Study of Kappa Chimeric Antigen Receptor (CAR) T Lymphocytes Co-Expressing the Kappa and CD28 CARs for Relapsed/Refractory Kappa+ Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma.
Study of Kappa Chimeric Antigen Receptor (CAR) T Lymphocytes Co-Expressing the Kappa and CD28 CARs for Relapsed/Refractory Kappa+ Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma.
This study will combine both T cells and antibodies in order to create a more effective
 treatment. The treatment tested in this study uses modified T-cells called Autologous T
 Lymphocyte Chimeric Antigen Receptor (ATLCAR) cells targeted against the kappa light chain
 antibody on cancer cells. For this study, the anti-kappa light chain antibody has been
 changed so instead of floating free in the blood, a part of it is now joined to the T cells.
 Only the part of the antibody that sticks to the lymphoma cells is attached to the T cells.
 When an antibody is joined to a T cell in this way, it is called a chimeric receptor. The
 kappa light chain chimeric (combination) receptor-activated T cells are called ATLCAR.κ.28
 cells. These cells may be able to destroy lymphoma cancer cells. They do not, however, last
 very long in the body so their chances of fighting the cancer are unknown.

 Previous studies have shown that a new gene can be put into T cells to increase their ability
 to recognize and kill cancer cells. A gene is a unit of DNA. Genes make up the chemical
 structure carrying your genetic information that may determine human characteristics (i.e.,
 eye color, height and sex). The new gene that is put in the T cells in this study makes an
 antibody called an anti-kappa light chain. This anti-kappa light chain antibody usually
 floats around in the blood. The antibody can detect and stick to cancer cells called lymphoma
 cells because they have a substance on the outside of the cells called kappa light chains.

 The purpose of this study is to determine whether receiving the ATLCAR.κ.28 cells is safe and
 tolerable and learn more about the side effects and how effective these cells are in fighting
 lymphoma. Initially, the study doctors will test different doses of the ATLCAR.κ.28, to see
 which dose is safer for use in lymphoma patients. Once a safe dose is identified, the study
 team will administer this dose to more patients, to learn about how these cells affect
 lymphoma cancer cells and identify other side effects they might have on the body.

 This is the first time ATLCAR.κ.28 cells are given to patients with lymphoma. The Food and
 Drug Administration (FDA), has not approved giving ATLCAR.κ.28 as treatment for lymphoma.
 This is the first step in determining whether giving ATLCAR.κ.28 to others with lymphoma in
 the future will help them.
This study is a single center, open-label phase 1 clinical trial designed to determine the
 safety of escalating doses of autologous activated T lymphocytes (ATLs) expressing the
 chimeric antigen receptor specific for the kappa-light chain of human immunoglobulins (CAR.κ)
 in subjects with relapsed/refractory kappa-positive (κ+) mantle cell and indolent non-Hodgkin
 lymphomas (NHL). During dose finding, up to 12 subjects will receive a single infusion of ATL
 product expressing the CAR.κ encoding the CD28 co-stimulatory endodomain (CAR.κ.28). The
 starting dose will be 5.0 × 105 cells/kg. Up to 3 dose levels of CAR.κ.28 cells will be
 tested with at least 3 subjects enrolled in each dose cohort before dose escalation is
 considered based on the incidence of dose limiting toxicity (DLT). Prior to receiving the
 cell product, subjects will undergo lymphodepletion with fludarabine and bendamustine or
 cyclophophamide. Dose escalation will be guided by the modified 3+3 design. Any dose level
 may be expanded to 4-9 subjects to obtain more data at that dose or to include subjects for
 which insufficient cells are manufactured to enroll on their assigned higher dose level. If
 due to the expansion the estimated DLT rate at a dose is ≥0.33, the study would not escalate
 to the next highest dose level and the recommended phase 2 dose (RP2D) would be exceeded. If
 needed, an expansion cohort will enroll up to 8 subjects at the RP2D to further assess safety
 and efficacy of CAR.κ.28 cells. Secondary endpoints include evaluation of progression free
 survival (PFS), response rate (RR), duration of response (DoR) and overall survival (OS). The
 persistence of CAR.κ.28 cells in the peripheral blood will be assessed as an exploratory
 objective. The final RP2D including expansion data will be the dose with the DLT rate closest
 to 0.2.

