Administration of Anti-CD19-Chimeric-Antigen-Receptor-Transduced T-cells From the Original Transplant Donor to Patients With Recurrent or Persistent B-Cell Malignancies After Allogeneic Stem ... View Homepage


Ontology type: schema:MedicalStudy     


Clinical Trial Info

YEARS

2010-2024

ABSTRACT

Background: - Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a procedure that transplants bone marrow cells (stem cells) from a matching donor into a recipient in order to allow the donor stem cells to produce cells that will attack the recipient s cancer cells. AlloHSCT is performed when chemotherapy, immunotherapy, or radiation therapy do not adequately control cancer growth. However, cancers that are not controlled by alloHSCT frequently become resistant to other standard treatment options. - The outcomes of alloHSCT might be improved if certain kinds of white blood cells (T cells) could be manipulated so that they generate a more potent effect against the cancer cells. This effect can be augmented by genetically engineering donor T cells to specifically recognize cancerous cells in order to attack them. For this purpose, researchers are studying a specific kind of genetically engineered T cell known as the anti-CD19-CAR-transduced T cell. More research is needed to determine if this T cell will be an effective treatment for certain kinds of B cell cancer (such as non-Hodgkin s lymphoma and chronic lymphocytic leukemia) that has not been controlled with alloHSCT. Objectives: - To assess the safety and effectiveness of administering allogeneic anti-CD19-CAR-transduced T cells to patients with B-cell cancer that has not responded to alloHSCT. Eligibility: - Individuals between 18 and 75 years of age who have received allogeneic hematopoietic stem cell transplantation for a B cell cancer, but whose cancer has either not responded to or recurred after the transplant. - Recipients must have the same stem cell donor from their previous procedure. Design: - Before the start of the study, all participants will be screened with a medical history and blood tests. Recipients will have tumor imaging scans, additional blood tests, and other tests as directed by the study doctors. - Donor participants will undergo apheresis to provide white blood cells for researchers to use in the treatment. - Recipients will have dose escalation to determine the most effective yet safe dose of anti-CD19 T cells. There will be four dose levels of anti-CD19 T cells. The first patients enrolled will have the smallest dose, and the dose will be increased when a level has been determined to be safe. To reduce the risk of side effects, participants who received a stem cell transplant from an unrelated donor will receive a lower dose of anti-CD19 T cells than those who received a transplant from a related donor. - Recipients will be hospitalized for 3 days after receiving the cell infusion, and will need to come to clinic for follow-up visits 1, 2, 3, 4, 8, and 12 weeks after the infusion. - Additional scans and frequent blood tests will be required for the first 3 months after the infusion, followed by less frequent visits over time. - Recipients will be followed for a maximum of 15 years after receiving the infusion. Detailed Description BACKGROUND: Many patients with advanced B-cell malignancies that cannot be cured by chemotherapy and monoclonal antibodies have prolonged relapse-free survival after allogeneic hematopoietic stem cell transplantation (alloHSCT); however, a substantial fraction of patients with B-cell malignancies relapse following alloHSCT. The first therapeutic maneuver attempted when patients without graft-versus-host disease (GVHD) relapse after alloHSCT is usually withdraw of immunosuppressive drugs. If a remission does not occur after withdraw of immunosuppression, patients are often treated with donor lymphocyte infusions (DLI). Withdraw of immunosuppression and DLI can lead to complete remissions in patients with B-cell malignancies that relapse after alloHSCT. Unfortunately, a substantial fraction of patients do not enter a complete remission after withdraw of immunosuppression followed by DLI, and these therapies are often complicated by GVHD. The outcomes of alloHSCT might be improved if T