Clinical trial NCT06333275: Restoration of Immunity to Vaccine Preventable Diseases After CART-T Cell Therapy
Official title: Restoration of Immunity to Vaccine Preventable Diseases After CART-T Cell Therapy
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Vaccine Immunity in CAR-T Cell Therapy Recipients
Keywords: CAR T-cell therapy
Vaccination
Lead sponsor: Insel Gruppe AG, University Hospital Bern
Sponsor class: OTHER
First posted: 2024-03-27
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Adult (≥ 18 years old) patients with B-cell malignancies (B-cell acute lymphoblastic leukemia, B-cell lymphoma, multiple myeloma) planned for CAR-T cell therapy at the oncology department of the University Hospital Bern, Switzerland will be prospectively included in the study.

Brief summary: The goal of this observational study is to learn about vaccine immunity in patients with B-cell malignancies treated by chimeric antigen receptor T-cell therapies (CAR-T). The main questions it aims to answer are:

* Do CAR-T cell therapy recipients lose vaccine protection against common vaccine-preventable pathogens
* Are current re-vaccination recommendations sufficient in restoring vaccine-protection
* Is this restored vaccine-protection after CAR-T cell therapy lost faster than usual
* Do clinical or immunological factors predict vaccine response after CAR-T cell therapy

Detailed description: B-cell malignancies are a diverse group of cancers that arise from abnormal growth and proliferation of B-cells, a type of cells that plays a crucial role in the immune system. The function of B-cells comprises the production of antibodies (immunoglobulins). Antibodies bind to specific molecules (antigens) on the surface of pathogens (e.g. viruses, bacteria) marking them for destruction by other components of the immune system. B-cell malignancies can arise from various stages of B-cell development and can manifest as a range of clinical presentations, from lymphomas with diverse clinical courses to aggressive leukemias. Treatment options for B-cell malignancies vary depending on the specific type of cancer and the stage of disease. Recently a broad array of newer immunotherapies became available\[Feins 2019\]. Specifically, the introduction of anti-CD19 and anti- BCMA (B cell maturation antigen) targeted chimeric antigen receptor T- cell therapy (CAR-T) represents a major treatment breakthrough in treatment of many B-cell malignancies\[Sterner 2021, Haslauer 2021\].

CAR-T therapy for B-cell malignancies involves extracting lymphocytes from a patient's blood and modifying them to produce chimeric antigen receptors (CARs) that can recognize and bind to proteins CD19 or BCMA expressed on cancer cells. The modified cells are then infused into the patient's bloodstream, where they seek out and bind to cancer cells expressing the target proteins. Once attached, the CAR-T cells are activated and initiate the destruction of the bound cancer cells. While CAR-T cell therapy has shown remarkable success in clinical trials\[Sterner 2021, Haslauer 2021\], it is a new and complex treatment with potential side effects such as cytokine release syndrome, neurotoxicity, and a significant impact on the host immune system\[Kampouri 2022\]. The tumor antigens targeted by CAR-T cells are also expressed on healthy B-cells (CD-19) and plasma-cells (BCMA). Therefore, CAR-T therapy leads to a decline in healthy B-cell populations with a subsequent decrease in antibody production (hypogammaglobulinemia)\[Haslauer 2021\]. The negative effects of CAR-T cell therapies on antibody concentrations leave individuals at risk of infection for a prolonged period\[Wang 2020, Stewart 2021\]. Currently, there is limited knowledge about the extent of loss of immunity against vaccine preventable diseases after CAR-T cell therapy\[Kampouri 2022, Walti 2021\]. High-quality evidence on how to prevent infections in CAR-T recipients and particularly on the necessity of re-vaccination against common vaccine-preventable pathogens, is lacking. Expert opinion statements recommend re-vaccinating these patients 6-12 months after CAR-T therapy against the most common pathogens\[Hill 2020, Wudhikarn 2022\]. Based on available recommendations and the vaccine-guidelines provided by the Swiss Federal Office of Public Health (FOPH) revaccination is started 6 months after CAR-T Therapy for inactivated vaccines and 12 months after CAR-T Therapy for life-attenuated vaccines.

With the present cohort study, the investigators aim to explore to which extent patients lose their humoral immunity to vaccine preventable pathogens after CAR-T cell therapies. Additionally, the investigators assess vaccine responses to routinely administered vaccinations in this population to examine whether re-vaccination after 6 months, as suggested in expert-opinion based recommendations\[Hill 2020, Los-Arcos 2021\] , is a reasonable approach. The vaccinations that are administered during the study period are usual care interventions according to published expert-opinion based guidelines\[Hill 2020, Los-Arcos 2021, Plotkin 2010, FOPH\]. These vaccines are presently administered to all CAR-T recipients at the University Hospital Bern and will be also administered to all CAR-T patients during the study period irrespective of study participation.

