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

Inclusion Criteria:

• Documented informed consent of the participant and/or legally authorizedrepresentative

• 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 maybe used with a City of Hope (COH) certified interpreter/translator to proceed withscreening and leukapheresis, while the request for a translated full consent isprocessed

• 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 flowcytometry, 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 hasactive disease or before the last therapy if the patient is in CR

• Note: CD19 positivity must be documented in a pathology report; however, it isnot a requirement that the CD19 testing be performed by a COH pathologist

• Planned allogeneic HSCT (myeloablative or reduced intensity conditioning) accordingto institutional eligibility requirements with an available 8/8 (HLA A, B, C, DR)allele-matched related is allowed per discretion of the principal investigator. forallogeneic HSCT will be unmanipulated mobilized peripheral blood stem cell (PBSC) orbone 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 tohematopoeitic 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 beperformed 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 toHSC infusion unless otherwise stated)

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

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

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

• Oxygen (O2) saturation > 92% without requiring supplemental oxygen (to be performedno 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 infusionunless otherwise stated)

• If positive, hepatitis C ribonucleic acid (RNA) quantitation must be performedOR

• If seropositive for HIV, HCV or HBV, nucleic acid quantitation must beperformed. Viral load must be undetectable

• Negative for COVID-19 within 72 hours of day 0 of protocol therapy (to be performedno 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 morethan 45-days prior to HSC infusion unless otherwise stated)

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

• Participants must have negative QuantiFERON-TB Gold (QFTG) test (to be performed nomore than 45-days prior to HSC infusion unless otherwise stated)

• Participants with positive QFTG test need clearance from ID before protocoltherapy

• Women of childbearing potential (WOCBP): Negative urine or serum pregnancy test (tobe 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 serumpregnancy test will be required

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

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

• DONOR CRITERIA: The identified donor must be the original donor whose stem cellswere 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

• DONOR CRITERIA: The donor's hepatitis B surface antigen must be negative and thehepatitis C antibody must be nonreactive. In the case of a positive hepatitis Cantibody result, the HCV viral PCR will have to be performed and the results shouldbe 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 cellleukapheresis for the collection of PBMCs for cellular manufacture

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

• DONOR CRITERIA: The donor is approved and has completed the donor evaluation perinstitutional guidelines. Additionally, donor will also be screened for thefollowing 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 andparvovirus B19 are necessary to proceed with the apheresis procedure but dohave 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 topicalsteroids 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 suppressivetherapy are not allowed

• Any contraindications to standard conditioning transplant regimens per standard ofcare practices at COH

• Subjects with clinically significant arrhythmia or arrhythmias not stable on medicalmanagement within two weeks of screening

• History or prior diagnosis of other immunologic or inflammatory disease affectingthe central nervous system (CNS), including uncontrolled seizure disorder, anymeasurable masses of CNS, or any other active CNS disease. Note: Researchparticipants with a history of CNS disease that has been effectively treated tocomplete remission (< 5 white blood cells [WBC]/mm^3 and no blasts in CSF) will beeligible

• Participants should not have any uncontrolled illness including symptomaticcongestive heart failure, unstable angina pectoris, poorly controlled pulmonarydisease, or psychiatric illness/social situations that would limit compliance withstudy requirements

• History of allergic reactions attributed to compounds of similar chemical orbiologic 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 treatedwith other modalities) with curative intent, basal cell carcinoma of the skin orlocalized squamous cell carcinoma of the skin; non-muscle invasive bladder cancer;malignancy treated with curative intent with no known active disease present for ≥ 2years

• 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 thepatient's participation in the clinical study due to safety concerns with clinicalstudy procedures

• Prospective participants who, in the opinion of the investigator, may not be able tocomply with all study procedures (including compliance issues related tofeasibility/logistics)