 The adoptive transfer of T cells targeting the kappa light chain (CAR.κ) is a promising
 treatment for patients with relapsed/refractory κ + NHL and has shown encouraging preclinical
 activity [37]. The CD8α stalk incorporated into CD28 signaling domain within the CAR, may
 improve the persistence of the CAR.κ T cells. Therefore, subjects in this study are being
 infused with this newly modified version of CAR.κ.28 so that persistence and efficacy will be
 improved compared to the older version of the CAR.κ molecule.

 We hypothesize that CAR.κ.28 will be well tolerated in subjects with relapsed/refractory
 indolent and aggressive lymphomas positive for the kappa light chain and will show efficacy.
 We also anticipate that CAR.κ.28 will show fast expansion in the peripheral blood in the
 first 2 - 3 weeks, but also longer term persistence than the previous version of CAR.κ.28.

 In this phase 1 single center study, peripheral blood will be collected for production of
 CAR.κ.28 cells prior to conditioning chemotherapy in subjects with relapsed/refractory κ+
 indolent lymphoma including follicular lymphoma grade 1-3b, splenic marginal zone lymphoma,
 extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue, nodal marginal zone
 lymphoma, and mantle cell lymphoma. During the approximately 1-2 months necessary for CAR-T
 cell production, subjects may undergo standard of care treatment ("bridging therapy") per
 physician's discretion. Subjects must sign consent forms before cells are procured and again
 prior to undergoing lymphodepleting chemotherapy and cellular treatment. At 2-14 days
 (preferably 2-4 days) after lymphodepletion with bendamustine and fludarabine, we will infuse
 the CAR.κ.28 cell product. Subjects in this study will receive CAR.κ.28 cell product in one
 of the three planned dose escalation cohorts. Dose levels of CAR.κ.28 cells administered will
 range between 5.0 × 105 cells/kg and 2 × 106 cells/kg. These doses have been evaluated in
 previous phase 1 studies of CAR-T cell lymphocytes [37-39] including a phase 1 trial
 targeting the kappa light chain on malignant B cells in which the construct included the CD28
 co-stimulatory endodomain [37]. An expansion cohort will enroll up to 8 subjects at the RP2D
 to further assess safety and efficacy of CAR.κ.28 cells. In all subjects, we will measure the
 persistence of CAR.κ.28 cells in the peripheral blood at different time points by measuring
 the level of the transgene and by phenotypic analyses.

 OUTLINE

 Cell Procurement Peripheral blood, up to 300 mL (in up to 3 collections) will be obtained
 from subjects for cell procurement. In subjects with inadequate lymphocyte count in the
 peripheral blood, a leukapheresis may be performed to isolate sufficient T cells. The
 parameters for apheresis will be up to 2 blood volumes.

 Lymphodepleting Regimen Subjects will receive a "pre-conditioning" cytoreductive regimen of
 bendamustine 70 mg/m2/day administered IV followed by fludarabine 30 mg/m2/day administered
 IV over 3 consecutive days. These agents will be administered per institutional guidelines.
 Prophylaxis (e.g., hydration, antiemetics, etc.) needed prior to fludarabine and bendamustine
 chemotherapy will be provided per institutional guidelines. At the discretion of the clinical
 investigator, subjects with a known history of intolerance to bendamustine may be considered
 for lymphodepletion with cyclophosphamide 500 mg/m2/day administered IV followed by an IV
 dose of fludarabine 30 mg/m2/day administered over 3 consecutive days. These agents will be
 administered per institutional guidelines.

 Cell Administration The cellular product consisting of CAR.κ.28 cells will be administered by
 a licensed healthcare provider (oncology nurse or physician) via intravenous injection over 5
 - 10 minutes through either a peripheral or a central line. The volume of infusion will
 depend upon the concentration of the cells when frozen and the size of the subject. The
 expected volume will be 1-50cc.

 Post lymphodepletion, subjects who meet eligibility criteria for cellular therapy will
 receive CAR.κ.28 cells within 2 - 14 days, but preferably within 2-4 days, after completing
 the lymphodepleting chemotherapy regimen.

