CD19.CAR-aNKT Cells for Lymphoma and Leukemia
Recruiting in Palo Alto (17 mi)
+1 other location
Age: Any Age
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Baylor College of Medicine
Disqualifiers: Investigational agents, GVHD, HIV, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This study is for patients who have lymphoma or leukemia that has come back or has not gone away after treatment. Because there is no standard treatment for this cancer, patients are being asked to volunteer for a gene transfer research study using special immune cells.
The body has different ways of fighting infection and disease. No single way seems perfect for fighting cancers. This research study combines two different ways of fighting disease, antibodies and immune cells. Antibodies are types of proteins that protect the body from bacteria and other diseases. Immune cells, also called lymphocytes, are special infection-fighting blood cells that can kill other cells including tumor cells. Both antibodies and lymphocytes have been used to treat patients with cancer. They have shown promise, but have not been strong enough to cure most patients.
The antibody used in this study is called anti-CD19. This antibody sticks to lymphoma cells because of a substance on the outside of the cells called CD19. CD19 antibodies have been used to treat people with lymphoma and leukemia. For this study, the anti-CD19 antibody has been changed so that instead of floating free in the blood it is now joined to the NKT cells, a special type of lymphocytes that can kill tumor cells but not very effectively on their own. When an antibody is joined to a T cell in this way it is called a chimeric receptor. Investigators have also found that NKT cells work better if proteins are added that stimulate lymphocytes, such as one called CD28. Adding the CD28 makes the cells last for a longer time in the body but maybe not long enough for them to be able to kill the lymphoma cells. It is believed that by adding an extra stimulating protein, called IL-15, the cells will have an even better chance of killing the lymphoma cells.
In this study the investigators are going to see if this is true by putting the anti-CD19 chimeric receptor with CD28 and the IL-15 into NKT cells grown from a healthy individual. These cells are called ANCHOR cells. These cells will be infused into patients that have lymphomas or leukemias that have CD19 on their surface. The ANCHOR cells are investigational products not approved by the Food and Drug Administration.
The purpose of this study is to find the biggest dose of ANCHOR cells that is safe, to see how long the ANCHOR cells last, to learn what their side effects are and to see whether this therapy might help people with lymphoma or leukemia.
Will I have to stop taking my current medications?
The trial information does not specify if you need to stop taking your current medications. However, you cannot participate if you are currently receiving any investigational agents or have received cellular therapies in the past 6 weeks.
What data supports the effectiveness of the treatment CD19.CAR-aNKT cells for lymphoma and leukemia?
Research shows that CD19-targeted CAR T-cell therapies have been effective in treating B-cell malignancies like chronic lymphocytic leukemia and acute lymphoblastic leukemia, with significant responses observed. Additionally, CAR19-iNKT cells, which are similar to CD19.CAR-aNKT cells, have demonstrated enhanced anti-lymphoma activity, suggesting potential effectiveness for this treatment.
12345Is the CD19.CAR-aNKT cell treatment safe for humans?
The safety of CD19.CAR-aNKT cells, similar to other CD19-CAR therapies, has been evaluated in clinical trials. While some patients experienced a systemic inflammatory reaction (a body-wide immune response) that could be serious, it was almost always reversible with proper medical care. Additionally, NK-92 cells, which are similar to aNKT cells, have shown safety in several early-phase clinical studies.
26789What makes the CD19.CAR-aNKT cell treatment unique for lymphoma and leukemia?
The CD19.CAR-aNKT cell treatment is unique because it combines the targeting of CD19, a protein found on most B-cell malignancies, with the use of invariant natural killer T (iNKT) cells, which can also target CD1d-expressing lymphomas. This dual targeting approach enhances the treatment's effectiveness, especially against certain types of lymphomas, and may improve survival rates compared to traditional CAR T-cell therapies.
245810Eligibility Criteria
This trial is for people aged 3-75 with certain types of B-cell lymphoma or leukemia that have CD19 on their surface and have not responded to treatment. They must be in relatively good health, with proper liver and kidney function, no severe infections, and a reasonable life expectancy. Participants need to agree to use effective birth control during the study.Inclusion Criteria
I am between 3 and 75 years old.
I have been diagnosed with a type of blood cancer that tests positive for CD19.
My ALL has not responded to at least two treatments.
+11 more
Exclusion Criteria
I have had a moderate to severe reaction from a transplant.
I am not currently on experimental drugs or had cell therapy in the last 6 weeks.