cells could be manipulated so that they generate a more potent graft-versus-malignancy (GVM) effect than unmanipulated T cells. We hypothesize that the GVM effect against B-cell malignancies can be augmented by genetically engineering donor T cells to express receptors that specifically recognize antigens expressed by malignant B cells. Chimeric antigen receptors (CARs) consist of an antigen recognition moiety combined with T-cell signaling domains. CARs are capable of activating T cells in an antigen-specific manner. Expression of the CD19 antigen is limited to B cells and perhaps follicular dendritic cells. Most malignant B cells express CD19. We have constructed a retroviral vector encoding an anti-CD19 CAR. Large numbers of T cells that have been transduced with this retroviral vector can be generated in vitro for clinical adoptive T cell therapy. These anti-CD19-CAR-transduced T cells specifically recognize a variety of CD19+ target cells and kill primary chronic lymphocytic leukemia (CLL) cells in vitro. Anti-CD19-CAR-expressing T cells have not been previously used to treat patients after alloHSCT. PRIMARY OBJECTIVE: To assess the safety of administering allogeneic anti-CD19-CAR-transduced T cells to patients with B-cell malignancies that are persistent or relapsed after alloHSCT. The allogeneic anti-CD19-CAR-transduced T cells will be derived from the original allogeneic transplant donor. Secondary Objectives: To determine if administering anti-CD19-CAR-transduced T cells can cause regression of B-cell malignancies that are relapsed or persistent after alloHSCT. To measure persistence of adoptively-transferred anti-CD19-CAR-transduced T cells in the blood of patients. To assess the impact of a pentostatin plus cyclophosphamide conditioning regimen plus allogeneic anti-CD19 CAR T cells in patients who have residual malignancy after receiving allogeneic anti-CD19 CAR T cells alone. ELIGIBILITY: Patients with any CD19-expressing malignancy that is persistent or recurrent following successful T-cell engraftment after HLA-identical sibling, 1-antigen mismatched related, or greater than or equal to 7/8-matched unrelated donor (URD) alloHSCT and sequential treatment with withdraw of immunosuppression and DLI. Patients with acute lymphoblastic leukemia (ALL). ALL -like high grade lymphomas, Burkitt lymphoma or diffuse large B-cell lyphoma will be eligibile after alloHSCT and withdraw of immunosuppression whether or not they have received a DLI. The same donor that provided cells for the alloHSCT must be willing and able to undergo leukapheresis so that cells can be obtained to prepare the anti-CD19-CAR-transduced T cells. The recipient must have at most grade I acute GVHD (see Appendix 1) or at most mild global score chronic GVHD (see Appendix 9). The recipient must not have received systemic immunosuppressive drugs for at least 28 days at the time of study enrollment. DESIGN: - The alloHSCT donor will undergo leukapheresis. - Patients will undergo apheresis to obtain peripheral blood mononuclear cells. These cells will be processed to produce anti-CD19 CAR stem memory T cells (anti-CD19 CAR Tscm). This process involves sorting the cells and then culturing the cells in vitro for 9 days. During the 9-day culture period, the cells will be transduced with gammaretroviruses encoding the FMC63-28Z. - CAR recipients will be monitored for development of acute treatment-related toxicities for at least 9 days after cell infusion as inpatients. Dose-limiting toxicities (DLTs) will include severe acute GVHD and Grade 4 toxicities not associated with GVHD. - A maximum of 126 evaluable patients (donors plus recipients) will be treated. - Assessment of safety is a primary objective of this clinical trial. Safety will be defined as a lack of severe acute post-infusional toxicities and an incidence of GVHD that is not higher than historical rates of GVHD occurring after standard DCI. - Anti-CD19-CAR-transduced T-cell persistence in the peripheral blood will be measured at multiple time points from 1 week to 1 year after anti-CD19-CARtransduced T cell infusion by flow cytometry. - To assess for an anti-malignancy effect of the infused cells, patients will be staged using standard staging systems. More... »