 During dose finding, a single dose of CAR.κ.28 will be given after lymphodepletion. The cell
 dose levels that will be evaluated are outlined below.

 Expansion Cohort, CAR.κ.28 will be given after lymphodepletion. Subjects will receive the
 RP2D.

 Duration of Therapy

 Therapy in LCCC1811-ATL involves a single cell infusion of ATLCAR cells. Treatment with at
 least one infusion will be administered unless:

 -  Subject decides to withdraw from study treatment, or

 -  General or specific changes in the subject's condition render the subject unacceptable
 for further treatment in the judgment of the investigator.

 Duration of Follow-up Subjects will be followed for up to 15 years for RCR evaluation or
 until death, whichever occurs first. In addition to this follow-up, subjects removed from
 study treatment for unacceptable adverse events will be followed until resolution or
 stabilization of the adverse event.

 Subjects who experience unequivocal disease progression and start alternate therapy after
 receiving a cell infusion still be required to complete abbreviated follow up procedures.
SUBJECT ELIGIBILITY

 Note: During the period of cell procurement and CAR.κ.28 T cell production, subjects are
 allowed to receive additional standard of care chemotherapy to stabilize their disease if
 the treating physician feels it is in the subject's best interest. For subjects requiring
 bridging chemotherapy while awaiting manufacture of their CAR.κ.28 T-cells, details
 regarding treatment(s) administered including dose, frequency, number of cycles, etc. will
 be collected.

 Inclusion Criteria for the Study

 Unless otherwise noted, subjects must meet all of the following criteria to participate in
 this study:

 1. Written informed consent and HIPAA authorization for release of personal health
 information.

 2. Adults ≥18 years of age.

 3. Diagnosis of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic
 lymphoma OR histologically confirmed B-cell NHL, including the following types defined
 by WHO 2016:

 Aggressive Lymphomas:

 -  DLBCL not otherwise specified (NOS)

 -  T cell/histiocyte rich large B cell lymphoma; primary cutaneous DLBCL, leg type;
 EBV-positive DLBCL NOS; DLBCL associated with chronic inflammation; Lymphomatoid
 granulomatosis; Large B-cell lymphoma with IRF4 rearrangement; Intravascular
 large B-cell lymphoma; ALK-positive large B-cell lymphoma

 -  Primary mediastinal (thymic) large B-cell lymphoma

 -  High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement; high
 grade B-cell lymphoma, NOS

 -  B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and
 classical Hodgkin lymphoma

 -  Transformation of indolent lymphoma or CLL to DLBCL will also be included

 -  Burkitt lymphoma

 Indolent Lymphomas:

 -  Follicular lymphoma grade 1-3b

 -  Splenic marginal zone lymphoma

 -  Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue

 -  Nodal marginal zone lymphoma

 -  Mantle cell lymphoma

 -  Subjects with CNS disease will not be excluded as long it has been stable for 3
 months

 Subjects with bone marrow only involvement are eligible

 4. Subjects relapsed after autologous or allogeneic stem cell transplant are eligible for
 this study.

 5. Subjects who have received prior CD19-directed CAR therapies for relapsed/refractory
 disease are eligible for this study. However, at least 3 months must have passed since
 the subject received CD19 CAR-T cells.

 6. Patients with aggressive lymphomas must have relapsed or refractory disease after
 having received at least 2 prior lines of systemic therapy, including, at a minimum:

 -  An anti-CD20 monoclonal antibody

 -  An anthracycline containing chemotherapy regimen (if eligible)

 -  An autologous stem cell transplant (if eligible)

 7. For indolent lymphomas, subjects must have received at least 2 prior lines of therapy
 for their lymphoma

 8. Subjects with specifically relapsed/refractory chronic lymphocytic leukemia/small
 lymphocytic lymphoma must have received at least 2 prior therapy regimens which can
 include, but not limited to:

 -  A combination of an anti-CD20 monoclonal antibody and an alkylating agent, OR

 -  A Bruton's Tyrosine Kinase Inhibitor, OR

 -  A BCL-2 inhibitor in combination with an anti-CD20 monoclonal antibody

 9. Subjects with a prior or concurrent malignancy whose natural history or treatment does
 not have the potential to interfere with the safety or efficacy assessment of the
 investigational regimen are eligible for this trial.

