Please select the eligibility criteria that correspond to the clinical trial below.
Title: An Assessment of the Safety and Feasibility of Administering T-Cells Expressing an Anti-CD19 Chimeric Antigen Receptor to Patients With B-Cell Lymphoma
Brief Summary: Background:

The National Cancer Institute (NCI) Surgery Branch has developed an experimental therapy for treating patients with B cell lymphomas or leukemias that involves taking white blood cells from the patient, growing them in the laboratory in large numbers, genetically modifying these specific cells with a type of virus (retrovirus) to attack only the tumor cells, and then giving the cells back to the patient. This type of therapy is called gene transfer. In this protocol, we are modifying the patient s white blood cells with a retrovirus that has the gene for anti-cluster of differentiation 19 (CD19) incorporated in the retrovirus.

Objective:

The purpose of this study is to determine a safe number of these cells to infuse and to see if these particular tumor-fighting cells (anti-CD19 cells) cause tumors to shrink.

Eligibility:

- Adults age 18-70 with B cell lymphomas or leukemias expressing the CD19 molecule.

Design:

Work up stage: Patients will be seen as an outpatient at the National Institutes of Health (NIH) clinical Center and undergo a history and physical examination, scans, x-rays, lab tests, and other tests as needed

Leukapheresis: If the patients meet all of the requirements for the study they will undergo leukapheresis to obtain white blood cells to make the anti-CD19 cells. Leukapheresis is a common procedure, which removes only the white blood cells from the patient.

Treatment: Once their cells have grown, the patients will be admitted to the hospital for the conditioning chemotherapy and the anti-CD19 cells. They will stay in the hospital for about 4 weeks for the treatment.

Follow up: Patients will return to the clinic for a physical exam, review of side effects, lab tests, and scans about every 1-3 months for the first year, and then every 6 months to 1 year as long as their tumors are shrinking. Follow up visits will take up to 2 days.


Options:
A: Inclusion Criteria:

1. Patients must have a diagnosis of relapsed or refractory B-cell NHL:

   * DLBCL, Mantle Cell, Follicular Lymphoma, Lymphoplasmacytic lymphoma, Small Lymphocytic Lymphoma, Primary Mediastinal B-Cell Lymphoma, Burkitt Lymphoma, transformed lymphoma.

     * Subjects with small lymphocytic lymphoma (SLL) must have progressed after at least 2 prior therapies and prior treatment with or intolerance of both ibrutinib and venetoclax.
     * Subjects with DLBCL, primary mediastinal B- Cell lymphoma, Burkitt lymphoma and transformed lymphoma must have relapsed or failed to respond to \>= 2 prior lines of multiagent chemoimmunotherapy with prior exposure to both an anti-CD20 antibody agent and an anthracycline.
     * Subjects with indolent lymphomas ((nodal or extranodal marginal zone lymphoma, follicular lymphoma and lymphoplasmacytic lymphoma) must have relapsed after or been refractory to \>=2 prior lines of multi-agent chemoimmunotherapy including prior exposure to rituximab and at least 2 other chemotherapy agents.
     * For subjects with Mantle cell lymphoma, previous lines of therapy may include multiagent chemotherapy including alkylating agent or anthracycline and anti CD20 antibody therapy and Bruton's tyrosine kinase (BTK) inhibitor therapy.
   * Positron Emission Tomography (PET) -positive disease according to "Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification"
   * At least one of the following:

     * Primary refractory or early relapse (first remission \< 12 months) and not eligible for stem cell transplant
     * Relapsed or refractory disease after two or more lines of systemic therapy
   * No significant circulating disease, defined as an elevated total lymphocyte count above the ULN due to the presence of malignant cells.
2. CD19 positive by either immunohistochemistry or flow cytometry analysis on any biopsy. If prior anti-CD19 therapy has been administered, CD19 positivity has to be re-established on the most recent biopsy.
3. Age \>=18 years at the time of consent
4. Absolute lymphocyte count \> 100/ (microliter)
5. Eastern Cooperative Oncology Group (ECOG) performance status \< 2
6. Adequate organ function, defined as:

