T Cells Expressing a Fully-Human Anti-CD30 Chimeric Antigen Receptor for Treating CD30-Expressing Lymphomas
T Cells Expressing a Fully-Human Anti-CD30 Chimeric Antigen Receptor for Treating CD30-Expressing Lymphomas
Background:

 -  Improved treatments for a variety of treatment-resistant, CD30-expressing malignancies
 including Hodgkin lymphoma, anaplastic large cell lymphoma, and other CD30- expressing
 lymphomas are needed.

 -  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 a small number of patients with lymphoma. These
 results demonstrate that CAR-expressing T cells can have anti-lymphoma activity in
 humans.

 -  CD30 expression can be easily detected by immunohistochemistry on lymphoma cells, which
 allows selection of CD30-expressing malignancies for treatment.

 -  CD30 is not known to be expressed by normal cells except for a small number of activated
 lymphocytes.

 -  We have constructed a novel fully-human anti-CD30 CAR that can specifically recognize
 CD30-expressing target cells in vitro and eradicate CD30-expressing tumors in mice.

 -  This particular CAR has not been tested before in humans.

 -  Possible toxicities include cytokine-associated toxicities such as fever, hypotension,
 and neurological toxicities. Elimination of a small number of normal activated
 lymphocytes is possible, and unknown toxicities are also possible.

 Objectives:

 Primary

 -Determine the safety and feasibility of administering T-cells expressing a novel fullyhuman
 anti-CD30 CAR to patients with advanced CD30-expresssing lymphomas.

 Eligibility:

 -  Patients must have anaplastic large cell lymphoma, peripheral T-cell lymphoma not
 otherwise specified, diffuse large B-cell lymphoma not otherwise specified, primary
 mediastinal B-cell lymphoma, grey zone lymphoma, enteropathyassociated T-cell lymphoma,
 or extranodal NK/T-cell lymphoma, nasal type

 -  Patients must have malignancy that is both measurable on a CT scan with a largest
 diameter of at least 1.5 cm and possessing increased metabolic activity detectable by
 PET scan. Alternatively patients with lymphoma detected by flow cytometry of bone marrow

 are eligible.

 -  Patients must have a creatinine of 1.6 mg/dL or less and a normal cardiac ejection
 fraction.

 -  An ECOG performance status of 0-2 is required.

 -  No active infections are allowed including evidence of active HIV, hepatitis B, or
 hepatitis C. At the time of protocol enrollment patients must be seronegative for CMV by
 antibody testing or must have a negative blood CMV PCR.

 -  Absolute neutrophil count greater than or equal to 1000/micro L, platelet count greater
 than or equal to 55,000/micro L, 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 above 5 mg/day of prednisone or equivalent corticosteroid dose) and
 initiation of required leukapheresis.

 -  Clear CD30 expression must be detected on 75% or more of malignant cells from either
 bone marrow or lymphoma mass by flow cytometry or immunohistochemistry. The patient s
 malignancy will need to be assessed for CD30 expression by flow cytometry or
 immunohistochemistry performed at the NIH. If unstained, paraffin-embedded bone marrow
 or lymphoma sections are available from prior biopsies, these can be used to determine
 CD30 expression by immunohistochemistry; otherwise, patients will need to come to the
 NIH for a biopsy to determine CD30 expression. The sample for CD30 expression can come
 from a biopsy obtained at any time before enrollment, unless the patient has received a
 prior anti-CD30 monoclonal antibody, in which case the sample must come from a biopsy
 following completion of the most recent anti-CD30 monoclonal antibody treatment.

 -  Eligible patients with diffuse large B-cell lymphoma or primary mediastinal B-cell
 lymphoma must have received 2 prior treatment regimens at least 1 of which included an
 anthracycline and an anti-CD20 monoclonal antibody.

 -  Patients who have never had an allogeneic hematopoietic stem cell transplant as well as
 patients who have had a 9/10 or 10/10 HLA-matched sibling or a 9/10 or 10/10 HLA-
 matched unrelated donor hematopoietic stem cell transplant are potentially eligible.

 -  Women who are pregnant or plan to become pregnant will be excluded.

 Design:

 -  This is a phase I dose-escalation trial.

 -  Patients will undergo leukapheresis.

 -  T cells obtained by leukapheresis will be genetically modified to express an anti-CD30
 CAR.

 -  Patients will receive a lymphocyte-depleting chemotherapy conditioning regimen with the
 intent of enhancing the activity of the infused anti-CD30 CAR-expressing T cells.

 -  The ch...
Background:

 -  Improved treatments for a variety of treatment-resistant, CD30-expressing malignancies
 including Hodgkin lymphoma, anaplastic large cell lymphoma, and other CD30- expressing
 lymphomas are needed.