 10. Kappa-positive expression on lymphoma or CLL/SLL tissue sample, or kappa restriction
 on flow cytometry (archival or fresh) as confirmed by institutional hematopathology
 standard (result must be confirmed at the time of cell procurement).

 11. Karnofsky score of > 60% (see Appendix C).

 12. Female subjects of childbearing potential must be willing to use 2 methods of birth
 control or be surgically sterile, or abstain from heterosexual activity for the course
 of the study, and for 6 months after the study is concluded. Female subjects of
 childbearing potential are those who have not been surgically sterilized or have not
 been free from menses for > 1 year. The two birth control methods can be composed of:
 two barrier methods or a barrier method plus a hormonal method to prevent pregnancy.
 Female subjects of childbearing potential will also be instructed to tell their male
 partners to use a condom.

 Exclusion Criteria for the Study

 Subjects meeting any of the following exclusion criteria will not be able to participate in
 this study (procurement, lymphodepletion and cell infusion):

 1. A diagnosis of lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia or multiple
 myeloma.

 2. A history of intolerance to bendamustine or fludarabine. Note: subjects with known
 history of intolerance to bendamustine may be considered for lymphodepletion with
 cyclophosphamide and fludarabine at the discretion of the clinical investigator.

 3. Subject is pregnant or lactating.

 4. Tumor in a location where enlargement could cause airway obstruction.

 5. Current use of systemic corticosteroids at doses ≥10 mg prednisone daily or its
 equivalent; those receiving <10 mg daily may be enrolled at discretion of
 investigator.

 6. Active infection with HTLV, HCV (can be pending at the time of cell procurement; only
 those samples confirming lack of active infection will be used to generate transduced
 cells) defined as not being well controlled on therapy as well as no history of HIV.
 Subjects are required to have negative HIV antibody, negative HTLV1 and HTLV2
 antibodies, negative hepatitis B surface antigen, and negative HCV antibody or viral
 load.

 7. Subjects who are positive for hepatitis B surface antigen (can be pending at the time
 of cell procurement; only those samples confirming lack of active infection will be
 used to generate transduced cells) are excluded. Subjects who are hepatitis B surface
 antigen negative but hepatitis B core antibody positive must have their hepatitis B
 viral load checked. These subjects will be excluded if their viral load is positive at
 baseline (when tested during screening for procurement). Subjects who are core
 antibody positive and viral load negative at baseline will be considered eligible.

 Eligibility Criteria to be Met Prior to Procurement

 1. Subject has signed a consent to undergo cell procurement.

 2. Evidence of adequate organ function as defined by:

 -  Hemoglobin ≥ 8.0 g/dL (transfusion independent for 2 weeks prior to enrollment)

 -  Total bilirubin <1.5 × ULN (subjects with Gilbert's syndrome may be enrolled
 despite a total bilirubin level >1.5 mg/dL if their conjugated bilirubin is <1.5
 × ULN)

 -  AST and ALT < 5x ULN

 -  Pulse oximetry of >90% on room air

 -  Creatinine ≤1.5x ULN or Creatinine Clearance (CrCl) >60 mL/min per Cockcroft and
 Gault (see Appendix F).

 3. Imaging results from within 120 days prior to procurement to assess presence of active
 disease.

 4. Confirmed kappa-positive expression on lymphoma or CLL/SLL tissue or bone marrow
 sample (archival or fresh) as confirmed by pathology.

 5. Subject has adequate cardiac function, defined as:

 -  No ECG evidence of acute ischemia

 -  No ECG evidence of active, clinically significant conduction system abnormalities

 -  Prior to study entry, any ECG abnormality at screening not felt to put the
 subject at risk has to be documented by the investigator as not medically
 significant

 -  No uncontrolled angina or severe ventricular arrhythmia

 -  Left ventricular ejection fraction (LVEF) >40% as measured by ECHO, with no
 additional evidence of decompensated heart failure, performed within 30 days
 prior to procurement

 6. In women of child-bearing potential, negative serum pregnancy test within 72 hours
 prior to procurement or documentation that the subject is post-menopausal.
 Post-menopausal status must be confirmed with documentation of absence of menses for >
 1 year.