   * Adequate bone marrow function for apheresis and lymphodepleting chemotherapy

     * Hemoglobin (Hgb) \>8 grams per deciliter (gm/dl) (transfusions allowed)
     * Platelets \>50,000/microliter (uL) (transfusions allowed)
     * Absolute Neutrophil Count (ANC) \> 500/uL
   * Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) \< 3 x institutional upper limit of normal (ULN) and Total bilirubin \< 1.5 mg/dl x institutional ULN, except with Gilbert's syndrome
   * Serum Creatinine \< 2 x the institutional ULN
   * Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) \> 40% as assessed by echocardiogram or multiple uptake gated acquisition (MUGA) within 3 months of screening. Repeat testing may occur at Investigator's discretion.
7. Adequate vascular access for leukapheresis procedure (either peripheral line or surgically placed line).
8. Women of childbearing potential (defined as all women physiologically capable of becoming pregnant) must have a negative serum or urine pregnancy test AND agree to use highly effective methods of contraception for 1 year after the last dose of anti-CD19 CAR-T cells
9. Males who have partners of childbearing potential must agree to use an effective barrier contraceptive method
10. Ability to understand a written informed consent document, and the willingness to sign it.

Exclusion Criteria:

1. Autologous transplant within 6 weeks of planned CAR-T cell infusion
2. Recipient of prior CAR-T cell therapy targeting CD19 outside of this protocol
3. Active other malignancy, other than non-melanoma skin cancer, carcinoma in situ (e.g., cervix, bladder, or breast).
4. HIV seropositivity
5. Serologic status reflecting active hepatitis B or C infection. Patients that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment. (PCR positive patients will be excluded.)
6. Subjects with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, pulmonary abnormalities or psychiatric illness/social situations that would limit compliance with study requirements.
7. Pregnant or breastfeeding women are excluded from this study because CAR-T cell therapy may be associated with the potential for teratogenic or abortifacient effects. Because there is an unknown, but potential risk for adverse events in nursing infants secondary to treatment of the mother with CAR-T cells, breastfeeding should be discontinued. These potential risks may also apply to other agents used in this study. NOTE: Women of childbearing potential must have a negative serum or urine pregnancy test.
8. Patients with history of clinically relevant central nervous system (CNS) pathology such as epilepsy, seizure disorders, paresis, aphasia, uncontrolled cerebrovascular disease, severe brain injuries, dementia and Parkinson's disease.
9. History of autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus) with requirement of immunosuppressive medication within 6 months.
10. Body weight \<40 kilograms(kg)

Eligibility for Infusion of Investigational Product:

Subjects will undergo an evaluation of eligibility on day 1 prior to infusion of anti-CD19 CAR-T cell product. This eligibility criterion will include the inclusion and exclusion criteria required for enrollment with the following exceptions and additions:

1. No significant laboratory abnormalities. Laboratory result abnormalities that are considered not clinically significant by the principal investigator AND are not the result of a demonstrated active infection or an active central nervous system condition.
2. ECOG performance status \< 2
3. No evidence of uncontrolled intercurrent illness including, but not limited to ongoing or active infection, inflammatory response, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, pulmonary abnormalities or psychiatric illness/social situations.
4. No new neurologic symptoms suggestive of an active central nervous system condition, or uncontrolled CNS involvement by lymphoma.
5. No corticosteroid use within 7 days prior to infusion (with exception of agents used for prevention of emesis during lymphodepletive chemotherapy).
B: Inclusion Criteria:

* Confirmation of relapsed or refractory aggressive B-cell non-Hodgkin lymphoma of the following histology at relapse: diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS; de novo or transformed follicular lymphoma \[tFL\]), high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (double/triple hit lymphoma \[DHL/THL\]), and follicular lymphoma Grade 3B per WHO 2016 classification
* Previous treatment must include treatment with a single line of chemoimmunotherapy containing an anthracycline and a CD20-targeted agent
* Subjects must be deemed ineligible for both high-dose chemotherapy and hematopoietic stem cell transplant (based on age, performance status and/or comorbidities) while also having adequate organ function for CAR T cell treatment.
* Positron emission tomography (PET)-positive disease
* Histological confirmation of diagnosis at last relapse. Enough tumor material must be available for central confirmation of diagnosis, otherwise a new tumor biopsy is mandated.
* ECOG performance status of 0, or 1, or 2
* Adequate vascular access for leukapheresis procedure (either peripheral line or surgically-placed line)
* Subjects must agree to use appropriate contraception
* Subjects must agree to not donate blood, organs, semen, and egg cells for usage in other individuals for at least 1 year following lymphodepleting chemotherapy

Exclusion Criteria:

* Subjects with central nervous system (CNS)-only involvement by malignancy (note: subjects with secondary CNS involvement are allowed on study)
* History of another primary malignancy that has not been in remission for at least 2 years.
* Previous treatment with CD19-targeted therapy, with the exception of prior lisocabtagene maraleucel treatment in this protocol for subjects receiving retreatment
* Active hepatitis B or hepatitis C infection at the time of screening
* History of or active human immunodeficiency virus (HIV) infection at the time of screening
* Uncontrolled systemic fungal, bacterial, viral or other infection despite appropriate antibiotics or other treatment at the time of leukapheresis or lisocabtagene maraleucel administration
* History of any one of the following cardiovascular conditions within the past 6 months: Class III or IV heart failure as defined by the New York Heart Association, cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically significant cardiac disease
* History or presence of clinically relevant CNS pathology
* Pregnant or nursing women
* Subject does not meet protocol-specified washout periods for prior treatments
* Prior hematopoietic stem cell transplant
* Progressive vascular tumor invasion, thrombosis, or embolism
* Venous thrombosis or embolism not managed on stable regimen of anticoagulation
* Uncontrolled medical, psychological, familial, sociological, or geographical conditions
C: Inclusion Criteria:

* Patient´s written informed consent
* ≥ 18 years of age; male and female
* Confirmed CLL, low grade NHL or high grade NHL on standard histological or immunophenotypical criteria described in the WHO classification of lymphoid malignancies
* CD20 positivity (if not already confirmed)
* Adequate haematological, liver and kidney functions
* Platelet count ≥25,000mm³ (=25 x 10\^9/l)
* Patients with active disease (relapsed/refractory) that survived at least 60 days after allogeneic transplantation
* Eastern Cooperative Oncology Group (ECOG) performance status \<=2 (Appendix IV)
* Negative pregnancy test (no more than 2 days before enrolment) and adequate contraception during the study in women of child bearing potential (pre- menopausal, \<2 years post-menopausal or not surgically sterile)

Exclusion Criteria:

* Any anti-CD20 and / or any other anti-T cell directed antibody treatments \< 3 months before application of FBTA05
* Positivity for human anti-mouse antibodies (HAMAs)
* History of GvHD ° III or IV, or GvHD requiring steroid therapy with more than 10 mg/day
* Known or suspected hypersensitivity to recombinant, murine or rat proteins
* AST/SGOT greater than 10 x ULN (grade 3, CTCAE)
* Bilirubin greater than 5 x ULN (grade 3, CTCAE)
* Creatinine greater than 3.5 mg/dl (grade 3, CTCAE)
* Acute or uncontrolled chronic infections, viral infections at risk of reactivation (e.g.HCV, HBV, HIV)
* Unable or unwilling to comply fully with the protocol
* Any condition which in the judgement of the Investigator would place the subject at undue risk or interfere with the results of the study
D: * INCLUSION CRITERIA:

  1. Patient must have a cluster of differentiation 19 (CD19)-expressing B-cell lymphoma. Patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and diffuse large B-cell lymphoma transformed from follicular lymphoma must have measurable disease after at least two prior chemotherapy regimens one of which must have contained doxorubicin and rituximab.
  2. Confirmation of diagnosis of B-cell malignancy and positivity for CD19 confirmed by the Laboratory of Pathology of the National Cancer Institute (NCI). The choice of whether to use flow cytometry or immunohistochemistry will be determined by what is the most easily available tissue sample in each patient. Immunohistochemistry will be used for lymph node biopsies, flow cytometry will be used for peripheral blood, fine needle aspirates and bone marrow samples.
  3. Patients must have indications for treatment for their B-cell malignancy at the time of enrollment on this trial.
  4. Greater than or equal to 18 years of age and less than or equal to age 70.
  5. Willing to sign a durable power of attorney.
  6. Able to understand and sign the Informed Consent Document.
  7. Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1.
  8. Life expectancy of greater than three months.
  9. Patients of both genders must be willing to practice birth control from the time of enrollment on this study and for four months after treatment.
  10. Women of child bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus.
  11. Serology:

      * Seronegative for human immunodeficiency virus (HIV) antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune -competence and thus be less responsive to the experimental treatment and more susceptible to its toxicities.).
      * Seronegative for hepatitis B antigen and hepatitis C antibody unless antigen negative. If hepatitis C antibody test is positive. Then patients must be tested for the presence of antigen by reverse transcription-polymerase chain reaction (RT-PCR) and be hepatitis C virus ribonucleic acid (HCV RNA) negative.
  12. Hematology:

      * Absolute neutrophil count greater than or equal to 1000/mm\^3 without the support of filgrastim.
      * Platelet count greater than or equal to 50,000/mm\^3.
      * Hemoglobin greater than 8.0 g/dl.
      * Lymphocyte count less than or equal to 4,000/ mm\^3
  13. Chemistry:

      * Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less or equal to 5 times the upper limit of normal.
      * Serum creatinine less than or equal to 1.6 mg/dl
      * Total bilirubin less than or equal to 1.5 mg/dl, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl
  14. More than three weeks must have elapsed since any prior systemic therapy at the time the patient receives the preparative regimen, and patient toxicities must have recovered to a grade 1 or less (except for toxicities such as alopecia or vitiligo).
  15. Normal cardiac ejection fraction and no evidence of pericardial effusion as determined by an echocardiogram.