 -  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 a small number of patients with lymphoma. These
 results demonstrate that CAR-expressing T cells can have anti-lymphoma activity in
 humans.

 -  CD30 expression can be easily detected by immunohistochemistry on lymphoma cells, which
 allows selection of CD30-expressing malignancies for treatment.

 -  CD30 is not known to be expressed by normal cells except for a small number of activated
 lymphocytes.

 -  We have constructed a novel fully-human anti-CD30 CAR that can specifically recognize
 CD30-expressing target cells in vitro and eradicate CD30-expressing tumors in mice.

 -  This particular CAR has not been tested before in humans.

 -  Possible toxicities include cytokine-associated toxicities such as fever, hypotension,
 and neurological toxicities. Elimination of a small number of normal activated
 lymphocytes is possible, and unknown toxicities are also possible.

 Objectives:

 Primary

 -Determine the safety and feasibility of administering T-cells expressing a novel fullyhuman
 anti-CD30 CAR to patients with advanced CD30-expresssing lymphomas.

 Eligibility:

 -  Patients must have anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma,
 peripheral T-cell lymphoma not otherwise specified, diffuse large B-cell lymphoma not
 otherwise specified, primary mediastinal B-cell lymphoma, grey zone lymphoma,
 enteropathy-associated T-cell lymphoma, or extranodal NK/T-cell lymphoma, nasal type

 -  Patients must have malignancy that is both measurable on a CT scan with a largest
 diameter of at least 1.5 cm and possessing increased metabolic activity detectable by
 PET scan. Alternatively patients with lymphoma detected by flow cytometry of bone marrow
 are eligible.

 -  Patients must have a creatinine of 1.6 mg/dL or less and a normal cardiac ejection
 fraction.

 -  An ECOG performance status of 0-2 is required.

 -  No active infections are allowed including evidence of active HIV, hepatitis B, or
 hepatitis C. At the time of protocol enrollment, patients must be seronegative for CMV
 by antibody testing or must have a negative blood CMV PCR.

 -  Absolute neutrophil count greater than or equal to 1000/micro L, platelet count greater
 than or equal to 55,000/micro L, 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 above 5 mg/day of prednisone or equivalent corticosteroid dose) and
 initiation of required leukapheresis.

 -  Clear CD30 expression must be detected on 75% or more of malignant cells from either
 bone marrow or lymphoma mass by flow cytometry or immunohistochemistry. The patient s
 malignancy will need to be assessed for CD30 expression by flow cytometry or
 immunohistochemistry performed at the NIH. If unstained, paraffin-embedded bone marrow
 or lymphoma sections are available from prior biopsies, these can be used to determine
 CD30 expression by immunohistochemistry; otherwise, patients will need to come to the
 NIH for a biopsy to determine CD30 expression. The sample for CD30 expression can come
 from a biopsy obtained at any time before enrollment, unless the patient has received a
 prior anti-CD30 monoclonal antibody, in which case the sample must come from a biopsy
 following completion of the most recent anti-CD30 monoclonal antibody treatment.

 -  Eligible patients with diffuse large B-cell lymphoma or primary mediastinal B-cell
 lymphoma must have received 2 prior treatment regimens at least 1 of which included an
 anthracycline and an anti-CD20 monoclonal antibody.

 -  Patients who have never had an allogeneic hematopoietic stem cell transplant as well as
 patients who have had a 9/10 or 10/10 HLA-matched sibling or a 9/10 or 10/10 HLA-
 matched unrelated donor hematopoietic stem cell transplant are potentially eligible.

 -  Women who are pregnant or plan to become pregnant will be excluded.

 Design:

 -  This is a phase I dose-escalation trial.

 -  Patients will undergo leukapheresis.

 -  T cells obtained by leukapheresis will be genetically modified to express an anti-CD30
 CAR.

 -  Patients will receive a lymphocyte-depleting chemotherapy conditioning regimen with the
 intent of enhancing the activity of the infused anti-CD30 CAR-expressing T cells.

 -  A chemotherapy conditioning regimen of cyclophosphamide and fludarabine will be
 administered prior to all CAR T-Cell infusions. Fludarabine will be given on the same
 days as the cyclophosphamide.

 -  Two days after the chemotherapy ends, patients will receive an infusion of
 anti-CD30-CAR-expressing T cells.

 -  The initial dose level of this dose-escalation trial will be 0.3x10(6) CAR+ T cells/kg
 of recipient bodyweight for Cohort 1. The initial dose level will be 1 x 10 (6) CAR+T
 cells/kg for Cohort 2.

 -  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. Long-term gene-therapy follow-up consisting of yearly visits to
 a doctor near the patient s home for 4 more years and then yearly telephone contact for
 10 additional years will be required.

