T Cells Expressing Fully-human Anti-CD19 and Anti-CD20 Chimeric Antigen Receptors for Treating B-cell Malignancies and Hodgkin Lymphoma
T Cells Expressing Fully-human Anti-CD19 and Anti-CD20 Chimeric Antigen Receptors for Treating B-cell Malignancies and Hodgkin Lymphoma
Background:

 CD19 and CD20 are often found on certain cancer cells. Researchers think that a person s T
 cells can be modified in a lab to kill cells that have CD19 and CD20 on the surface.

 Objective:

 To see if it is safe to give anti-CD19 and anti-CD20 CAR T cells to people with a B cell
 cancer or Hodgkin lymphoma.

 Eligibility:

 People ages 18 and older with a B cell cancer or Hodgkin lymphoma that has not been
 controlled with standard therapies

 Design:

 Participants will be screened under protocol 01C0129 with:

 Medical history

 Physical exam

 Blood and heart tests

 Bone marrow biopsy: A needle is inserted into the participant s hip bone to remove a small
 amount of marrow.

 Scans

 Participants will have apheresis: Blood will be removed through a vein. The blood with
 circulate through a machine that removes the T cells. The rest of the blood will be returned
 to the participant.

 Once a day for 3 days before they get the T cells, participants will receive chemotherapy
 through a vein.

 Participants will receive the T cells through a vein. They will stay in the hospital for at
 least 9 days.

 Participants may have a lumbar puncture: A needle will remove fluid from the spinal cord.

 Participants may have a tumor biopsy.

 Participants will repeat the screening tests throughout the study.

 Participants will have follow-up visits 2 weeks after infusion; monthly for 4 months; at 6,
 9, and 12 months; every 6 months for 3 years; and then annually for 5 years. Participants
 will then be contacted annually for 15 years.
Background:

 -  Improved treatments for a variety of treatment-resistant malignancies including B-cell
 lymphomas, and chronic lymphocytic leukemia (CLL) and Hodgkin lymphoma are needed.

 -  A particular need is development of new treatments for chemotherapy-refractory B-cell
 malignancies.

 -  T cells can be genetically modified to express chimeric antigen receptors (CARs) that
 specifically target malignancy-associated antigens.

 -  Autologous T cells genetically modified to express CARs targeting the B-cell antigen
 CD19 have caused complete remissions in patients with leukemia or lymphoma. These
 results have established anti-CD19 CAR T cells as an important therapy for relapsed
 lymphoma, but only about 40% of patients receiving anti-CD19 CAR T cells have durable
 complete remissions.

 -  Most B-cell malignancies express CD19 and CD20, but expression of CD19 and CD20 can be
 lost or diminished.

 -  The malignant cells of Hodgkin lymphoma, Hodgkin Reed-Sternberg cells, originate from B
 cells, which is the rationale for treating Hodgkin lymphoma with T cells targeting CD19
 and CD20.

 -  CD19 and CD20 are not expressed by normal cells except for B cells and some plasma
 cells.

 -  We have constructed a novel gene therapy construct that encodes a fully-human anti-CD19
 CAR with a CD28 domain and a fully-human anti-CD20 CAR with a 4-1BB domain.

 -  T cells expressing this CAR construct, called Hu1928-Hu20BB, can specifically recognize
 CD19 and CD20-expressing target cells in vitro and eradicate CD19 or CD20-expressing
 tumors in mice.

 -  One CAR expressed in this CAR construct, Hu19-CD828Z has been tested in humans before.
 The other CAR in the total construct, Hu20-CD8BBZ, has not been tested in humans before.

 -  Possible toxicities include cytokine-associated toxicities such as fever, hypotension,
 and neurological toxicities. Elimination of normal B cells is probable, and unknown
 toxicities are also possible.

 Objectives:

 Primary

 Determine the safety and feasibility of administering T cells expressing a novel fully- human
 anti-CD19 and anti-CD20 CAR construct to patients with advanced B-cell malignancies and
 Hodgkin lymphoma.

 Exploratory

 -  Evaluate serum cytokine levels and associations with anti-malignancy efficacy and
 toxicity

 -  Evaluate clinical predictors of anti-lymphoma responses and toxicity.

 -  Evaluate phenotype of infused CAR T cells and CAR T cells from the blood of patients.