I do not have any untreated serious infections.
+4 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
1 visit (in-person)
Lymphodepletion Chemotherapy
Participants receive lymphodepletion chemotherapy with cyclophosphamide and fludarabine before ANCHOR cell infusion
1 week
1 visit (in-person)
ANCHOR Cell Infusion
Participants receive an infusion of ANCHOR cells and are monitored for immediate side effects
1 day
1 visit (in-person)
Initial Monitoring
Participants are monitored for side effects and cell persistence, with follow-up visits 3 times per week for the first 4 weeks
4 weeks
12 visits (in-person)
Extended Follow-up
Participants are monitored for long-term safety and effectiveness, with visits at specified intervals up to 15 years
15 years
Regular visits (in-person)
Participant Groups
The trial tests ANCHOR cells (CD19.CAR-aNKT), which are genetically modified immune cells designed to fight cancer by targeting CD19 on tumor cells. The goal is to determine the highest safe dose, how long these cells last in the body, their side effects, and if they help treat lymphoma or leukemia.
2Treatment groups
Experimental Treatment
Group I: CD19.CAR-aNKT cells (cohort B, ALL).Experimental Treatment1 Intervention
This cohort is for patients with refractory/relapsed B-cell NHL or leukemia (ALL). Three dose levels will be evaluated. Patients will also receive lymphodepletion chemotherapy consisting of cyclophosphamide and fludarabine followed by the CD19.CAR-aNKT cell infusion.
Group II: CD19.CAR-aNKT cells (cohort A, non-ALL)Experimental Treatment1 Intervention
This cohort is for patients without refractory/relapsed B-cell NHL or leukemia (ALL). Three dose levels will be evaluated. Patients will also receive lymphodepletion chemotherapy consisting of cyclophosphamide and fludarabine followed by the CD19.CAR-aNKT cell infusion.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Texas Children's HospitalHouston, TX
Houston Methodist HospitalHouston, TX
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Who Is Running the Clinical Trial?
Baylor College of MedicineLead Sponsor
The Methodist Hospital Research InstituteCollaborator
Center for Cell and Gene Therapy, Baylor College of MedicineCollaborator
References
CAR T-Cell Therapy for Relapsed/Refractory Aggressive Large B-Cell Lymphoma. [2023]Cellular immunotherapy with CD19-directed chimeric antigen receptor (CAR) T-cell therapy has changed the treatment landscape for aggressive B-cell non-Hodgkin lymphoma (B-NHL). Three CAR T-cell therapies are commercially avai.
CD19-CAR trials. [2022]CD19 is a B-lineage-specific transmembrane glycoprotein, the expression of which is maintained on more than 95% B-cell malignancies. This strict lineage restriction makes CD19 an ideal target for immune therapies using chimeric antigen receptors (CARs). Here, we review published phase 1 trials of T cells expressing CARs targeting CD19 and describe briefly the biological questions that they addressed. All patients treated in these trials had relapsed B-cell malignancies, which in many cases were chemorefractory. Nonetheless, major responses have been observed, especially in patients with chronic lymphocytic leukemia and acute lymphoblastic leukemia. Many of these responses were accompanied by a systemic inflammatory reaction syndrome that could be life threatening but was almost always reversible with adequate medical management. Given their remarkable activity, CD19-CAR T cells are likely to be quickly incorporated into the management of B-cell neoplasms; these cells have become the paradigm for similar strategies targeting other cancers.
Anti-CD19 chimeric antigen receptor T-cell therapy in B-cell lymphomas: current status and future directions. [2022]To review recent data and relevant of the role of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy for B-cell non-Hodgkin lymphoma (NHL).
Enhanced Anti-lymphoma Activity of CAR19-iNKT Cells Underpinned by Dual CD19 and CD1d Targeting. [2021]Chimeric antigen receptor anti-CD19 (CAR19)-T cell immunotherapy-induced clinical remissions in CD19+ B cell lymphomas are often short lived. We tested whether CAR19-engineering of the CD1d-restricted invariant natural killer T (iNKT) cells would result in enhanced anti-lymphoma activity. CAR19-iNKT cells co-operatively activated by CD1d- and CAR19-CD19-dependent interactions are more effective than CAR19-T cells against CD1d-expressing lymphomas in vitro and in vivo. The swifter in vivo anti-lymphoma activity of CAR19-iNKT cells and their enhanced ability to eradicate brain lymphomas underpinned an improved tumor-free and overall survival. CD1D transcriptional de-repression by all-trans retinoic acid results in further enhanced cytotoxicity of CAR19-iNKT cells against CD19+ chronic lymphocytic leukemia cells. Thus, iNKT cells are a highly efficient platform for CAR-based immunotherapy of lymphomas and possibly other CD1d-expressing cancers.
