Phase 1 Study of the Administration of T Lymphocytes Expressing the Kappa Chimeric Antigen Receptor (CAR) and CD28 Endodomain 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.
∙ Unless otherwise noted, subjects must meet all of the following criteria to participate in this study:
• Written informed consent and HIPAA authorization for release of personal health information.
• Adults ≥18 years of age.
• 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 central nervous system (CNS) disease will not be excluded as long as it has been stable for 3 months
• Subjects with bone marrow only involvement are eligible
• Subjects relapsed after autologous or allogeneic stem cell transplant are eligible for this study.
• 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.
• 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)
• For indolent lymphomas, subjects must have received at least 2 prior lines of therapy for their lymphoma
• 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
• 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 at the investigator's discretion.
⁃ 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).
⁃ Karnofsky score of \> 60%
⁃ 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.