URL

https://clinicaltrials.gov/show/NCT01087294

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1 sg:clinicaltrial.NCT01087294 schema:about anzsrc-for:3048
2 anzsrc-for:3103
3 anzsrc-for:3142
4 schema:description Background: - Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a procedure that transplants bone marrow cells (stem cells) from a matching donor into a recipient in order to allow the donor stem cells to produce cells that will attack the recipient s cancer cells. AlloHSCT is performed when chemotherapy, immunotherapy, or radiation therapy do not adequately control cancer growth. However, cancers that are not controlled by alloHSCT frequently become resistant to other standard treatment options. - The outcomes of alloHSCT might be improved if certain kinds of white blood cells (T cells) could be manipulated so that they generate a more potent effect against the cancer cells. This effect can be augmented by genetically engineering donor T cells to specifically recognize cancerous cells in order to attack them. For this purpose, researchers are studying a specific kind of genetically engineered T cell known as the anti-CD19-CAR-transduced T cell. More research is needed to determine if this T cell will be an effective treatment for certain kinds of B cell cancer (such as non-Hodgkin s lymphoma and chronic lymphocytic leukemia) that has not been controlled with alloHSCT. Objectives: - To assess the safety and effectiveness of administering allogeneic anti-CD19-CAR-transduced T cells to patients with B-cell cancer that has not responded to alloHSCT. Eligibility: - Individuals between 18 and 75 years of age who have received allogeneic hematopoietic stem cell transplantation for a B cell cancer, but whose cancer has either not responded to or recurred after the transplant. - Recipients must have the same stem cell donor from their previous procedure. Design: - Before the start of the study, all participants will be screened with a medical history and blood tests. Recipients will have tumor imaging scans, additional blood tests, and other tests as directed by the study doctors. - Donor participants will undergo apheresis to provide white blood cells for researchers to use in the treatment. - Recipients will have dose escalation to determine the most effective yet safe dose of anti-CD19 T cells. There will be four dose levels of anti-CD19 T cells. The first patients enrolled will have the smallest dose, and the dose will be increased when a level has been determined to be safe. To reduce the risk of side effects, participants who received a stem cell transplant from an unrelated donor will receive a lower dose of anti-CD19 T cells than those who received a transplant from a related donor. - Recipients will be hospitalized for 3 days after receiving the cell infusion, and will need to come to clinic for follow-up visits 1, 2, 3, 4, 8, and 12 weeks after the infusion. - Additional scans and frequent blood tests will be required for the first 3 months after the infusion, followed by less frequent visits over time. - Recipients will be followed for a maximum of 15 years after receiving the infusion. Detailed Description BACKGROUND: Many patients with advanced B-cell malignancies that cannot be cured by chemotherapy and monoclonal antibodies have prolonged relapse-free survival after allogeneic hematopoietic stem cell transplantation (alloHSCT); however, a substantial fraction of patients with B-cell malignancies relapse following alloHSCT. The first therapeutic maneuver attempted when patients without graft-versus-host disease (GVHD) relapse after alloHSCT is usually withdraw of immunosuppressive drugs. If a remission does not occur after withdraw of immunosuppression, patients are often treated with donor lymphocyte infusions (DLI). Withdraw of immunosuppression and DLI can lead to complete remissions in patients with B-cell malignancies that relapse after alloHSCT. Unfortunately, a substantial fraction of patients do not enter a complete remission after withdraw of immunosuppression followed by DLI, and these therapies are often complicated by GVHD. The outcomes of alloHSCT might be improved if T cells could be manipulated so that they generate a more potent graft-versus-malignancy (GVM) effect than unmanipulated T cells. 