Phase I Study of Adoptive Immunotherapy With CD8+ and CD4+ Memory T Cells Transduced to Express an HA-1-Specific T Cell Receptor (TCR) for Children and Adults With Recurrent Acute Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation (HCT)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 24
- 试验地点
- 2
- 主要终点
- Feasibility of manufacturing minor H antigen (HA-1) T cell receptor (TCR) CD8+ and CD4+ T cells
研究概览
简要总结
This phase I trial studies the side effects and best dose of CD4+ and CD8+ HA-1 T cell receptor (TCR) (HA-1 T TCR) T cells in treating patients with acute leukemia that persists, has come back (recurrent) or does not respond to treatment (refractory) following donor stem cell transplant. T cell receptor is a special protein on T cells that helps them recognize proteins on other cells including leukemia. HA-1 is a protein that is present on the surface of some peoples' blood cells, including leukemia. HA-1 T cell immunotherapy enables genes to be added to the donor cells to make them recognize HA-1 markers on leukemia cells.
详细描述
OUTLINE:
This is a dose-escalation study of CD4+ and CD8+ HA-1 TCR T cells.
Patients receive lymphodepleting chemotherapy (e.g., fludarabine and cyclophosphamide or debulking regimens as specified in the protocol) ending 2-14 days prior to HA-1 TCR T cell administration. Patients then receive CD4+ and CD8+ HA-1 TCR T cells intravenously (IV).
After completion of study treatment, patients are followed up closely for 12 weeks and then every 6 months for years 1-5, and every year for years 6-15.
Initial study activity was funded in part by HighPass Bio, Inc. Current study activity is funded in part by PromiCell Therapeutics, Inc.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- — 至 80 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Subject age 0-80 years at the time of enrollment.
- •Subject must express HLA-A*0201
- •Subject must have the HA-1(H) genotype (RS_1801284: A/G, A/A)
- •Subject must have an adult donor for HCT who is adequately HLA matched by institutional standards (includes HLA-matched related or unrelated donors, and HLA-mismatched family donors, including haploidentical donors) and is either:
- •HLA-A*0201 positive and HA-1(H) negative (RS_1801284: G/G) or
- •HLA-A*0201 negative
- •Subjects who are currently undergoing or who previously underwent allogeneic HCT for
- •Acute myeloid leukemia (AML) of any subtype
- •Acute lymphoid leukemia (ALL) of any subtype
- •Mixed phenotype/undifferentiated/any other type of acute leukemia, including blastic plasmacytoid dendritic cell neoplasm
- •Chronic myeloid leukemia with a history of blast crisis and:
- •With relapse or refractory disease (>= 5% marrow blasts, or circulating blasts) at any time after HCT
- •With persistent rising minimal residual disease (defined as detectable disease by morphology, flow cytometry, molecular or cytogenetic testing but < 5% marrow blasts by morphology, no circulating blasts on >= 2 of two consecutive tests), refractory or ineligible for treatment with tyrosine kinase inhibitors at any time after HCT
- •Myelodysplastic syndrome (MDS) of any subtype
- •Chronic myelomonocytic leukemia (CMML)
- •Juvenile myelomonocytic leukemia (JMML)
- •Subjects must be able to understand and be willing to give informed consent; decision-impaired adults may consent with their legally authorized representative; parent or legal representative will be asked to consent for subjects younger than 18 years old
- •Subjects must agree to participate in long-term follow-up for up to 15 years if they are enrolled in the study and receive T cell infusion
- •Subjects who have relapsed or have MRD after HCT may receive other agents for treatment of disease and remain eligible for the protocol
- •A specific performance status score is not required for enrolling on the protocol; a delay in infusion of the HA-1 TCR T cells may be required for subjects with low performance status
- •DONOR SELECTION INCLUSION
- •Donor age >= 18 years
- •Donors must be able to give informed consent
排除标准
- •Medical or psychological conditions that would make the subject unsuitable candidate for cell therapy at the discretion of the principal investigator (PI)
- •Fertile subjects unwilling to use contraception during and for 12 months after treatment
- •Subjects with a life expectancy of < 3 months of enrollment from coexisting disease other than leukemia
- •Subjects who have ongoing grade IV acute GVHD or severe chronic GVHD following most recent transplant. Exception: the principal investigator (PI) may make an exception on a case-by-case basis to include such a subject if there is doubt surrounding the GVHD diagnosis and/or sustained significant improvement in GVHD severity
- •The presence of organ toxicities will not necessarily exclude subjects from enrolling on the protocol at the discretion of the PI; however, a delay in the infusion of HA-1 TCR T cells may be required
- •DONOR SELECTION EXCLUSION
- •Donors who are human immunodeficiency virus (HIV)-1, HIV-2, human T-lymphotropic virus (HTLV)-1, HTLV-2 seropositive or with active hepatitis B or hepatitis C virus infection
- •Unrelated donor residing outside of the United States of America (USA) unless the donor screening, testing and leukapheresis occur at an National Marrow Donor Program (NMDP)-affiliated and qualified donor center and are facilitated by the NMDP
研究组 & 干预措施
Treatment (CD4+ and CD8+ HA-1 TCR T cells)
Patients receive lymphodepleting chemotherapy (e.g., fludarabine and cyclophosphamide or debulking regimens as specified in the protocol) ending 2-14 days prior to HA-1 TCR T cell administration. Patients then receive CD4+ and CD8+ HA-1 TCR T cells IV.
