last clinical contact post–CAR T-cell therapy

During a median follow-up of 508 days (range = 251-1,067 days) following CAR T-cell infusion, one patient was excluded due to insufficient records, leaving 39 people in the final analysis.

Before CD19-directed CAR T-cell treatment, more than half of participants had B-cell depletion (<0.01% CD19-positive B cells); within 28 days of infusion, all patients had B-cell depletion.

“Despite prolonged CD19-positive B-cell depletion and CD19 CAR T-cell persistence in most participants, the incidence of serious viral infections >90 days after anti-CD19 CAR T-cell therapy in all 39 participants was low,” the authors reported. Investigators observed two serious, grade ≥3 infections in one patient (rhinovirus in the lower respiratory tract in the context of bacterial pneumonia) – neither of which required hospitalization. This translated to an incidence rate of 0.91 infections per person-year.

Next, the authors looked at the direct effectsof CD19-directed CAR T-cell infusion on patients’ IgG concentrations. Hypogammaglobulinemia was common before CAR T-cell infusion, and there was a “modest decline” of 100 mg/dL in mean serum total IgG concentrations after infusion. However, among the 30 patients evaluable for measles IgG concentrations, the pathogen-specific IgG levels did not substantially change after CAR T-cell infusion, with a mean change of 1.2% (range = –7.9% to 11.1%). Measles seroprotection was lost in only one participant, who the authors noted had also undergone allogeneic hematopoietic cell transplantation.

Participants’ antiviromes also were preserved: The mean number of detected viruses and epitopes did not differ before and after anti-CD19 CAR T-cell therapy, at 0.3 viruses and six viral epitopes.

The researchers were surprised to find that patients had evidence of generating new or recovering humoral immunity following CD19-targeted CAR T-cell therapy, Dr. Hill said. Even after successful anti-CD19 CAR T-cell treatment, most patients with virus- and epitope-specific profiles gained new antibody responses to previously unrecognized viruses (19/28; 68%). In addition, most patients gained IgG to at least two epitopes for at least two viruses.

Although the results of the present study provide reassurance about the preservation of patients’ normal immunity after CAR T-cell therapy, Dr. Hill noted that the findings are not enough to change clinical practice. “They do point to the need to design studies that help us understand whether prophylactic intravenous immune globulin is beneficial in children and adult recipients of CAR T-cell therapy,” he stated. “Additionally, since one-quarter of the patients were not seroprotected for measles, there is a clear need for understanding how to approach vaccination after CAR T-cell therapies.”

Limitations of the study included the small sample size and the exclusion of children from the study, which may limit the generalizability of the results. The authors noted that the subgroup analyses were not powered to compare rates or severity of viral infections with those in other patient populations. “The other big question is whether these findings differ when using other targeted CARs, such as anti-B cell maturation antigen–targeting CAR T-cell therapy,” Dr. Hill added.

The authors report no relevant conflicts of interest.

Reference

Hill JA, Krantz EM, Hay KA, et al. Durable preservation of antiviral antibodies after CD19 chimeric antigen receptor T cell immunotherapy. Blood Adv. 2019.

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