Allogeneic CMV-Specific CD19-CAR T Cells Plus CMV-MVA Triplex Vaccine After Matched Related Donor Hematopoietic Cell Transplant for the Treatment of Patients With High-Risk Acute Lymphoblastic Leukemia

Pilot/Feasibility Study of CMV-Specific CD19-CAR T Cells Plus CMV-MVA Triplex Following Matched Related Allogeneic Hematopoietic Cell Transplantation for Patients With High-Risk Acute Lymphoblastic Leukemia

This early phase I trial tests the safety and side effects of allogeneic CMV-specific CD19-CAR T cells plus CMV-MVA vaccine and how well it works in treating patients with high-risk acute lymphoblastic leukemia after a matched related donor (allogeneic) hematopoietic stem cell transplant (alloHSCT). Chimeric antigen receptor (CAR) T-cell therapy is a type of treatment in which 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, in this study, the T cells are cytomegalovirus (CMV) specific. Then the gene for a special receptor that binds to a certain protein, CD19, on the patient's cancer cells is added to the CMV-specific T cells in the laboratory. The special receptor is called a CAR. Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. Vaccines made from three CMV tumor associated antigens, may help the body build an effective immune response to kill cancer cells. Giving allogeneic CMV-specific CD19-CAR T cells plus CMV-MVA vaccine after matched related alloHSCT may be safe, tolerable, and/or effective in treating patients with high-risk acute lymphoblastic leukemia.

PRIMARY OBJECTIVE:

I. Assess the safety and describe the toxicity profile of allogeneic anti-CD19-CAR CMV-specific T-lymphocytes (CMV-specific CD19-CAR T cells) (allo CMV-specific CD19-CAR T cells) alone and when given in combination with multi-peptide CMV-modified vaccinia ankara vaccine (CMV-MVA) triplex vaccine following allogeneic hematopoietic cell transplantation (alloHSCT) to treat participants with high-risk acute lymphoblastic leukemia (ALL).

SECONDARY OBJECTIVES:

I. Determine the feasibility of allo CMV-specific CD19-CAR T cell manufacturing, as assessed by the ability to meet the required cell dose and product release requirements.

II. Estimate the rate of CMV reactivation after CAR T cell infusion with 100 days of HSCT.

III. Estimate the incidence of secondary graft failure. IV. Estimate the incidence and severity of acute graft versus host disease (GVHD) at 100 days and chronic GVHD at 1 year after transplant.

V. Estimate the rate of 100 day non-relapse mortality. VI. Estimate disease-free and overall survival (DFS/OS) rate at 12 months post alloHSCT.

EXPLORATORY OBJECTIVES:

I. Determine short and longer-term allo CMV-specific CD19-CAR T cell expansion and persistence; II. Assess whether the allo CMV-specific CD19-CAR T cells respond to CMV-MVA triplex vaccine III. Assess whether the allo 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 phased of the study (i.e., once safety of the CMV-MVA triplex vaccine is established in the feasibility portion of the study).

OUTLINE:

DONORS: Donors undergo leukapheresis over 2-4 hours.

PART 1: Patients receive HSCT conditioning regimen followed by alloHSCT per standard of care. Starting 28-49 days after alloHSCT, patients receive allo CMV-specific CD19-CAR T cells intravenously (IV) over 10-15 minutes on day 0. Patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA), blood and optional cerebrospinal fluid (CSF) sample collection and bone marrow biopsy and aspiration throughout the study. Patient may also undergo chest x-ray and lumbar puncture as needed per principal investigator (PI) discretion and positron emission tomography (PET)/computed tomography (CT) or CT as clinically indicated throughout the study. Additionally, patients with neurological abnormalities at baseline may undergo MRI of brain throughout the study.

PART 2: This is a dose-escalation study of followed by a dose-expansion study.

Patients receive HSCT conditioning regimen followed by alloHSCT per standard of care. Starting 28-49 days after alloHSCT, patients receive allo CMV-specific CD19-CAR T cells IV over 10-15 minutes on day 0. Patients receive CMV-MVA triplex vaccine intramuscularly (IM) on day 28 in the absence of DLTs and may receive an additional CMV-MVA triplex vaccine IM on day 56 in the absence of DLTs during the second evaluation period. Patients undergo ECHO or MUGA, blood and optional CSF sample collection and bone marrow biopsy and aspiration throughout the study. Patient may also undergo chest x-ray and lumbar puncture as needed per PI discretion and PET/CT or CT as clinically indicated throughout the study. Additionally, patients with neurological abnormalities at baseline may undergo MRI of brain throughout the study.