 Eligibility:

 -  Patients must have any B-cell lymphoma, or CLL/SLL, Gray-zone lymphoma, nodular
 lymphocyte-predominance Hodgkin lymphoma, or classical Hodgkin lymphoma with any CD19 or
 CD20 expression on Reed-Sternberg cells. Lower grade lymphomas transformed to DLBCL are
 potentially eligible as is primary mediastinal B-cell lymphoma and all other subtypes of
 DLBCL. Burkitt and mantle cell lymphoma are potentially eligible.

 -  Patients must have malignancy that is measurable on a CT scan or by flow cytometry of
 bone marrow or blood.

 -  Patients must have a creatinine of 1.5 mg/dL or less and a normal cardiac ejection
 fraction.

 -  An ECOG performance status of 0-1 is required.

 -  No active infections are allowed including hepatitis B or hepatitis C.

 -  Absolute neutrophil count greater than or equal to 1000/micro Liters, platelet count
 greater than or equal to 50,000/ micro Liters, hemoglobin greater than or equal to 8g/dL

 -  Serum ALT and AST less or equal to 3 times the upper limit of the institutional normal
 unless liver involvement by malignancy is demonstrated.

 -  At least 14 days must elapse between the time of any prior systemic treatment (including
 corticosteroids) and protocol-required leukapheresis or CAR T-cell infusion. Thirty days
 must elapse from therapy with antibodies targeting CD19 or CD20 and CAR T-cell infusion.

 -  The patient s malignancy will need to be assessed for CD19 and C20 expression by flow
 cytometry or immunohistochemistry performed at the NIH. If unstained, paraffin- embedded
 bone marrow or lymphoma tissue sections are available from prior biopsies, these can be
 used to determine CD19 and CD20 expression by immunohistochemistry; otherwise, patients
 will need to come to the NIH for a biopsy to determine CD19 and CD20 expression. The
 sample for CD19 and CD20 expression must come from a biopsy obtained after any CD19 or
 CD20-targeted therapies such as monoclonal antibodies if such antibodies or CAR T-cell
 therapies have been received by the patient.

 For classical Hodgkin lymphoma only, a biopsy from any time from any institution that shows
 any CD19 or CD20 expression on Reed-Sternberg cells is adequate for eligibility. CD19 or CD20
 expression on the Reed-Sternberg cells that is weak or only present on some Reed-Sternberg
 cells by immunohistochemistry is compatible with protocol eligibility.

 -For all lymphoma types except for classical Hodgkin lymphoma, either CD19 or CD20 expression
 must be uniform . Uniform CD19 or CD20 expression is defined as no obvious lymphoma
 population lacking antigen expression can be present. Antigen expression can be assessed by
 either immunohistochemistry or flow cytometry.

 Design:

 -  This is a phase I dose-escalation trial

 -  Patients will undergo leukapheresis

 -  T-cells obtained by leukapheresis will be genetically modified to express the Hu1928-
 Hu20BB CAR construct.

 -  Patients will receive a lymphocyte-depleting chemotherapy conditioning regimen with the
 intent of enhancing the activity of the infused CAR-expressing T cells.

 -  The chemotherapy conditioning regimen is cyclophosphamide 500 mg/m^2 daily for 3 days
 and fludarabine 30 mg/m^2 daily for 3 days. Fludarabine will be given on the same days
 as the cyclophosphamide.

 -  Two days after the chemotherapy ends, patients will receive an infusion of anti-CAR-
 expressing T cells.

 -  The initial dose level of this dose-escalation trial will be 0.66x10^6 CAR^+ T cells/kg
 of recipient bodyweight.

 -  The cell dose administered will be escalated until a maximum tolerated dose is
 determined.

 -  Following the T-cell infusion, there is a mandatory 9-day inpatient hospitalization to
 monitor for toxicity.

 -  Outpatient follow-up is planned for 2 weeks, and 1, 2, 3, 4, 6, 9, and 12 months after
 the CAR T-cell infusion; less frequent follow-up is required more than 1 year after
 infusion. Long-term gene-therapy follow-up for a total of 15 years after infusion is
 required.
-  INCLUSION CRITERIA:

 MALIGNANCY CRITERIA:

 -  Patients must have any B-cell lymphoma, or CLL/SLL, Gray-zone lymphoma, nodular
 lymphocyte-predominant Hodgkin lymphoma, or classical Hodgkin lymphoma with any CD19
 or CD20 expression on Reed-Sternberg cells. Lower grade lymphomas or CLL transformed
 to DLBCL are potentially eligible as is primary mediastinal B-cell lymphoma and all
 other subtypes of DLBCL. Burkitt and mantle cell lymphoma are potentially eligible.

