Pilot/Feasibility Study of CMV-Specific CD19-CAR T Cells Plus CMV-MVA Triplex Following Autologous Hematopoietic Stem Cell Transplantation for Patients With Intermediate or High Grade B-Lineage Non-Hodgkin Lymphoma (B-NHL)
Summary
This phase I trial studies the safety and side effects of cytomegalovirus (CMV) specific CD19-chimeric antigen receptor (CAR) T-cells along with the CMV-modified vaccinia Ankara (MVA) triplex vaccine following a stem cell transplant in treating patients with high grade B-cell non-Hodgkin lymphoma. CAR T-cells are a type of treatment in which a patient's T-cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T-cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein on the patient's cancer cells is added in the laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the CAR T-cells are grown in the laboratory and given to the patient by infusion. Vaccines such as CMV-MVA triplex are made from gene-modified viruses and may help the body build an effective immune response to kill cancer cells. Giving CMV-specific CD19-CAR T-cells plus the CMV-MVA triplex vaccine following a stem cell transplant may help prevent the cancer from coming back.
Detailed description
PRIMARY OBJECTIVE: I. Assess the safety and describe the toxicity profile of anti-CD19-CAR CMV-specific T-lymphocytes (CMV-specific CD19-CAR T cells) alone and when given in combination with multi-peptide CMV-modified vaccinia Ankara vaccine (CMV-modified vaccinia Ankara \[MVA\] triplex vaccine) following autologous hematopoietic cell transplantation (autoHSCT) to treat participants with intermediate or high grade B-lineage non-Hodgkin lymphoma (NHL) who are in first relapse after achieving complete remission (CR) or did not achieve CR after a first line therapy. SECONDARY OBJECTIVES: I. Determine the feasibility of autologous CMV-specific CD19-CAR T cell manufacturing, as assessed by the ability to meet the required cell dose and product release requirements in 5 out of 6 enrolled participants. II. Determine short- and longer-term CMV-specific CD19-CAR T cell in vivo expansion and persistence. III. Assess whether the CMV-specific CD19-CAR T cells respond to CMV-MVA triplex vaccine. IV. Estimate the rate of CMV reactivation after CAR T cell infusion. V. Estimate the rate of progression-free survival (PFS) and median overall survival (OS) at 12 months post-autoHSCT. EXPLORATORY OBJECTIVES: I. Assess whether the CMV-specific CD19-CAR T cells respond to CMV-MVA triplex vaccine when administered to participants that received CAR T cells only in the safety lead-in portion in the expansion phase of the study (i.e., once safety of the CMV-MVA triplex vaccine is established in the feasibility portion of the study). Ia. Participants who receive CMV-specific CD19-CAR T cells in the safety lead-in portion of the study may be eligible to receive the CMV-MVA Triplex vaccine in the expansion portion of the study per principal investigator (PI) discretion and if all other criteria to proceed with vaccine administration are met. OUTLINE: CONDITIONING REGIMEN: Patients receive standard conditioning regimen (typically carmustine, etoposide, cytarabine, melphalan) beginning approximately on day -9 in the absence of disease progression or unacceptable toxicity. TRANSPLANTATION: Patients undergo autoHSCT on day -2. CAR T-CELLS AND VACCINATION: Patients receive CMV-specific CD19-CAR T cells intravenously (IV) on day 0 and CMV-MVA triplex vaccine intramuscularly (IM) on days 28 and 56 in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 18-24 hours, weeks 1-3, at 1 month, at day 84, months 4-11, and at 1 year. Patients with disease progression or starting a prohibited therapy are also followed up on months 2-4, 6, and 12 after CAR T cell infusion, and then yearly for up to 15 years.
Arms & interventions
- BiologicalAnti-CD19-CAR CMV-specific T-lymphocytes
Given IV
- ProcedureAutologous Hematopoietic Stem Cell Transplantation
Undergo autoHSCT
- BiologicalMulti-peptide CMV-Modified Vaccinia Ankara Vaccine
Given IM
- ProcedureMyeloablative Conditioning
Given standard conditioning regimen
Outcome measures
Primary
Incidence of adverse events
Will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0 from data obtained at each clinical assessment. Will be summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study treatment and reversibility or outcome.
Time frame: Up to 15 years
Secondary
Achievement of proposed 10×10^6 cytomegalovirus (CMV)-specific CD19-chimeric antigen receptor (CAR) T cells per product and meeting product release requirements for enrolled participants
Time frame: Up to 56 days
Short- and long-term CMV-specific CD19-CAR T cell expansion and persistence
Time frame: Up to 15 years
Clinically significant CMV reactivation
Time frame: Up to 15 years
Progression-free survival (PFS)
Time frame: From the start of treatment to the date of death, disease relapse, or last follow-up whichever occurs first, assessed up to 15 years
Overall survival (OS)
Time frame: From start of protocol therapy to death, or last follow-up, whichever comes first, assessed up to 15 years
Eligibility criteria
Study locations (1)
City of Hope Medical Center
Duarte, California, 91010