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.
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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
15
Given IV
Undergo autoHSCT
Given IM
Given standard conditioning regimen
City of Hope Medical Center
Duarte, California, United States
RECRUITINGIncidence 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
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
Yield of at least 10×10\^6 cytomegalovirus (CMV)-specific CD19-chimeric antigen receptor (CAR) T cells per product meeting product release requirements
Time frame: Up to 56 days
Short- and long-term CMV-specific CD19-CAR T cell expansion and persistence
Will be assessed longitudinally. Persistence is defined as detection of \>= 0.1% of CMV-specific CD19-CAR T cells in CD3+ cells in peripheral blood, 28 days after vaccine administration, by flow cytometry and Woodchuck Hepatitis Virus Posttranscriptional Regulatory Element (WPRE) quantitative polymerase chain reaction (Q-PCR). Expansion is defined as an increase of 2-fold in CMV-specific CD19-CAR T cells after Triplex administration compared with pre-vaccination cell number. Response to Triplex will be assessed based on numbers of EGFR+, pp65-specific IFNgamma+ and CD137+T cells.
Time frame: Up to 15 years
Clinically significant CMV reactivation
Clinically significant defined as \> 1250 IU/ml or 500 GC/mL) CMV reactivation requiring management treatment after CAR T cell infusion as assessed by PCR.
Time frame: Up to 15 years
Progression-free survival (PFS)
Participants are considered a failure for this endpoint if they die (regardless of cause) or experience disease relapse.
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)
Participants are considered a failure for this endpoint if they die, regardless of cause. Will be estimated using the product-limit method of Kaplan and Meier.
Time frame: From start of protocol therapy to death, or last follow-up, whichever comes first, assessed up to 15 years
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