 -  For classical Hodgkin lymphoma only, a biopsy from any time from any institution that
 shows any CD19 or CD20 expression on Reed-Sternberg cells is adequate for eligibility.
 CD19 or CD20 expression on the Reed-Sternberg cells that is weak or only present on
 some Reed-Sternberg cells by immunohistochemistry is compatible with protocol
 eligibility.

 -  For all lymphoma types except for classical Hodgkin lymphoma, either CD19 or CD20
 expression must be uniform . Uniform CD19 or CD20 expression is defined as no obvious
 lymphoma population lacking antigen expression is present. Antigen expression can be
 assessed by either immunohistochemistry or flow cytometry.

 -  Only when insufficient biopsy material is available to allow CD19 and CD20 expression
 assessment at the NIH, CD19 and/or CD20 staining performed at another institution can
 be used

 -  DLBCL patients must have received at least two prior chemotherapy-containing regimens
 at least one of which must have contained doxorubicin and a monoclonal antibody.
 Follicular lymphoma patients must have received at least 2 prior regimens including at
 least 1 regimen with chemotherapy. All other B-cell lymphoma and leukemia patients
 must have had at least 1 prior chemotherapy-containing regimen. All patients with CLL
 or small lymphocytic lymphoma must have had prior treatment with ibrutinib or another
 signal transduction inhibitor.and venetoclax.

 -  Hodgkin lymphoma patients must have:

 -  had at least 3 prior lines of therapy.

 -  documented progression of lymphoma while on checkpoint inhibitor therapy or
 failure to respond to checkpoint inhibitor therapy, or intolerance to checkpoint
 inhibitor therapy.

 -  had at least 1 prior cytotoxic chemotherapy-containing regimen.

 -  had prior exposure to brentuximab vedotin.

 -  had undergone autologous stem cell transplant or been transplant ineligible or
 refused autologous transplantation

 -  Eligibility will be expanded to include CD19 and CD20-negative classical Hodgkin
 lymphoma if any 2 patients with classical Hodgkin lymphoma and CD19/CD20 expression on
 RS cells have durations of response 6 months or greater (responses could be PRs or
 CRs) or a CR of 3 months or greater.

 -  All patients must have measurable malignancy as defined by at least one of the
 criteria below.

 -  Lymphoma or leukemia masses that are measurable (minimum 1.5 cm in largest diameter)
 by CT scan is required for all diagnoses except CLL. All masses must be less than or
 equal to 10.0 cm in the largest diameter.

 -  For a lymphoma mass to count as measurable malignancy, it must have abnormally
 increased metabolic activity when assessed by positron emission tomography (PET) scan.
 CLL masses do not need to have increased activity on PET scan.

 -  For CLL and lymphoma with only bone marrow involvement no mass is necessary, but if a
 mass is not present, bone marrow malignancy must be detectable by flow cytometry in
 lymphoma and CLL. Note that leukemia cells must make up 1% or less of peripheral blood
 lymphocytes in CLL patients for these patients to be eligible.

 OTHER INCLUSION CRITERIA:

 -  Greater than or equal to 18 years of age.

 -  Able to understand and sign the Informed Consent Document.

 -  Clinical performance status of ECOG 0-1

 -  Room air oxygen saturation of 92% or greater

 -  Patients of both sexes must be willing to practice birth control from the time of
 enrollment on this study and for four months after receiving the protocol treatment.

 -  A patient with a negative blood PCR test for hepatitis B DNA test can be enrolled. If
 hepatitis B DNA (PCR) testing is not available, patients with a negative hepatitis B
 surface antigen and negative hepatitis B core antibody can be enrolled.

 -  Patients must be tested for the presence of Hepatitis C antigen by PCR and be HCV RNA
 negative in order to be eligible. Only if Hepatitis C PCR testing is not available in
 a timely manner, patients who are Hepatitis C antibody-negative can be enrolled.

 -  Absolute neutrophil count greater than or equal to 1000/mm^3 without the support of
 filgrastim or other growth factors.

 -  Platelet count greater than or equal to 50,000/mm^3 without transfusion support

 -  Hemoglobin greater than 8.0 g/dl.

 -  For CLL only, less than or equal to 1% malignant cells in the peripheral blood
 lymphocytes must be documented by flow cytometry of blood within 2 weeks of protocol
 enrollment.

 -  Serum ALT and AST less or equal to 3 times the upper limit of the institutional normal
 unless liver involvement by malignancy is demonstrated.