After completion of study treatment, patients are followed up monthly for the first year, then at 18, 24, 30 and 36 months after CAR T cell infusion. Patients are then followed up yearly for up to 15 years.

Inclusion Criteria:

• Documented informed consent of the participant and/or legally authorized representative

  • Assent, when appropriate, will be obtained per institutional guidelines

• Agreement to allow the use of archival tissue from diagnostic tumor biopsies

  • If unavailable, exceptions may be granted with study PI approval

• Note: For research participants who do not speak English, a short form consent may be used with a City of Hope (COH) certified interpreter/translator to proceed with screening and leukapheresis, while the request for a translated full consent is processed

• Age: ≥ 18 years

• Karnofsky performance status (KPS) ≥ 70

• Participants with high-risk ALL defined as:

  • Any complete remission (CR) with minimal residual disease (MRD)+ (by flow cytometry, polymerase chain reaction [PCR] or clonoSEQ) at the time of HSCT; or
  • Blasts ≥ 5% at the time of transplant; or
  • Complete response (CR)2 or higher irrespective of MRD status; or
  • Requiring > 1 regimen to achieve CR1

• Pathology confirmed CD19+ ALL after the last targeted therapy if the patient has active disease or before the last therapy if the patient is in CR

  • Note: CD19 positivity must be documented in a pathology report; however, it is not a requirement that the CD19 testing be performed by a COH pathologist

• Planned allogeneic HSCT (myeloablative or reduced intensity conditioning) according to institutional eligibility requirements with an available 8/8 (HLA A, B, C, DR) allele-matched related is allowed per discretion of the principal investigator. for allogeneic HSCT will be unmanipulated mobilized peripheral blood stem cell (PBSC) or bone marrow

• Participants who received other prior forms of CAR T therapy are eligible

• No known contraindications to HSCT, leukapheresis, steroids or tocilizum,ab, smallpox vaccine and any other modified vaccinia ankara virus (MVA)-based vaccines

• Total serum bilirubin ≤ 2.0 mg/dL (to be performed no more than 45-days prior to hematopoeitic stem cell [HSC] infusion unless otherwise stated)

• Participants with Gilbert syndrome may be included if their total bilirubin is ≤ 3.0 (to be performed no more than 45-days prior to HSC infusion unless otherwise stated)

• Aspartate aminotransferase (AST) < 2.5 x upper limit of normal (ULN) (to be performed no more than 45-days prior to HSC infusion unless otherwise stated)

• Alanine aminotransferase < 2.5 x ULN (to be performed no more than 45-days prior to HSC infusion unless otherwise stated)

• Serum creatinine ≤ 2.5 x ULN or estimated creatinine clearance of ≥ 40 mL/min per the Cockcroft-Gault formula, and the participant is not on hemodialysis (to be performed no more than 45-days prior to HSC infusion unless otherwise stated)

• Cardiac function (12 lead-electrocardiogram [ECG]): Corrected QT interval (QTc) must be ≤ 480 msec (to be performed no more than 45-days prior to HSC infusion unless otherwise stated)

• Left ventricular ejection fraction ≥ 45% within 8 weeks before protocol therapy (to be performed no more than 45-days prior to HSC infusion unless otherwise stated)

• Oxygen (O2) saturation > 92% without requiring supplemental oxygen (to be performed no more than 45-days prior to HSC infusion unless otherwise stated)

• Seronegative for HIV quantitative real time polymerase chain reaction (qPCR), hepatitis C virus (HCV), active hepatitis B virus (HBV) (surface antigen negative), and syphilis (RPR) (to be performed no more than 45-days prior to HSC infusion unless otherwise stated)

  • If positive, hepatitis C ribonucleic acid (RNA) quantitation must be performed OR
  • If seropositive for HIV, HCV or HBV, nucleic acid quantitation must be performed. Viral load must be undetectable

