Vaccine Responsiveness After CAR-T Cell Therapy

Study Overview
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Brief Summary
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This phase I trial will use the inactivated rabies virus vaccine to assess immune function in patients who previously underwent B cell targeted chimeric antigen receptor-modified T cell immunotherapy (CARTx). A cohort of healthy volunteers will also be enrolled as a comparator group. CARTx is a new treatment for patients with B-cell malignancies (cancer of the B-cells), and the long-term effects of CARTx on immune function are not yet well understood. Learning more about vaccine responsiveness in patients who previously underwent CARTx may help doctors better understand immune function. The findings will guide evidence-based strategies for infection prevention to improve outcomes in this rapidly growing population of high-risk individuals.

Detailed Description
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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.

Official Title
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Rabies Vaccination to Assess Vaccine Responsiveness After B Cell Targeted CAR-T Cell Therapies

Conditions
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B-Cell Neoplasm

Intervention / Treatment
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* Biological: Wistar Rabies Virus Strain PM-1503-3M Vaccine
* Procedure: Biospecimen Collection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: CARTx RECIPIENTS: Patients must be capable of understanding and providing a written informed consent CARTx RECIPIENTS: Patients must be 18 years of age or older, of any gender, race or ethnicity CARTx RECIPIENTS: Patients must have had relapse-free survival for >= 6 months after receiving CARTx for B-cell malignancies CARTx RECIPIENTS: Platelet count > 30,000 / mm^3 HEALTHY CONTROLS: Patients must be capable of understanding and providing a written informed consent HEALTHY CONTROLS: Patients must be 18 years of age or older, of any gender, race or ethnicity Exclusion Criteria: CARTx RECIPIENTS: Patients who have received a hematopoietic cell transplant after CARTx CARTx RECIPIENTS: Previously received 1 or more rabies vaccines prior to the first vaccine visit CARTx RECIPIENTS: Patients who have received lymphodepleting therapies after CARTx and within the past 6 months CARTx RECIPIENTS: Patients with signs or symptoms of active infection CARTx RECIPIENTS: Patients who are pregnant or breastfeeding CARTx RECIPIENTS: Patients with previous known allergies to any component of the vaccine CARTx RECIPIENTS: Patients who have previously experienced a reaction to any vaccine that required medical attention CARTx RECIPIENTS: Study participants who report a severe adverse event following the first rabies vaccine will not be eligible for a second dose CARTx RECIPIENTS: Receiving corticosteroids > 0.5 mg/kg/day prednisone equivalence in the 7 days prior to first or second vaccination HEALTHY CONTROLS: Previously received 1 or more rabies vaccines HEALTHY CONTROLS: Chronic illness HEALTHY CONTROLS: Signs or symptoms of active infection HEALTHY CONTROLS: Pregnant or breastfeeding HEALTHY CONTROLS: Patients with previous known allergies to any component of the vaccine HEALTHY CONTROLS: Previous reaction to a vaccine that required medical attention

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental (anti-rabies vaccine, collection of blood)<br>BOLUS COHORT: Patients receive the inactivated rabies vaccine 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. 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. | Biological: Wistar Rabies Virus Strain PM-1503-3M Vaccine<br>* Given IM<br>* Other names: Imovax Rabies;Procedure: Biospecimen Collection<br>* Undergo collection of blood samples<br>* Other names: Biospecimen Collected;|
| Active Comparator: Control (anti-rabies vaccine, collection of blood)<br>Patients receive anti-rabies vaccine IM on day 1 and 6-10 weeks later. Patients also undergo collection of blood samples at baseline, and at approximately 1, 2, and 4 weeks after each vaccination. There will be an additional blood draw 6 months (+/- 14 days) after the first immunization. | Biological: Wistar Rabies Virus Strain PM-1503-3M Vaccine<br>* Given IM<br>* Other names: Imovax Rabies;Procedure: Biospecimen Collection<br>* Undergo collection of blood samples<br>* Other names: Biospecimen Collected;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants with positive vaccine response | This will be defined as a rabies virus neutralizing antibody (RVNA) titer ≥0.5 IU/ml at week 4 post-secondary immunization. This RVNA titer is considered to be evidence of an adequate immune response by the World Health Organization. Will estimate with 95% confidence intervals. | 4 weeks after the secondary vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants with sustained vaccine response | This will be defined as a rabies virus neutralizing antibody (RVNA) titer ≥0.5 IU/ml at 6 months following the primary vaccination in participants who also receive secondary vaccination per-protocol | 6 months after the primary vaccination | 
| Longitudinal rabies virus neutralizing antibody (RVNA) titers | Will compare quantitative levels of RVNA (log10 IU/mL) between CAR-T cell therapy and healthy participants at weekly intervals after each vaccination and at 6 months after primary vaccination. | From baseline (prior to primary vaccination) through 6 months after primary vaccination based on measurements at weeks 0, 1, 2, 4, 6, 7, 8, 10, and 24. | 
| Longitudinal rabies virus binding IgM antibody titers | Will compare quantitative levels of anti-rabies virus IgM between CAR-T cell therapy and healthy participants at weekly intervals after each vaccination and at 6 months after primary vaccination. | From baseline (prior to primary vaccination) through 6 months after primary vaccination based on measurements at weeks 0, 1, 2, 4, 6, 7, 8, 10, and 24. | 
| Longitudinal rabies virus binding IgG antibody titers | Will compare quantitative levels of anti-rabies virus IgG between CAR-T cell therapy and healthy participants at weekly intervals after each vaccination and at 6 months after primary vaccination. | From baseline (prior to primary vaccination) through 6 months after primary vaccination based on measurements at weeks 0, 1, 2, 4, 6, 7, 8, 10, and 24. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CAR T cells, infection, vaccine, immunity