 Eligibility Criteria to be Met Prior to Lymphodepletion

 1. Written informed consent to enroll in the CAR-T cell therapy trial must be obtained
 prior to lymphodepletion.

 2. The last bridging therapy should be completed at least 3 weeks prior to
 lymphodepletion. Subjects who have received bridging therapy will be reassessed with
 imaging within 5 days prior to lymphodepletion and at least 3 weeks after bridging
 therapy. If a patient did not receive bridging chemotherapy, they will e imaged within
 10 days prior to lymphodepletion.

 3. Adequate organ function per the following criteria are required prior to
 lymphodepletion:

 -  Adequate bone marrow function, as defined by:

 -  ANC >1.0 × 109/L

 -  Platelets >50 × 109/L unless related to lymphoma involvement (independent of
 transfusion within 7 days of lymphodepletion)

 -  Total bilirubin ≤1.5× ULN (subjects with Gilbert's syndrome may be enrolled
 despite a total bilirubin level >1.5 mg/dL if their conjugated bilirubin is <1.5×
 ULN)

 -  AST and ALT ≤ 5× ULN

 -  Pulse oximetry of > 90% on room air

 -  Creatinine <1.5x ULN or Creatinine clearance (CrCl) >60 mL/min per Cockcroft and
 Gault (see Appendix F),

 4. If subjects display any clinical signs or symptoms of cardiac dysfunction after
 receiving bridging chemotherapy, they will undergo repeat ECG and ECHO to reassess
 their cardiac function and status

 5. In female subjects of childbearing potential, a negative serum pregnancy test within
 72 hours prior to l ymphodepletion or documentation that the subject is
 post-menopausal or has been surgically sterilized.

 Post-menopausal status must be confirmed with documentation of absence of menses for >
 1 year.

 6. In subjects with CLL/SLL, a bone marrow biopsy within 28 days prior to
 lymphodepletion.

 7. Subjects must have autologous transduced activated T-cells that meet the Certificate
 of Analysis (CofA) acceptance criteria.

 8. Has not received any investigational agents or received any tumor vaccines within the
 previous six weeks prior to lymphodepletion.

 9. Has not received chemotherapy or immunotherapy within the previous 3 weeks prior to
 lymphodepletion.

 10. Subjects may not be receiving strong inhibitors of CYP1A2 (e.g., fluvoxamine,
 ciprofloxacin) up through

 72 hours after the last dose of bendamustine, as these may increase plasma concentrations
 of bendamustine, and decrease plasma concentrations of its metabolites. See
 http://medicine.iupui.edu/clinpharm/ddis/ for an updated list of strong inhibitors of
 CYP1A2 (additionally, see Appendix I: Prohibited Medications or Those to Use with Caution)
 11 Subject is not taking a prohibited or contraindicated medication listed in Section 5.12
 and Appendix I: Prohibited Medications or Those to Use with Caution prior to
 lymphodepletion. Contraindicated medications should be discontinued at least two weeks
 prior to the scheduled lymphodepletion or by at least 5 half-lives of the contraindicated
 medication, whichever is shorter. 12 No evidence of uncontrolled infection or sepsis.

 Eligibility Criteria to be Met Prior to Cell Infusion After Lymphodepletion

 1. No evidence of uncontrolled infection or sepsis.

 2. Evidence of adequate organ function as defined by:

 1. Total bilirubin ≤2 × ULN, unless attributed to Gilbert's syndrome

 2. AST < 5 × ULN

 3. ALT < 5 × ULN

 4. Creatinine ≤ 1.5 × ULN or Creatinine clearance (CrCl) >60 mL/min per Cockcroft
 and Gault (see Appendix F)

 3. Subject has no clinical indication of rapidly progressing disease in the opinion of
 the clinical investigator.

 4. Subject is a good candidate for treatment with CAR.κ.28 cell product per the clinical
 investigator's discretion.