 -  Serum creatinine less than or equal to 1.5 mg/dl.

 -  Total bilirubin less than or equal to 2.0 mg/dl.

 -  Normal cardiac ejection fraction (greater than or equal to 50% by echocardiography)
 and no evidence of hemodynamically significant pericardial effusion as determined by
 an echocardiogram within 4 weeks of treatment start.

 -  Patients must not take corticosteroids including prednisone, dexamethasone or any
 other corticosteroid for 14 days before apheresis and CAR T-cell infusion. Patients
 must also not take corticosteroids at doses higher than 5 mg/day of prednisone or
 equivalent at any time after the CAR T cell infusion.

 -  Patients must be able to understand and be willing to sign a written informed consent.

 -  Patients who have either been previously treated on protocols of genetically-modified
 T cells on a clinical trial at the NCI or received T cells modified with the MSGV or
 MSGV1 gamma-retroviral vectors at any institution are potentially eligible under these
 conditions:

 -  At least 3 months have elapsed since the last genetically-modified T-cell therapy that
 the patient received, and there is no evidence of replication-competent retroviruses
 (evidence must be provided from prior protocol Principal Investigator), and persisting
 genetically-modified T cells are either not detectable in the patient s blood or
 detectable at levels less than or equal to 0.2% of blood T cells as measured by flow
 cytometry using the Kip-1 antibody in the flow cytometry lab of the NCI Laboratory of
 Pathology (Maryalice Stetler-Stevenson s lab).

 EXCLUSION CRITERIA:

 -  Patients that require urgent therapy due to tumor mass effects or spinal cord
 compression.

 -  Patients must not have received any anti-CD20 or anti-CD19 antibody products in the
 past 30 days prior to CAR T-cell infusion.

 -  Prior administration of anti-PD-1 or anti-PD-L1 antibodies or other agents that in the
 opinion of the PI can stimulate immune activity and interfere with infusion of CAR-T
 cells within 8 weeks of enrollment

 -  Patients that have active hemolytic anemia.

 -  HIV-positive patients are excluded because HIV causes complicated immune deficiency
 and study treatment can pose more risks for these patients.

 -  Patients with second malignancies in addition to their B-cell malignancy are not
 eligible if the second malignancy has required treatment (including maintenance
 therapy) within the past 3 years or is not in complete remission. There are two
 exceptions to this criterion: successfully treated non-metastatic basal cell or
 squamous cell skin carcinoma.

 -  Women of child-bearing potential who are pregnant or breastfeeding because of the
 potentially dangerous effects of the preparative chemotherapy on the fetus or infant.

 Pregnant women are excluded from this study because study therapy can cause fetal harm.
 Because there is potential risk for adverse events in nursing infants secondary to
 treatment of the mother with study therapy, breastfeeding should be discontinued if the
 mother is treated with study drugs.

 -  Active uncontrolled systemic infections (defined as infections causing fevers and
 infections requiring intravenous antibiotics when intravenous antibiotics have been
 administered for less than 72 hours), active coagulation disorders or other major
 uncontrolled medical illnesses of the cardiovascular, respiratory, endocrine, renal,
 gastrointestinal, genitourinary or immune system, history of myocardial infarction,
 history of ventricular tachycardia or ventricular fibrillation, active cardiac
 arrhythmias (active atrial fibrillation is not allowed, resolved atrial fibrillation
 not requiring current treatment is allowed (anticoagulants count as current treatment)
 ), active obstructive or restrictive pulmonary disease, active autoimmune diseases
 such as rheumatoid arthritis.

 -  Hospitalization within the 7 days prior to enrollment.

 -  Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency
 Disease).

 -  Prior allogeneic stem cell transplant

 -  Systemic corticosteroid steroid therapy of any dose greater than 5 mg/day or more of
 prednisone or equivalent is not allowed within 14 days prior to the required
 leukapheresis, or the initiation of the conditioning chemotherapy regimen.
 Corticosteroid creams, ointments, and eye drops are allowed.

 -  History of severe immediate hypersensitivity reaction to any of the agents used in
 this study.

 -  Patients on systemic anticoagulant therapy except aspirin.

 -  Active central nervous system metastases or cerebrospinal fluid malignancy. Patients
 with known brain metastases will be excluded from this clinical trial because of their
 poor prognosis and because they often develop progressive neurologic dysfunction that
 would confound the evaluation of neurologic and other adverse events.