EXCLUSION CRITERIA:

1. Patients that require urgent therapy due to tumor mass effects such as bowel obstruction or blood vessel compression.
2. Patients that have active hemolytic anemia.
3. Patients with active brain metastases, or with a history of any central nervous system (CNS) metastases or cerebrospinal fluid malignant cells.

   Note: patients who are asymptomatic but are found to have malignant cells in the cerebrospinal fluid (CSF) on lumbar puncture prior to treatment will be considered eligible.
4. Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.
5. Active systemic infections, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease.
6. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
7. Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities).
8. Concurrent systemic steroid therapy.
9. History of severe immediate hypersensitivity reaction to any of the agents used in this study.
10. History of allogeneic stem cell transplantation
11. Patients with cardiac atrial or cardiac ventricular lymphoma involvement.

Screening Evaluation:

Within 4 weeks prior to starting the chemotherapy regimen:

1. Complete history and physical examination, including, weight and vital signs, noting in detail the exact size and location of any lesions that exist. (Note: patient history may be obtained within 8 weeks.)
2. Chest x-ray
3. Electrocardiography (EKG)
4. Baseline computed tomography (CT) of the chest, abdomen and pelvis, positron emission tomography (PET) scan, and brain magnetic resonance imaging (MRI) to evaluate the status of disease. Additional scans and x-rays may be performed if clinically indicated based on patient signs and symptoms.
5. HIV antibody titer and Hepatitis B surface antigen (HbsAG) determination, and anti HCV, (Note: May be performed within 3 months of the chemotherapy start date).
6. Anti cytomegalovirus (CMV) antibody titer, herpes simplex virus (HSV) serology, and Epstein-Barr virus (EBV) panel (Note: patients who are known to be positive for any of the above do not need to be retested; may be performed within 3 months of chemotherapy start date)
7. Patients with a left ventricular ejection fraction (LVEF) of less than or equal to 55% will not proceed to treatment (Note: may be performed within 8 weeks of treatment).
8. Cluster of differentiation 19 (CD19) staining of malignant cells by immunohistochemistry or flow cytometry (testing is permitted to be conducted at any time prior to this point).
9. All patients must have a T cells, B cells, and natural killer cells (TBNK) for Peripheral blood cluster of differentiation 3 (CD3) count and CD19#.
10. Patients with a history of leptomeningeal disease, or signs/symptoms suggestive of leptomeningeal involvement, or with symptoms of central nervous system malignancy such as new onset severe headaches, neck stiffness, or any focal neurologic findings on physical exam will have lumbar puncture for examination of cerebral spinal fluid.
11. Patients may undergo lumbar puncture (LP) for flow cytometry of the CSF in order to assess the presence of CD19 positive lymphocytes for potential correlation with neurologic toxicity. Patients who have no neurologic symptoms at the time of LP will be eligible for enrollment regardless of the results of the flow cytometry.

    Within 14 days prior to starting the chemotherapy regimen:
12. Chem 20: (Sodium (Na), Potassium (K), Chloride (Cl), Total carbon dioxide (CO2) (bicarbonate), Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium total, Magnesium total (Mg), Inorganic Phosphorus, Alkaline Phosphatase, ALT/glutamic pyruvic transaminase (GPT), AST/glutamic oxaloacetic (GOT), Total Bilirubin, Direct Bilirubin, lactate hydrogenase (LD), Total Protein, Total creatine kinase (CK), Uric Acid)
13. Thyroid panel
14. Complete blood count (CBC) with differential and platelet count
15. Prothrombin time (PT)/partial thromboplastin time (PTT)
16. Urinalysis and culture, if indicated

    Within 7 days prior to starting the chemotherapy regimen:
17. Beta-human chorionic gonadotropin (βHCG) pregnancy test (serum or urine) on all women of child-bearing potential
18. ECOG performance status of 0 or 1

Answer: D