 -  As of Amendment E (Protocol version: 08/03/2018), repeat treatments consisting of the
 conditioning chemotherapy followed by a CAR T-cell infusion at the MTD for the patient s
 cohort are allowed for eligible patients with any best responses except continuing
 complete remission or progressive malignancy.

 -  Re-enrollment will be allowed for a small number of subjects.
-  INCLUSION CRITERIA:

 Malignancy Criteria:

 -  Patients must have anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma,
 peripheral T-cell lymphoma not otherwise specified, diffuse large B-cell lymphoma not
 otherwise specified, primary mediastinal B-cell lymphoma, grey zone lymphoma,
 enteropathy-associated T-cell lymphoma, or extranodal NK/T-cell lymphoma, nasal type

 -  Clear CD30 expression must be detected on 75% or more of malignant cells from either
 bone marrow or lymphoma mass by flow cytometry or immunohistochemistry. The patient s
 malignancy will need to be assessed for CD30 expression by flow cytometry or
 immunohistochemistry performed at the NIH. If unstained, paraffin-embedded bone marrow
 or lymphoma sections are available from prior biopsies, these can be used to determine
 CD30 expression by immunohistochemistry; otherwise, patients will need to come to the
 NIH for a biopsy to determine CD30 expression. The sample for CD30 expression can come
 from a biopsy obtained at any time before enrollment, unless the patient has received
 a prior anti-CD30 monoclonal antibody, in which case the sample must come from a
 biopsy following completion of the most recent anti-CD30 monoclonal antibody
 treatment.

 -  Eligible patients with diffuse large B-cell lymphoma or primary mediastinal B-cell
 lymphoma must have received 2 prior treatment regimens at least 1 of which included an
 anthracycline and an anti-CD20 monoclonal antibody.

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

 -  Lymphoma mass that is measurable (minimum 1.5 cm in largest diameter) by CT scan is
 required unless bone marrow lymphoma is detectable.

 -  For a lymphoma mass to count as measurable malignancy, it must have abnormally
 increased metabolic activity when assessed by positron emission tomography (PET) scan.

 -  For 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.

 Other Inclusion Criteria:

 -  Greater than or equal to 18 years of age and less than or equal to age 73.

 -  Able to understand and sign the Informed Consent Document.

 -  Clinical performance status of ECOG 0-2

 -  Room air oxygen saturation of 92% or greater

 -  Male patients and must be willing to practice birth control from the time of
 enrollment on this study and for four months following the final CAR T-cell infusion.
 Pre-menopausal patients (female patients who have had a menstrual period within the
 last year) must be willing to practice birth control from the time of enrollment and
 for one year following the final CAR T cell infusion.

 -  Seronegative for 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 are less responsive to the experimental
 treatment and more susceptible to its toxicities.)

 -  Seronegative for HTLV-1.

 -  Negative for hepatitis B surface antigen. Positive hepatitis B tests can be further
 evaluated by confirmatory tests; and if confirmatory tests are negative, the patient
 can be enrolled.

 -  Seronegative for hepatitis C antibody unless antigen negative. If hepatitis C antibody
 test is positive, then patients must be tested for the presence of RNA by RT-PCR and
 be HCV RNA negative to be enrolled.

 -  A patient with a prior history of hepatits B or a prior history of hepatitis C may
 participate, as long as the patient s viral hepatitis has been treated, and the
 patient has no detectable HBV DNA or HCV RNA.

 -  At time of protocol enrollment, the patient should be negative for CMV by antibody
 testing or by PCR. In case of disagreement between these 2 CMV tests, the tests will
 be repeated and Dept. of Laboratory Medicine consulted.

 -  Absolute neutrophil count greater than or equal to 1000/mm3 without the support of
 filgrastim or other growth factors.

 -  Platelet count greater than or equal to 55,000/mm3

 -  Hemoglobin greater than 8.0 g/dl. Transfusion support is allowed.

 -  Less than 5% malignant cells in the peripheral blood leukocytes

 -  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 1.6 mg/dL.

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

 -  At least 14 days must have elapsed since any prior systemic therapy prior to apheresis
 and prior to the initiation of chemotherapy (including systemic corticosteroids at
 doses greater than prednisone 5 mg/day or the equivalent corticosteroid doses).
 Because this protocol requires collection of autologous blood cells by leukapheresis
 in order to prepare CAR T cells, systemic anti-malignancy therapy including systemic
 corticosteroid therapy at doses greater than prednisone 5 mg/day or the equivalent
 corticosteroid doses is not allowed within 14 days prior to the required
 leukapheresis. NOTE: Because of the long half-life and potential to affect CAR
 T-cells, 30 days must elapse from the time of 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 infusion of CAR T-cells.