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PRIMARY OBJECTIVE: To assess the safety of administering allogeneic anti-CD19-CAR-transduced T cells to patients with B-cell malignancies that are persistent or relapsed after alloHSCT. The allogeneic anti-CD19-CAR-transduced T cells will be derived from the original allogeneic transplant donor. Secondary Objectives: To determine if administering anti-CD19-CAR-transduced T cells can cause regression of B-cell malignancies that are relapsed or persistent after alloHSCT. To measure persistence of adoptively-transferred anti-CD19-CAR-transduced T cells in the blood of patients. To assess the impact of a pentostatin plus cyclophosphamide conditioning regimen plus allogeneic anti-CD19 CAR T cells in patients who have residual malignancy after receiving allogeneic anti-CD19 CAR T cells alone. ELIGIBILITY: Patients with any CD19-expressing malignancy that is persistent or recurrent following successful T-cell engraftment after HLA-identical sibling, 1-antigen mismatched related, or greater than or equal to 7/8-matched unrelated donor (URD) alloHSCT and sequential treatment with withdraw of immunosuppression and DLI. Patients with acute lymphoblastic leukemia (ALL). ALL -like high grade lymphomas, Burkitt lymphoma or diffuse large B-cell lyphoma will be eligibile after alloHSCT and withdraw of immunosuppression whether or not they have received a DLI. The same donor that provided cells for the alloHSCT must be willing and able to undergo leukapheresis so that cells can be obtained to prepare the anti-CD19-CAR-transduced T cells. The recipient must have at most grade I acute GVHD (see Appendix 1) or at most mild global score chronic GVHD (see Appendix 9). The recipient must not have received systemic immunosuppressive drugs for at least 28 days at the time of study enrollment. DESIGN: - The alloHSCT donor will undergo leukapheresis. - Patients will undergo apheresis to obtain peripheral blood mononuclear cells. These cells will be processed to produce anti-CD19 CAR stem memory T cells (anti-CD19 CAR Tscm). This process involves sorting the cells and then culturing the cells in vitro for 9 days. During the 9-day culture period, the cells will be transduced with gammaretroviruses encoding the FMC63-28Z. - CAR recipients will be monitored for development of acute treatment-related toxicities for at least 9 days after cell infusion as inpatients. Dose-limiting toxicities (DLTs) will include severe acute GVHD and Grade 4 toxicities not associated with GVHD. - A maximum of 126 evaluable patients (donors plus recipients) will be treated. - Assessment of safety is a primary objective of this clinical trial. Safety will be defined as a lack of severe acute post-infusional toxicities and an incidence of GVHD that is not higher than historical rates of GVHD occurring after standard DCI. - Anti-CD19-CAR-transduced T-cell persistence in the peripheral blood will be measured at multiple time points from 1 week to 1 year after anti-CD19-CARtransduced T cell infusion by flow cytometry. - To assess for an anti-malignancy effect of the infused cells, patients will be staged using standard staging systems.
5 schema:endDate 2024-03-01T00:00:00Z
6 schema:keywords Appendix 1
7 B-Cell Chronic Lymphocytic Leukemia
8 B-cell malignancy
9 Blood Component Removal
10 Burkitt Lymphoma
11 CD19
12 DCI
13 Drug Therapy
14 Gammaretrovirus
15 Graft vs Host Disease
16 Hematologic Test
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24 Tissue Donor
25 Transplant
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27 adoptive T cell therapy
28 age
29 allogeneic hematopoietic stem cell transplantation
30 allogeneic stem cell transplantation
31 allogeneic transplant
32 antigen
33 antigen recognition
34 antigen-specific manner
35 assessment
36 attack
37 blood
38 bone marrow cell
39 cancer cell
40 cancerous cell
41 cell
42 cell cancer
43 cell engraftment
44 certain kind
45 chimeric antigen receptor
46 chronic graft-versus-host disease
47 clinic
48 clinical trial
49 complete remission
50 conditioning regimen
51 control cancer
52 culture period
53 culturing
54 development
55 diffuses
56 doctor
57 donor T cell
58 donor lymphocyte infusion
59 donor stem cell
60 dose
61 dose escalation
62 dose level
63 dose-limiting toxicity
64 effective treatment
65 effectiveness
66 eligibility
67 engineered T cell
68 evaluable patient
69 expression
70 first patient
71 flow cytometry
72 follicular dendritic cell
73 follow-up
74 frequent visit
75 graft-versus-host-disease
76 high grade
77 immunosuppressive drug
78 immunotherapy
79 incidence
80 individual
81 infusion
82 inpatient
83 large number
84 leukapheresis
85 leukocyte
86 low dose
87 lymphoma
88 malignancy
89 malignant B-cells
90 maximum
91 medical history
92 method
93 monoclonal antibody
94 multiple time point
95 patient
96 pentostatin
97 peripheral blood
98 peripheral blood mononuclear cell
99 persistence
100 potent effect
101 primary objective
102 radiation therapy
103 receptor
104 recipient
105 regression
106 relapse-free survival
107 related donor
108 remission
109 retroviral vector
110 risk
111 safe dose
112 safety
113 same donor
114 secondary objective
115 sibling
116 side effect
117 small dose
118 sorting
119 specific kind
120 staging system
121 standard treatment
122 start
123 stem cell
124 stem cell transplant
125 study enrollment
126 substantial fraction
127 target cell
128 therapeutic maneuver
129 therapy
130 toxicity
131 transduced T cell
132 treatment-related toxicity
133 tumor imaging
134 unrelated donor
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