干预措施: CD8+ and CD4+ Donor Memory T-cells-expressing HA1-Specific TCR (Biological)
Treatment (CD4+ and CD8+ HA-1 TCR T cells)
Patients receive lymphodepleting chemotherapy (e.g., fludarabine and cyclophosphamide or debulking regimens as specified in the protocol) ending 2-14 days prior to HA-1 TCR T cell administration. Patients then receive CD4+ and CD8+ HA-1 TCR T cells IV.
干预措施: Bone Marrow Aspiration (Procedure)
Treatment (CD4+ and CD8+ HA-1 TCR T cells)
Patients receive lymphodepleting chemotherapy (e.g., fludarabine and cyclophosphamide or debulking regimens as specified in the protocol) ending 2-14 days prior to HA-1 TCR T cell administration. Patients then receive CD4+ and CD8+ HA-1 TCR T cells IV.
干预措施: Biospecimen Collection (Procedure)
结局指标
主要结局
Feasibility of manufacturing minor H antigen (HA-1) T cell receptor (TCR) CD8+ and CD4+ T cells
时间窗: At time of T cell infusion (at day 0)
Proportion of subjects for whom a HA-1 TCR T cell product can be produced.
Feasibility of administering minor H antigen (HA-1) T cell receptor (TCR) CD8+ and CD4+ T cells
时间窗: At time of T cell infusion (at day 0)
Proportion of subjects for whom a HA-1 TCR T cell product can be administered.
Incidence of dose-limiting toxicities of HA-1 T cell receptor (TCR) T cells
时间窗: Up to 12 weeks after T-cell infusion
Toxicities will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.
Feasibility of manufacturing minor H antigen (HA-1) T cell receptor (TCR) CD8+ and CD4+ T cells
时间窗: At time of T cell infusion (at day 0)
Proportion of subjects for whom a HA-1 TCR T cell product can be produced.
Feasibility of administering minor H antigen (HA-1) T cell receptor (TCR) CD8+ and CD4+ T cells
时间窗: At time of T cell infusion (at day 0)
Proportion of subjects for whom a HA-1 TCR T cell product can be administered.
Incidence of dose-limiting toxicities of HA-1 T cell receptor (TCR) T cells
时间窗: Up to 12 weeks after T-cell infusion
Toxicities will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.
次要结局
- Duration of in vivo persistence of transferred HA-1 T cell receptor (TCR) CD4+ T cells in peripheral blood(Up to 1 year)
- Duration of in vivo persistence of transferred HA-1 T cell receptor (TCR) CD8+ T cells in peripheral blood(Up to 1 year)
- Presence, proportion and persistence of HA-1 T cell receptor (TCR) CD4+ T cells in the bone marrow(Up to 1 year)
- Presence, proportion and persistence of HA-1 T cell receptor (TCR) CD8+ T cells in the bone marrow(Up to 1 year)
- Specific cytolytic activity of HA-1 T cell receptor (TCR) CD8+ and CD4+ T cells against HLA-A*0201+ HA-1+ target cells before adoptive T cell transfer(At the time of T cell infusion (at day 0))
- Specific cytolytic activity of HA-1 T cell receptor (TCR) CD8+ and CD4+ T cells against HLA-A*0201+ HA-1+ target cells after adoptive T cell transfer(Up to 1 year)
- Reduction of leukemia in the bone marrow in subjects who have measurable leukemia in the marrow prior to HA-1 T cell receptor (TCR) T cell infusion(Up to 1 year)
- Reduction of recipient normal hematopoietic cells in the bone marrow in subjects who have measurable recipient normal hematopoietic cells in the marrow prior to HA-1 T cell receptor (TCR) T cell infusion(Up to 1 year)
- Proportion of subjects who develop new or recurrent symptoms or signs of graft-versus-host disease(Up to 1 year)
- Duration of in vivo persistence of transferred HA-1 T cell receptor (TCR) CD4+ T cells in peripheral blood(Up to 1 year)
- Duration of in vivo persistence of transferred HA-1 T cell receptor (TCR) CD8+ T cells in peripheral blood(Up to 1 year)
- Presence, proportion and persistence of HA-1 T cell receptor (TCR) CD4+ T cells in the bone marrow(Up to 1 year)
- Presence, proportion and persistence of HA-1 T cell receptor (TCR) CD8+ T cells in the bone marrow(Up to 1 year)
- Specific cytolytic activity of HA-1 T cell receptor (TCR) CD8+ and CD4+ T cells against HLA-A*0201+ HA-1+ target cells before adoptive T cell transfer(At the time of T cell infusion (at day 0))
- Specific cytolytic activity of HA-1 T cell receptor (TCR) CD8+ and CD4+ T cells against HLA-A*0201+ HA-1+ target cells after adoptive T cell transfer(Up to 1 year)