• Negative for COVID-19 within 72 hours of day 0 of protocol therapy (to be performed no more than 45-days prior to HSC infusion unless otherwise stated)

• Negative for human herpes virus-6 (HHV6) by PCR-based assay (to be performed no more than 45-days prior to HSC infusion unless otherwise stated)

• Meets other institutional and federal requirements for infectious disease titer requirements (to be performed no more than 45-days prior to HSC infusion unless otherwise stated)

• Participants must have negative QuantiFERON-TB Gold (QFTG) test (to be performed no more than 45-days prior to HSC infusion unless otherwise stated)

  • Participants with positive QFTG test need clearance from ID before protocol therapy

• Women of childbearing potential (WOCBP): Negative urine or serum pregnancy test (to be performed no more than 45-days prior to HSC infusion unless otherwise stated)

  • If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

• Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 6 months after the last dose of protocol therapy

  • Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only)

• DONOR CRITERIA: The identified donor must be the original donor whose stem cells were used for the research participant's alloHSCT

• DONOR CRITERIA: Donor must be CMV seropositive through the following:

  • CMV seropositive AND
  • CMV positive by CMV insight T cell immunity testing through Viracor (Test code 30360)

• DONOR CRITERIA: The donor's hepatitis B surface antigen must be negative and the hepatitis C antibody must be nonreactive. In the case of a positive hepatitis C antibody result, the HCV viral PCR will have to be performed and the results should be negative

• DONOR CRITERIA: The donor must be HIV negative

• DONOR CRITERIA: KPS ≥ 70

• DONOR CRITERIA: Documented body weight

• DONOR CRITERIA: Willingness to sign 'donor consent form' and undergo T cell leukapheresis for the collection of PBMCs for cellular manufacture

• DONOR CRITERIA: COH standard operating procedures (SOP) will be used for allogeneic donor evaluation, selection, and consent.

• DONOR CRITERIA: The donor is approved and has completed the donor evaluation per institutional guidelines. Additionally, donor will also be screened for the following infectious diseases:

  • Epstein-Barr virus (EBV) by PCR,
  • Human herpes virus 6, 7, and 8 (HHV6, HHV7, HHV8)
  • Parvovirus B19 Note: ID test results for EBV by PCR, HHV6, HHV7, HHV8 and parvovirus B19 are necessary to proceed with the apheresis procedure but do have to be resulted and negative before participant CAR T infusion.

Donor screening will be in compliance with all requirements of Food and Drug Administration (FDA) regulation 21 CFR Part 1271 including donor screening for COVID-19 exposure or infection.

Exclusion Criteria:

• Concurrent use of systemic steroids. Recent or current use of inhaled or topical steroids in standard doses is not exclusionary. Physiologic replacement of steroids (prednisone ≤ 0.5 mg /day, or equivalent doses of other corticosteroids) is allowed
• Participants with active autoimmune disease requiring systemic immune suppressive therapy are not allowed
• Any contraindications to standard conditioning transplant regimens per standard of care practices at COH
• Subjects with clinically significant arrhythmia or arrhythmias not stable on medical management within two weeks of screening
• History or prior diagnosis of other immunologic or inflammatory disease affecting the central nervous system (CNS), including uncontrolled seizure disorder, any measurable masses of CNS, or any other active CNS disease. Note: Research participants with a history of CNS disease that has been effectively treated to complete remission (< 5 white blood cells [WBC]/mm^3 and no blasts in CSF) will be eligible
• Participants should not have any uncontrolled illness including symptomatic congestive heart failure, unstable angina pectoris, poorly controlled pulmonary disease, or psychiatric illness/social situations that would limit compliance with study requirements
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent
• History of stroke or intracranial hemorrhage within 3 months prior to screening
• Known bleeding disorders (e.g., von Willebrand's disease) or hemophilia
• Participants with uncontrolled seizures
• Active viral hepatitis
• History of other malignancies, except for malignancy surgically resected (or treated with other modalities) with curative intent, basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin; non-muscle invasive bladder cancer; malignancy treated with curative intent with no known active disease present for ≥ 2 years
• Clinically significant uncontrolled illness
• Active infection not responding to antibiotics
• Females only: Pregnant or breastfeeding
• Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
• Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)