Vaccine Responsiveness after CAR-T Cell Therapy

Chimeric antigen receptor-modified T cell immunotherapy (CARTx) is a novel treatment for patients with B-cell malignancies. The United States Food and Drug Administration (FDA) recently approved two CARTx products for treatment of lymphomas and acute lymphoblastic leukemia in children and adults. However, the long-term immunologic effects of CARTx are poorly understood. CARTx recipients are at high risk for infection due to prior cytotoxic treatments, development of cytokine release syndrome, and depletion of normal B cells from “on-target, off-tumor” toxicity of CARTx with subsequent hypogammaglobulinemia (low levels of antibodies). Infection prevention will be critical for the long-term safety and scalability of CARTx, but there are limited data to guide such strategies. Current guidelines recommend monthly intravenous immunoglobulin (IVIG) supplementation for patients with severe hypogammaglobulinemia after CARTx, which affects ~25-50% of patients. The utility of this approach is unknown, and IVIG has substantial costs and side effects. Vaccination after CARTx cell therapy may provide a more durable and cost-effective approach to infection prevention and may be particularly important in this patient population given their immunologic deficits. Clinical parameters to guide the timing of vaccinations after CARTx are unknown.

Rabies virus vaccination has been used to assess humoral immune responses (i.e. antibodies) to a novel antigen in patients with compromised immune systems to assess how well the immune system can response to a new exposure. The inactivated rabies vaccine is approved for use in humans by the FDA and is considered to be safe in patients with compromised immune systems. The rabies vaccine is endorsed by the American Academy of Allergy, Asthma & Immunology as an approach to evaluating antibody responses to a novel antigen in individuals with compromised immune systems.

We will conduct an open-label study including 31 participants who previously received CARTx for B cell malignancies (at least 6 months ago with ongoing remission of their underlying disease) and 10 healthy controls. Participants will receive two vaccinations with the rabies vaccine approximately six weeks apart. Blood will be collected prior to and after each vaccination for a total of nine blood draws over a period of six months. We will test blood samples for antibodies to rabies, in addition to other markers of the immune system. Primary and secondary rabies vaccinations will allow for an assessment of multiple aspects of antibody-based immunity (humoral immunity) including production of different antibody types (IgG and IgM), switching between antibody types, and immune memory.

PRIMARY OBJECTIVE:

I. To describe the proportion of CARTx recipients with positive responses after primary and secondary rabies vaccinations.

SECONDARY OBJECTIVE:

I. To describe the proportion of CARTx recipients with a sustained positive vaccine response at 6 months following primary and secondary rabies vaccinations.

II. To compare neutralizing antibody titers, as well as rabies virus IgM and IgG binding antibody titers, between CARTx recipients and healthy controls at weekly timepoints for 4 weeks after each vaccine.

III. To compare the proportion of CARTx recipients with a positive response at 4 weeks following a fractionated prime followed by a bolus boost to a cohort of CARTx recipients vaccinated with standard bolus administration for both doses.

IV. To identify clinical and immunologic correlates of a positive response to inactivated RABV vaccination in CARTx recipients.

STUDY DESIGN:

This study will be a prospective, open-label clinical trial of primary and secondary vaccination with the inactivated rabies vaccine in patients treated with CARTx for B cell malignancies and healthy individuals. The target enrollment for this trial is 43 CARTx recipients and 10 healthy controls. The study is open to anyone regardless of gender or ethnicity.

OUTLINE:

BOLUS COHORT: Patients receive the inactivated rabies vaccine intramuscularly (IM) on day 1 and 6-10 weeks later. Patients also undergo a blood collection prior to each vaccine, and at approximately 1, 2, and 4 weeks after each vaccination. A final blood collection occurs 6 months after the first immunization. This will include up to 31 participants.

FRACTIONAL DOSE COHORT: Patients receive the inactivated rabies vaccine fractionated primary dose IM on days 1, 3, 7, 10, 14, and 17 and the second dose 6-10 weeks later. Patients also undergo a blood collection prior to each vaccine, and at approximately 1, 2, and 4 weeks after each vaccination. A final blood collection occurs 6 months after the first immunization. This will include up to 12 participants.