 -  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 the start of the treatment protocol.

 -  Patients must not take corticosteroids at doses higher than 5 mg/day of prednisone or
 the equivalent for 14 days before apheresis, and for 14 days prior to the conditioning
 chemotherapy regimen.

 -  Patients must be willing to undergo endotracheal intubation, mechanical ventilation,
 dialysis, CPR, and electrical defibrillation. Patients must be willing to receive
 vasopressor drugs and all other standard intensive care unit interventions. Any living
 will must be amended to allow these interventions or the patient will not eligible.

 -  Patients who have been treated on other protocols of genetically-modified T-cells at
 the NIH only are potentially eligible under these conditions:

 -  At least 6 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 NIH gene-therapy protocol
 Principal Investigator) and persisting genetically-modified T cells are not
 detectable in the patient s blood (evidence must be provided by prior NIH
 gene-therapy protocol Principal Investigator).

 Additional Inclusion Criteria Pertinent Only for Patients with Prior Allogeneic
 Transplantation:

 -  Recipients must have received an 9/10 or 10/10 HLA-matched sibling allogeneic
 hematopoietic stem cell transplant, or a 9/10 or 10/10 HLA-matched unrelated donor
 (URD) allo-HSCT for an eligible CD30+ lymphoma.

 -  Donor T cell engraftment after allo-HSCT (>90% donor chimerism of the T-cell
 compartment).

 -  Patients must be at least 90 days post-transplant.

 -  Patients must be off all systemic immunosuppressive drugs including corticosteroids at
 doses of greater than 5 mg/day prednisone or equivalent, if given for treatment of
 graft versus host disease, for at least 28 days prior to protocol enrollment and must
 remain off immunosuppressive drugs while enrolled on the protocol. Patients must not
 be taking any systemic steroids at doses greater than 5 mg/day prednisone or
 equivalent at all for 14 days prior to apheresis and initiation of chemotherapy.
 Topical corticosteroid preparations applied to the skin such as solutions, creams, and
 ointments are allowed. Inhaled corticosteroids are allowed, and corticosteroid eye
 drops are allowed.

 -  Prior DLIs are not necessary.

 -  Either no evidence of GVHD or minimal clinical evidence of acute GVHD and chronic GVHD
 while off of systemic immunosuppressive therapy for at least 28 days. Minimal clinical
 evidence of acute GVHD defined as grade 0 to I acute GVHD 109 Minimal evidence of
 chronic GVHD is defined as mild global score chronic GVHD (as defined by the 2005 NIH
 consensus project) or no chronic GVHD .107 Subjects with disease that is controlled to
 stage I acute GVHD or to mild global score chronic GVHD with local topical cutaneous
 steroids will be eligible for enrollment.

 EXCLUSION CRITERIA:

 -  Patients with Hodgkin lymphoma are no longer eligible for participation (as of
 amendment G, Protocol version: 08/12/2019).

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

 -  Patients with lymphoma masses 10.0 cm or larger in longest diameter will not be
 eligible.

 -  Patients that have active hemolytic anemia.

 -  Patients who are currently taking any medications for systemic anticoagulation other
 than aspirin will not be eligible.

 -  Patients with second malignancies in addition to their lymphoma are not eligible if
 the second malignancy has required treatment (including maintenance therapy) within
 the past 4 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.
 Women of child-bearing potential are defined as all women except women who are
 postmenopausal or who have had a hysterectomy. Postmenopausal will be defined as women
 over the age of 55 who have not had a menstrual period in at least 1 year.

 -  Active uncontrolled systemic infections (defined as infections causing fevers and
 infections requiring intravenous antibiotics when the 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 idiopathic ventricular tachycardia or ventricular fibrillation in the past
 12 months or history of ventricular tachycardia or ventricular fibrillation (VT/VF)
 associated with VT/VF risk factors (e.g., QT prolongation and cardiomyopathy); active
 cardiac arrhythmias (Active atrial fibrillation is not allowed, but resolved atrial
 fibrillation is allowed.); active obstructive or restrictive pulmonary disease; or
 active autoimmune diseases such as rheumatoid arthritis.

 -  Patients will not be seen for screening appointments or enrolled on the protocol if
 they have been hospitalized within the 7 days prior to the screening appointment or
 the date of protocol enrollment.

 -  Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency
 Disease) , unless the immunodeficiency has been cured by allogeneic stem cell
 transplant.

 -  Systemic corticosteroid therapy at doses greater than 5 mg/day of prednisone or the
 equivalent dose 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 with current CNS involvement by malignancy (either by imaging or
 cerebrospinal fluid involvement or biopsy-proven).

 -  Patients currently taking anticoagulants.