The results of this cohort study will reveal if present expert-opinion based vaccination recommendations for CAR-T patients are reasonable or if there will be need for adapting the recommendations (e.g. if it turns out that CAR-T patients do not lose protective immunity to vaccine preventable pathogens or if the study reveals that immunization according to present vaccine schedules do not elicit protective antibody levels). Furthermore, this project could increase fundamental understanding of immunological responses to common vaccines in the immunosuppressed population.

The present project falls into the risk category A according to art. 7 (HRO): It is a cohort study (no study intervention) with blood sampling (low risk sampling according to HRO art. 7.3.) Sampling includes minimal risk (e.g. hematoma after blood draw, uncomfortable feeling during procedure) for patients. Within this project, the investigators will exclusively use methods that are readily available in clinical practice (flow-cytometric analysis of lymphocyte populations, serology). Therefore, the gained knowledge will be immediately applicable in clinical practice and the results of this sub-project will help improving present vaccine strategies for CAR-T patients. Vaccination schedules are according to official recommendations by the Swiss Federal Office of Public Health and according to expert-opinion based guidelines and do not differ from patients not included in the study.

Eligibility criteria: Inclusion Criteria:

* Patient ≥ 18 years old
* Suffering from a B-cell malignancy (B-cell acute lymphoblastic leukemia (ALL), B-cell non-hodgkin lymphoma (NHL), Follicular lymphoma (FL), Mantle Cell Lymphoma (MCL), Multiple myeloma (MM))
* Planned for a CAR-T cell therapy
* Provided written informed consent

Exclusion Criteria:

* Previous or already started CAR-T cell therapy
* \< 18 years old
* Lack of consent

Primary outcomes:
measure: CAR-T cell therapy associated change in antibody levels against 5 vaccine preventable pathogens
timeFrame: 6 months after CAR-T cell therapy
Secondary outcomes:
measure: Rate of seroprotection against tetanus 6 months after CAR-T cell therapy
timeFrame: 6 months after CAR-T cell therapy
measure: Rate of seroprotection against haemophilus influenza type B 6 months after CAR-T cell therapy
timeFrame: 6 months after CAR-T cell therapy
measure: Rate of seroprotection against hepatitis B virus 6 months after CAR-T cell therapy
timeFrame: 6 months after CAR-T cell therapy
measure: Rate of seroprotection against poliovirus 6 months after CAR-T cell therapy
timeFrame: 6 months after CAR-T cell therapy
measure: Rate of seroprotection against measles virus 12 months after CAR-T cell therapy
timeFrame: 12 months after CAR-T cell therapy
measure: Rate of seroprotection against tetanus after re-vaccination following CAR-T cell therapy
timeFrame: 3-8 weeks after re-vaccination following CAR-T cell therapy
measure: Rate of seroprotection against haemophilus influenza type B after re-vaccination following CAR-T cell therapy
timeFrame: 3-8 weeks after re-vaccination following CAR-T cell therapy
measure: Rate of seroprotection against hepatitis B virus after re-vaccination following CAR-T cell therapy
timeFrame: 3-8 weeks after re-vaccination following CAR-T cell therapy
measure: Rate of seroprotection against poliovirus after re-vaccination following CAR-T cell therapy
timeFrame: 3-8 weeks after re-vaccination following CAR-T cell therapy
measure: Rate of seroprotection against measles after re-vaccination following CAR-T cell therapy
timeFrame: 3-8 weeks after re-vaccination following CAR-T cell therapy
measure: Clinical predictors of vaccine elicited immune response
timeFrame: Immediately before vaccination (6 months after CAR-T) and 4 weeks after vaccination (7 months after CAR-T)
measure: Immunological predictors of vaccine elicited immune response
timeFrame: Immediately before vaccination and 4 weeks after vaccination
measure: Persistence of vaccine elicited seroprotection
timeFrame: 13 months post CAR-T (7 months after vaccination with inactivated vaccines)
Other outcomes:
Locations:
city: Bern
country: Switzerland
facility: University Hospital Bern
Study officials:
affiliation: University Hospital Bern, Switzerland
name: Christine Thurnheer Zürcher, PD, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital Bern, Switzerland
name: Cédric Hirzel, PD, MD
role: PRINCIPAL_INVESTIGATOR
References:
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