T-cells fighting B-cell lymphoproliferative malignancies: the emerging field of CD19 CAR T-cell therapy. [2017]CAR T-cells are autologous T-cells transduced with a chimeric antigen receptor (CAR). The CAR contains an antigen recognition part (originating from an antibody), a T-cell receptor transmembrane and cytoplasmic signalling part, and one or more co-stimulatory domains. While CAR T-cells can be directed against any tumour target, most experience thus far has been obtained with targeting of the B-cell antigen CD19 that is expressed by B-cell acute lymphocytic leukaemia, chronic lymphocytic leukaemia and other B-cell lymphomas. The first clinical results are promising, although there are profound differences in response between patients with different haematological malignancies. Treatment-related side effects have been observed that require specific management. This review will explain the mechanism of action, summarise the experience to date and point out future directions for this hopeful new addition to the therapeutic armamentarium in the treatment of lymphoproliferative B-cell malignancies.
Equipping NK Cells with CARs. [2019]Adding a chimeric antigen receptor (CAR) to natural killer (NK) cells is garnering interest as a therapeutic strategy because this immune cell type doesn't cause graft-versus-host disease, making its widespread, off-the-shelf use feasible. Based on promising preclinical data, a phase I/II trial of one such CAR NK-cell therapy is under way, targeting CD19 in hematologic malignancies.
Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. [2021]T cells can be genetically modified to express an anti-CD19 chimeric antigen receptor (CAR). We assessed the safety and efficacy of administering autologous anti-CD19 CAR T cells to patients with advanced CD19(+) B-cell malignancies.
CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies. [2021]Many B-cell acute and chronic leukaemias tend to be resistant to killing by natural killer (NK) cells. The introduction of chimeric antigen receptors (CAR) into T cells or NK cells could potentially overcome this resistance. Here, we extend our previous observations on the resistance of malignant lymphoblasts to NK-92 cells, a continuously growing NK cell line, showing that anti-CD19-CAR (αCD19-CAR) engineered NK-92 cells can regain significant cytotoxicity against CD19 positive leukaemic cell lines and primary leukaemia cells that are resistant to cytolytic activity of parental NK-92 cells. The 'first generation' CAR was generated from a scFv (CD19) antibody fragment, coupled to a flexible hinge region, the CD3ζ chain and a Myc-tag and cloned into a retrovirus backbone. No difference in cytotoxic activity of NK-92 and transduced αCD19-CAR NK-92 cells towards CD19 negative targets was found. However, αCD19-CAR NK-92 cells specifically and efficiently lysed CD19 expressing B-precursor leukaemia cell lines as well as lymphoblasts from leukaemia patients. Since NK-92 cells can be easily expanded to clinical grade numbers under current Good Manufactoring Practice (cGMP) conditions and its safety has been documented in several phase I clinical studies, treatment with CAR modified NK-92 should be considered a treatment option for patients with lymphoid malignancies.
Targeting CD19-CD22 Aids Younger Patients with ALL. [2021]In a phase I trial of chimeric antigen receptor T cells targeting CD19 and CD22 in younger patients with relapsed or refractory B-cell acute lymphoblastic leukemia, toxicity was manageable, and five of 12 patients had complete responses.
Anti-CD19 CAR T-Cell Therapy for B-Cell Non-Hodgkin Lymphoma. [2021]CAR T-cells are autologous T-cells transduced with a chimeric antigen receptor which targets the modified T-cell against a specified cancer antigen. Anti-CD19 CAR T-cells currently represent transformational therapy for relapsed/refractory aggressive B-cell lymphomas where durable remissions can be induced in patients with previously incurable chemotherapy-refractory disease. Three anti-CD19 CAR T-cells are currently Food and Drug Administration and European Medicines Agency approved or in advanced-stage development: axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel. Although all targeting CD19 on the surface of malignant (and healthy) B-cells, these products differ from one another in multiple ways including construct, manufacturing, dose, design of pivotal clinical trials, and toxicity profile. Efficacy and safety data for anti-CD19 CAR T-cell therapy in aggressive B-cell lymphomas will be reviewed, as well as novel CAR T-cell designs and strategies for overcoming treatment resistance.